ISSN 1866-8836
Клеточная терапия и трансплантация
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Introduction

Autologous bone marrow mononuclear stem cells (BMMC) have been used in clinical practice for more than nine years [13]. It has been proven proved that this therapy is effective in patients with dilated cardiomyopathy [5, 12] and patients with severe heart failure [1, 3, 14]. However, there have been very few studies on the usage of autologous bone marrow mononuclear stem cells in patients with severe angina pectoris when it is impossible to use mechanical revascularization (percutaneous coronary intervention: PCI, or coronary artery bypass grafting: CABG), or it is refractory to conventional medical therapy [8, 11, 16]. This group includes patients with distal coronary atherosclerotic damage, patients who received angioplasty and stenting with only part of involvement of the coronary artery, and patients with a relapse of angina pectoris after CABG. The last group of patients is the largest because it is known that only 38-45% of venous grafts are patent after ten years of operation [10]. The number of patients who have a relapse of angina pectoris after CABG increases in proportion to the number of operations.

Patients with severe heart failure or low left ventricle ejection fraction were excluded from our clinical trial. 

Patients and Methods

The BMMC group consisted of 17 patients who underwent autologous bone marrow mononuclear stem intracoronary infusion between 2008 and 2010. A control group consisted of 10 patients. A comparative breakdown of both groups is presented below (Table 1):  

Table 1. A comparative breakdown of the BMMC and the control groups

Indice

BMMC group
(n=17)

Control group (n=10)

Male

14 (83%)

9 (90%)

Female

3 (17%)

1 (10%)

Median age

60.2±9

62.5±7

Previous myocardial infarction

1.2±0,8

1.4±0,7

Functional class of angina pectoris (CCS)

2.9±0,4

2.3± 0,5

Exercise test (Mets)

4.6

4.6

Nitroglycerin usage (pill/week)

28

7

Arterial hypertension

12 (70%) 

5 (50%)

Diabetes mellitus

2 (12%) 

1(10%)

Smoking

7 (41%)

3 (30%)

Cholesterol (mmol/l)

5.5

4.6

Relapse angina pectoris after CABG 

6 (35%)

4 (40%)

Distal coronary atherosclerotic damage

8 (47%)

----

Incomplete myocardial revascularization (PCI)

3 (18%) 

6 (60%)

LVIDd (mm)

51.6±2

52±4

LVIDs (mm)

35.8± 2

36.5±4

LVEF (%)

57.2±4

60.3±5

One coronary vessel disease

4 (23,5%)

6 (60%)

Two coronary vessel diseases 

9 (53%)  

3 (30%)

Three coronary vessel diseases

4 (23.5%)

1 (10%)

Cell Ther Transplant. 2011;3:e.000097.01. doi:10.3205/ctt-2011-en-000097-table1


It is seen that groups are comparable in sex, age, concomitant disease, and left ventricle injection fraction. There are more patients with two and thee coronary vessel diseases in the BMMC group, which explains the higher rate of angina pectoris. All of patients received optimal medical treatment, which was fixed before and was not changed during the research period. All patients were examined before and after the research period. Single-photon emission computed tomography was performed to estimate myocardial perfusion. Questionnaire SF-36 was used for an estimation of the patient’s quality of life.

Results

During the research period one patient has died in each group, for a mortality rate of 6% in the BMMC group and 10% in the control group. The functional rate of angina pectoris (CCS) has showed an improvement in the BMMC group compared with the control group. The median of Canadian Cardiovascular Society class decreased from class 3 to 2 in the BMMC group (p<0.001) and increased in the control group from class 2 to 3 (p>0.05). However, control group contained more patients who received percutaneous coronary intervention.  We showed that the median of exercise time rose from 4.6 to 7.0 Mets in the treatment group (p>0.05), while there were no changes in the control group (p>0.05). Median nitroglycerine usage fell from 28 to 7 pills of nitroglycerine per week (p<0.05) in the treatment group and did not change in the control group over one year (p>0.05). There were not arrhythmias in either group. 

The table 2 shows versions of answers from the SF-36 questionnaire that patients gave for the question: “Compared to one year ago, how would you rate your health in general now?”:

Table 2. Versions of answers from the SF-36 questionnaire

Answers

Main group
(N=17)

Control group
(N=10)

Much better now

7 (35 %)

1 (10%)

Somewhat better now

 8 (53 %)

-

About the same

 2 (12 %)

5 (50 %)

Somewhat worse now

-

4 (40 %)

Much worse now

-

-

Cell Ther Transplant. 2011;3:e.000097.01. doi:10.3205/ctt-2011-en-000097-table2


It can be seen that 88% of patients from the BMMC group felt better one year after the intracoronary infusion of autologous bone marrow mononuclear stem cells. In  the control group only 1 person (10%) felt better, a half the patients did not notice any changes, and 40% felt worse than a year before.    

Baseline scores of the eight SF-36 scales were approximately the same in both groups before the study. At the end of one year a great increase in quality of life in the BMMC group can be observed (Fig. 1). The best result it is seen in the Physical Functioning (PF) scale, which describes exercise times of the patients, and the Role-Physical (RP) scale, which describes the influence of physical condition on our daily work.

We found a strong correlation between the value of the Bodily Pain (BP) scale and the Canadian Cardiovascular Society class. (Spirman’s coefficient of rank data analysis = 0756, p=0.48).  It is seen that the Bodily Pain scale went up in the BMMC group:

Figure 1. Quality of life in the BMMC group

Nesteruk_Figure1.png

In the control group it is not seen considerably increasing in all scales and the scale  of Bodily Pain has changed in opposite direction, which correlates well with an increase of Canadian Cardiovascular Society class in the control group.

Figure 2. Quality of life in the control group

Nesteruk_Figure2.png

A significant improvement in myocardial perfusion measured by single-photon emission computed tomography was noticed in the BMMC group; the median hypo perfusion zone decreased from 13.5 to 10.1 % (p>0.05).

Discussion

Intracoronary infusion of autologous bone marrow mononuclear stem cells decreases such parameters as the functional class of angina pectoris, and nitroglycerine consumption, and increases exercise time, and myocardial perfusion, while having no influence on arrhythmia.  On the other hand, the functional class of angina pectoris increased, the exercise time decreased in patients who received only medical treatment.
   
In his article D. Kirklin [9] showed that the survival rate in patients with coronary artery disease without left ventricle dysfunction is about 75 % over 5 years, 60%  over 10 years, and 45% over 15 years. That is why the most important indicator for the efficacy of stem cell treatment has become health-related quality of life (HRQL) [6, 7]. HRQL estimates components associated with disease and helps to understand the influence of disease and treatment of patient’s physical and mental health. It has been established that questionnaire SF-36 has good validity and reproducibility [2, 4, 15]. In our research it was shown that the functional parameters of patients have good correlation with SF-36 scales. In my opinion SF-36 can be a good guide for optimal treatment, especially in new areas such as stem cells therapy, where it is difficult to estimate reliable improvements in a patient’s condition.

Conclusions

1. Intracoronary infusion of autologous bone marrow mononuclear stem cells seems to be effective in treatment of patients who are not candidates for mechanical revascularization.

2. Questionnaire SF-36 seems to be the most effective method of estimating quality of life in patients after stem cell treatment.

3. Bodily Pain scale has strong correlation dependence with the functional class of angina pectoris (CCS). 

Acknowledgements

The author wishes to thank Alexander S. Nemkov and Sergey A. Belyi (Cardio surgery Department, Saint Petersburg State Medical University n.a. Academician I.P. Pavlov, Russia) for using BMMC in clinical practice, Victor A. Krel (Cardio surgery Department, Saint Petersburg State Medical University n.a. Academician I.P. Pavlov, Russia) for intracoronary infusion of BMMC, Darya V. Ryzhkova (Science center of radiology and surgery technology, Saint Petersburg, Russia) for single-photon emission computed tomography.

References

1. Akara AR, Durdua S, Aratb M, Kilickap M, Kucuk NO, Arslan O, Kuzu I, Ozyurda U. Five-year follow-up after transepicardial implantation of autologous bone marrow mononuclear cells to ungraftable coronary territories for patients with ischaemic cardiomyopathy. Eur J Cardiothorac Surg. 2009 Oct;36(4):633-43. doi: 10.1016/j.ejcts.2009.04.045.

2. Bouchet C, Guillemin F, Paul-Dauphin A, Briançon S. Selection of quality of life measures for a prevention trial: a psychometric analysis. Control Clin Trials. 2000 Feb;21(1):30-43. doi: 10.1016/S0197-2456(99)00038-0.

3. Diederichsen AC, Moller JE, Thayssen P, Videbaek L, Saekmose SG, Barington T, Kassem M. Changes in left ventricular filling patterns after repeated injection of autologous bone marrow cells in heart failure patients. Scand Cardiovasc J. 2010 Jun;44(3):139-45. doi: 10.3109/14017430903556294.

4. Falcoz PE, Chocron S, Mercier M, Puyraveaub M, Etievent JP. Comparison of the Nottingham Health Profile and the 36-item health survey questionnaires in cardiac surgery. Ann Thorac Surg. 2002 Apr;73(4):1222-8.

5. Fischer-Rasokat U, Assmus B, Seeger FH, Honold J. A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy. Circ Heart Fail. 2009 Sep;2(5):417-23. doi: 10.1161/​CIRCHEARTFAILURE.109.855023.

6. Guyatt G, Feeny D, Patrick D. Issues in quality of life measurement in clinical trials. Control Clin Trials. 1991 Aug;12(4 Suppl):81S-90S.

7. Hawthorne G, Richardson J, Osborne R, McNeil H. The assessment of quality of life (AQoL) instrument construction, initial validation & utility scaling. Working paper (Centre for Health Program Evaluation (Australia)), 76. 2.5-6.9. Melbourne : Centre for Health Program Evaluation. 1997.

8. Hossne NA Jr, Invitti AL, Buffolo E, Azevedo S, Rodrigues de Oliveira JS, Stolf NG, Cruz LE, Sanberg PR. Refractory angina cell therapy (ReACT) involving autologous bone marrow cells in patients without left ventricular dysfunction: a possible role for monocytes. Cell Transplant. 2009;18(12):1299-310. doi: dx.doi.org/10.3727/096368909X484671.

9. Kirklin D, Barratt-Boyes. Cardiac Surgery 3 ed. Elsevier Science. 2003:353.

10. Loop FD, Lytle BW, Cosgrove DM, Stewart RW, Goormastic M, Williams GW, Golding LA, Gill CC, Taylor PC, Sheldon WC. Influence of the internal-mammary-artery graft on 10-year survival and other cardiac events. N Engl J Med. 1986 Jan 2;314(1):1-6.

11. Reyes G, Allen KB, Alvarez P, Alegre A, Aguado B, Olivera M, Caballero P, Rodríguez J, Duarte J. Mid term results after bone marrow laser revascularization for treating refractory angina. BMC Cardiovasc Disord. 2010 Sep 17;10:42. doi: 10.1186/1471-2261-10-42.

12. Seth S, Bhargava B, Narang R, Ray R, Mohanty S, Gulati G, Kumar L, Airan B, Venugopal P; AIIMS Stem Cell Study Group. The ABCD (Autologous Bone Marrow Cells in Dilated Cardiomyopathy) trial a long-term follow-up study. J Am Coll Cardiol. 2010 Apr 13;55(15):1643-4. doi: 10.1016/j.jacc.2009.11.070.

13. Strauer BE, Brehm M, Zeus T, Gattermann N, Hernandez A, Sorg RV, Kögler G, Wernet P. Intrakoronare, humane autologe Stammzelltransplantation zur Myokardregeneration nach Herzinfarkt. Dtsch Med Wochenschr. 2001 Aug 24;126(34-35):932-8. doi: 10.1055/s-2001-16579-2.

14. Strauer B, Yousef M, Schannwell C. The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study. Eur J Heart Fail. 2010 Jul;12(7):721-9.

15. Vanderzee KI, Sanderman R, Heyink J. A comparison of two multidimensional measures of health status: the Nottingham Health Profile and the Rand 36-Item Health Survey 1.0. Qual Life Res. 1996 Feb;5(1):165-74.

16. Wang S, Cui J, Peng W, Lu M. Intracoronary autologous CD34+ stem cell therapy for intractable angina. Cardiology. 2010;117(2):140-7. doi:10.1159/000320217.

" ["~DETAIL_TEXT"]=> string(20124) "

Introduction

Autologous bone marrow mononuclear stem cells (BMMC) have been used in clinical practice for more than nine years [13]. It has been proven proved that this therapy is effective in patients with dilated cardiomyopathy [5, 12] and patients with severe heart failure [1, 3, 14]. However, there have been very few studies on the usage of autologous bone marrow mononuclear stem cells in patients with severe angina pectoris when it is impossible to use mechanical revascularization (percutaneous coronary intervention: PCI, or coronary artery bypass grafting: CABG), or it is refractory to conventional medical therapy [8, 11, 16]. This group includes patients with distal coronary atherosclerotic damage, patients who received angioplasty and stenting with only part of involvement of the coronary artery, and patients with a relapse of angina pectoris after CABG. The last group of patients is the largest because it is known that only 38-45% of venous grafts are patent after ten years of operation [10]. The number of patients who have a relapse of angina pectoris after CABG increases in proportion to the number of operations.

Patients with severe heart failure or low left ventricle ejection fraction were excluded from our clinical trial. 

Patients and Methods

The BMMC group consisted of 17 patients who underwent autologous bone marrow mononuclear stem intracoronary infusion between 2008 and 2010. A control group consisted of 10 patients. A comparative breakdown of both groups is presented below (Table 1):  

Table 1. A comparative breakdown of the BMMC and the control groups

Indice

BMMC group
(n=17)

Control group (n=10)

Male

14 (83%)

9 (90%)

Female

3 (17%)

1 (10%)

Median age

60.2±9

62.5±7

Previous myocardial infarction

1.2±0,8

1.4±0,7

Functional class of angina pectoris (CCS)

2.9±0,4

2.3± 0,5

Exercise test (Mets)

4.6

4.6

Nitroglycerin usage (pill/week)

28

7

Arterial hypertension

12 (70%) 

5 (50%)

Diabetes mellitus

2 (12%) 

1(10%)

Smoking

7 (41%)

3 (30%)

Cholesterol (mmol/l)

5.5

4.6

Relapse angina pectoris after CABG 

6 (35%)

4 (40%)

Distal coronary atherosclerotic damage

8 (47%)

----

Incomplete myocardial revascularization (PCI)

3 (18%) 

6 (60%)

LVIDd (mm)

51.6±2

52±4

LVIDs (mm)

35.8± 2

36.5±4

LVEF (%)

57.2±4

60.3±5

One coronary vessel disease

4 (23,5%)

6 (60%)

Two coronary vessel diseases 

9 (53%)  

3 (30%)

Three coronary vessel diseases

4 (23.5%)

1 (10%)

Cell Ther Transplant. 2011;3:e.000097.01. doi:10.3205/ctt-2011-en-000097-table1


It is seen that groups are comparable in sex, age, concomitant disease, and left ventricle injection fraction. There are more patients with two and thee coronary vessel diseases in the BMMC group, which explains the higher rate of angina pectoris. All of patients received optimal medical treatment, which was fixed before and was not changed during the research period. All patients were examined before and after the research period. Single-photon emission computed tomography was performed to estimate myocardial perfusion. Questionnaire SF-36 was used for an estimation of the patient’s quality of life.

Results

During the research period one patient has died in each group, for a mortality rate of 6% in the BMMC group and 10% in the control group. The functional rate of angina pectoris (CCS) has showed an improvement in the BMMC group compared with the control group. The median of Canadian Cardiovascular Society class decreased from class 3 to 2 in the BMMC group (p<0.001) and increased in the control group from class 2 to 3 (p>0.05). However, control group contained more patients who received percutaneous coronary intervention.  We showed that the median of exercise time rose from 4.6 to 7.0 Mets in the treatment group (p>0.05), while there were no changes in the control group (p>0.05). Median nitroglycerine usage fell from 28 to 7 pills of nitroglycerine per week (p<0.05) in the treatment group and did not change in the control group over one year (p>0.05). There were not arrhythmias in either group. 

The table 2 shows versions of answers from the SF-36 questionnaire that patients gave for the question: “Compared to one year ago, how would you rate your health in general now?”:

Table 2. Versions of answers from the SF-36 questionnaire

Answers

Main group
(N=17)

Control group
(N=10)

Much better now

7 (35 %)

1 (10%)

Somewhat better now

 8 (53 %)

-

About the same

 2 (12 %)

5 (50 %)

Somewhat worse now

-

4 (40 %)

Much worse now

-

-

Cell Ther Transplant. 2011;3:e.000097.01. doi:10.3205/ctt-2011-en-000097-table2


It can be seen that 88% of patients from the BMMC group felt better one year after the intracoronary infusion of autologous bone marrow mononuclear stem cells. In  the control group only 1 person (10%) felt better, a half the patients did not notice any changes, and 40% felt worse than a year before.    

Baseline scores of the eight SF-36 scales were approximately the same in both groups before the study. At the end of one year a great increase in quality of life in the BMMC group can be observed (Fig. 1). The best result it is seen in the Physical Functioning (PF) scale, which describes exercise times of the patients, and the Role-Physical (RP) scale, which describes the influence of physical condition on our daily work.

We found a strong correlation between the value of the Bodily Pain (BP) scale and the Canadian Cardiovascular Society class. (Spirman’s coefficient of rank data analysis = 0756, p=0.48).  It is seen that the Bodily Pain scale went up in the BMMC group:

Figure 1. Quality of life in the BMMC group

Nesteruk_Figure1.png

In the control group it is not seen considerably increasing in all scales and the scale  of Bodily Pain has changed in opposite direction, which correlates well with an increase of Canadian Cardiovascular Society class in the control group.

Figure 2. Quality of life in the control group

Nesteruk_Figure2.png

A significant improvement in myocardial perfusion measured by single-photon emission computed tomography was noticed in the BMMC group; the median hypo perfusion zone decreased from 13.5 to 10.1 % (p>0.05).

Discussion

Intracoronary infusion of autologous bone marrow mononuclear stem cells decreases such parameters as the functional class of angina pectoris, and nitroglycerine consumption, and increases exercise time, and myocardial perfusion, while having no influence on arrhythmia.  On the other hand, the functional class of angina pectoris increased, the exercise time decreased in patients who received only medical treatment.
   
In his article D. Kirklin [9] showed that the survival rate in patients with coronary artery disease without left ventricle dysfunction is about 75 % over 5 years, 60%  over 10 years, and 45% over 15 years. That is why the most important indicator for the efficacy of stem cell treatment has become health-related quality of life (HRQL) [6, 7]. HRQL estimates components associated with disease and helps to understand the influence of disease and treatment of patient’s physical and mental health. It has been established that questionnaire SF-36 has good validity and reproducibility [2, 4, 15]. In our research it was shown that the functional parameters of patients have good correlation with SF-36 scales. In my opinion SF-36 can be a good guide for optimal treatment, especially in new areas such as stem cells therapy, where it is difficult to estimate reliable improvements in a patient’s condition.

Conclusions

1. Intracoronary infusion of autologous bone marrow mononuclear stem cells seems to be effective in treatment of patients who are not candidates for mechanical revascularization.

2. Questionnaire SF-36 seems to be the most effective method of estimating quality of life in patients after stem cell treatment.

3. Bodily Pain scale has strong correlation dependence with the functional class of angina pectoris (CCS). 

Acknowledgements

The author wishes to thank Alexander S. Nemkov and Sergey A. Belyi (Cardio surgery Department, Saint Petersburg State Medical University n.a. Academician I.P. Pavlov, Russia) for using BMMC in clinical practice, Victor A. Krel (Cardio surgery Department, Saint Petersburg State Medical University n.a. Academician I.P. Pavlov, Russia) for intracoronary infusion of BMMC, Darya V. Ryzhkova (Science center of radiology and surgery technology, Saint Petersburg, Russia) for single-photon emission computed tomography.

References

1. Akara AR, Durdua S, Aratb M, Kilickap M, Kucuk NO, Arslan O, Kuzu I, Ozyurda U. Five-year follow-up after transepicardial implantation of autologous bone marrow mononuclear cells to ungraftable coronary territories for patients with ischaemic cardiomyopathy. Eur J Cardiothorac Surg. 2009 Oct;36(4):633-43. doi: 10.1016/j.ejcts.2009.04.045.

2. Bouchet C, Guillemin F, Paul-Dauphin A, Briançon S. Selection of quality of life measures for a prevention trial: a psychometric analysis. Control Clin Trials. 2000 Feb;21(1):30-43. doi: 10.1016/S0197-2456(99)00038-0.

3. Diederichsen AC, Moller JE, Thayssen P, Videbaek L, Saekmose SG, Barington T, Kassem M. Changes in left ventricular filling patterns after repeated injection of autologous bone marrow cells in heart failure patients. Scand Cardiovasc J. 2010 Jun;44(3):139-45. doi: 10.3109/14017430903556294.

4. Falcoz PE, Chocron S, Mercier M, Puyraveaub M, Etievent JP. Comparison of the Nottingham Health Profile and the 36-item health survey questionnaires in cardiac surgery. Ann Thorac Surg. 2002 Apr;73(4):1222-8.

5. Fischer-Rasokat U, Assmus B, Seeger FH, Honold J. A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy. Circ Heart Fail. 2009 Sep;2(5):417-23. doi: 10.1161/​CIRCHEARTFAILURE.109.855023.

6. Guyatt G, Feeny D, Patrick D. Issues in quality of life measurement in clinical trials. Control Clin Trials. 1991 Aug;12(4 Suppl):81S-90S.

7. Hawthorne G, Richardson J, Osborne R, McNeil H. The assessment of quality of life (AQoL) instrument construction, initial validation & utility scaling. Working paper (Centre for Health Program Evaluation (Australia)), 76. 2.5-6.9. Melbourne : Centre for Health Program Evaluation. 1997.

8. Hossne NA Jr, Invitti AL, Buffolo E, Azevedo S, Rodrigues de Oliveira JS, Stolf NG, Cruz LE, Sanberg PR. Refractory angina cell therapy (ReACT) involving autologous bone marrow cells in patients without left ventricular dysfunction: a possible role for monocytes. Cell Transplant. 2009;18(12):1299-310. doi: dx.doi.org/10.3727/096368909X484671.

9. Kirklin D, Barratt-Boyes. Cardiac Surgery 3 ed. Elsevier Science. 2003:353.

10. Loop FD, Lytle BW, Cosgrove DM, Stewart RW, Goormastic M, Williams GW, Golding LA, Gill CC, Taylor PC, Sheldon WC. Influence of the internal-mammary-artery graft on 10-year survival and other cardiac events. N Engl J Med. 1986 Jan 2;314(1):1-6.

11. Reyes G, Allen KB, Alvarez P, Alegre A, Aguado B, Olivera M, Caballero P, Rodríguez J, Duarte J. Mid term results after bone marrow laser revascularization for treating refractory angina. BMC Cardiovasc Disord. 2010 Sep 17;10:42. doi: 10.1186/1471-2261-10-42.

12. Seth S, Bhargava B, Narang R, Ray R, Mohanty S, Gulati G, Kumar L, Airan B, Venugopal P; AIIMS Stem Cell Study Group. The ABCD (Autologous Bone Marrow Cells in Dilated Cardiomyopathy) trial a long-term follow-up study. J Am Coll Cardiol. 2010 Apr 13;55(15):1643-4. doi: 10.1016/j.jacc.2009.11.070.

13. Strauer BE, Brehm M, Zeus T, Gattermann N, Hernandez A, Sorg RV, Kögler G, Wernet P. Intrakoronare, humane autologe Stammzelltransplantation zur Myokardregeneration nach Herzinfarkt. Dtsch Med Wochenschr. 2001 Aug 24;126(34-35):932-8. doi: 10.1055/s-2001-16579-2.

14. Strauer B, Yousef M, Schannwell C. The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study. Eur J Heart Fail. 2010 Jul;12(7):721-9.

15. Vanderzee KI, Sanderman R, Heyink J. A comparison of two multidimensional measures of health status: the Nottingham Health Profile and the Rand 36-Item Health Survey 1.0. Qual Life Res. 1996 Feb;5(1):165-74.

16. Wang S, Cui J, Peng W, Lu M. Intracoronary autologous CD34+ stem cell therapy for intractable angina. Cardiology. 2010;117(2):140-7. doi:10.1159/000320217.

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Нестерук</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(36) "

Юлия А. Нестерук

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В исследование включено 17 пациентов с тяжелой стенокардией, не подлежащих механической реваскуляризации. Этим пациентам в период с 2008 по 2010 гг. выполняли интракоронарную инфузию аутологичных мононуклеарных стволовых клеток костного мозга. Контрольная группа насчитывала 10 пациентов. Всех пациентов обследовали до и после лечения. Перфузию миокарда оценивали с помощью однофотонной эмиссионной компьютерной томографии. Для оценки качества жизни пациентов использовали опросник SF-36. Интракоронарная инфузия аутологичных мононуклеарных стволовых клеток костного мозга способствовала уменьшению функционального класса стенокардии, потребления нитроглицерина, увеличению времени нагрузки, улучшению перфузии миокарда и не оказывала влияния на нарушения ритма. У пациентов, получавших только медикаментозную терапию, возрастал функциональный класс стенокардии и уменьшалась продолжительность физической нагрузки. Спустя год после процедуры в группе интракоронарной инфузии отмечали выраженное улучшение качества жизни. Наибольшее улучшение происходило по индексам физического функционирования, ролевого функционирования и боли. В контрольной группе существенного увеличения данных индексов не наблюдалось, наоборот, для индекса боли отмечена обратная динамика. 

Ключевые слова

стволовые клетки, мононуклеарные клетки, стенокардия, болезнь сердца, аорто-коронарное шунтирование, ангиопластика, лечение стенокардии, продолжительность физической нагрузки, потребление нитроглицерина, опросник SF-36 

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Julia A. Nesteruk

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Cardio surgery department, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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A BMMC group consisted of 17 patients with severe angina pectoris when it is  impossible to use mechanical revascularization. These patients underwent autologous bone marrow mononuclear stem cells intracoronary infusion between 2008 and 2010. A control group consisted of 10 patients. All patients were examined before and after the treatment. Single-photon emission computed tomography was performed to estimate myocardial perfusion. Questionnaire SF-36 was used for an estimation of the patient’s quality of life. Intracoronary infusion of autologous bone marrow mononuclear stem cells has decreased such parameters as the functional class of angina pectoris, and nitroglycerine consumption, and has increased exercise time, and myocardial perfusion, while having no influence on arrhythmia.  On the other hand, the functional class of angina pectoris increased, and the exercise time decreased in patients who received only medical treatment. At the end of one the year a great increase in quality of life in BMMC group can be observed. The best result it is seen in the Physical Functioning scale, and the Role-Physical scale, and the Bodily Pain scale. In the control group it is not seen considerably increasing in all scales and the scale Bodily Pain has changed in opposite direction.

Keywords

stem cells, mononuclear cells, angina pectoris, heart disease, coronary artery bypass surgery, angioplasty, angina treatment, exercise time, nitroglycerine consumption, questionnaire SF-36

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Julia A. Nesteruk

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A BMMC group consisted of 17 patients with severe angina pectoris when it is  impossible to use mechanical revascularization. These patients underwent autologous bone marrow mononuclear stem cells intracoronary infusion between 2008 and 2010. A control group consisted of 10 patients. All patients were examined before and after the treatment. Single-photon emission computed tomography was performed to estimate myocardial perfusion. Questionnaire SF-36 was used for an estimation of the patient’s quality of life. Intracoronary infusion of autologous bone marrow mononuclear stem cells has decreased such parameters as the functional class of angina pectoris, and nitroglycerine consumption, and has increased exercise time, and myocardial perfusion, while having no influence on arrhythmia.  On the other hand, the functional class of angina pectoris increased, and the exercise time decreased in patients who received only medical treatment. At the end of one the year a great increase in quality of life in BMMC group can be observed. The best result it is seen in the Physical Functioning scale, and the Role-Physical scale, and the Bodily Pain scale. In the control group it is not seen considerably increasing in all scales and the scale Bodily Pain has changed in opposite direction.

Keywords

stem cells, mononuclear cells, angina pectoris, heart disease, coronary artery bypass surgery, angioplasty, angina treatment, exercise time, nitroglycerine consumption, questionnaire SF-36

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A BMMC group consisted of 17 patients with severe angina pectoris when it is  impossible to use mechanical revascularization. These patients underwent autologous bone marrow mononuclear stem cells intracoronary infusion between 2008 and 2010. A control group consisted of 10 patients. All patients were examined before and after the treatment. Single-photon emission computed tomography was performed to estimate myocardial perfusion. Questionnaire SF-36 was used for an estimation of the patient’s quality of life. Intracoronary infusion of autologous bone marrow mononuclear stem cells has decreased such parameters as the functional class of angina pectoris, and nitroglycerine consumption, and has increased exercise time, and myocardial perfusion, while having no influence on arrhythmia.  On the other hand, the functional class of angina pectoris increased, and the exercise time decreased in patients who received only medical treatment. At the end of one the year a great increase in quality of life in BMMC group can be observed. The best result it is seen in the Physical Functioning scale, and the Role-Physical scale, and the Bodily Pain scale. In the control group it is not seen considerably increasing in all scales and the scale Bodily Pain has changed in opposite direction.

Keywords

stem cells, mononuclear cells, angina pectoris, heart disease, coronary artery bypass surgery, angioplasty, angina treatment, exercise time, nitroglycerine consumption, questionnaire SF-36

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Cardio surgery department, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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Cardio surgery department, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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Юлия А. Нестерук

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Юлия А. Нестерук

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Этим пациентам в период с 2008 по 2010 гг. выполняли интракоронарную инфузию аутологичных мононуклеарных стволовых клеток костного мозга. Контрольная группа насчитывала 10 пациентов. Всех пациентов обследовали до и после лечения. Перфузию миокарда оценивали с помощью однофотонной эмиссионной компьютерной томографии. Для оценки качества жизни пациентов использовали опросник SF-36. Интракоронарная инфузия аутологичных мононуклеарных стволовых клеток костного мозга способствовала уменьшению функционального класса стенокардии, потребления нитроглицерина, увеличению времени нагрузки, улучшению перфузии миокарда и не оказывала влияния на нарушения ритма. У пациентов, получавших только медикаментозную терапию, возрастал функциональный класс стенокардии и уменьшалась продолжительность физической нагрузки. Спустя год после процедуры в группе интракоронарной инфузии отмечали выраженное улучшение качества жизни. 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В исследование включено 17 пациентов с тяжелой стенокардией, не подлежащих механической реваскуляризации. Этим пациентам в период с 2008 по 2010 гг. выполняли интракоронарную инфузию аутологичных мононуклеарных стволовых клеток костного мозга. Контрольная группа насчитывала 10 пациентов. Всех пациентов обследовали до и после лечения. Перфузию миокарда оценивали с помощью однофотонной эмиссионной компьютерной томографии. Для оценки качества жизни пациентов использовали опросник SF-36. Интракоронарная инфузия аутологичных мононуклеарных стволовых клеток костного мозга способствовала уменьшению функционального класса стенокардии, потребления нитроглицерина, увеличению времени нагрузки, улучшению перфузии миокарда и не оказывала влияния на нарушения ритма. У пациентов, получавших только медикаментозную терапию, возрастал функциональный класс стенокардии и уменьшалась продолжительность физической нагрузки. Спустя год после процедуры в группе интракоронарной инфузии отмечали выраженное улучшение качества жизни. Наибольшее улучшение происходило по индексам физического функционирования, ролевого функционирования и боли. В контрольной группе существенного увеличения данных индексов не наблюдалось, наоборот, для индекса боли отмечена обратная динамика. 

Ключевые слова

стволовые клетки, мононуклеарные клетки, стенокардия, болезнь сердца, аорто-коронарное шунтирование, ангиопластика, лечение стенокардии, продолжительность физической нагрузки, потребление нитроглицерина, опросник SF-36 

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В исследование включено 17 пациентов с тяжелой стенокардией, не подлежащих механической реваскуляризации. Этим пациентам в период с 2008 по 2010 гг. выполняли интракоронарную инфузию аутологичных мононуклеарных стволовых клеток костного мозга. Контрольная группа насчитывала 10 пациентов. Всех пациентов обследовали до и после лечения. Перфузию миокарда оценивали с помощью однофотонной эмиссионной компьютерной томографии. Для оценки качества жизни пациентов использовали опросник SF-36. Интракоронарная инфузия аутологичных мононуклеарных стволовых клеток костного мозга способствовала уменьшению функционального класса стенокардии, потребления нитроглицерина, увеличению времени нагрузки, улучшению перфузии миокарда и не оказывала влияния на нарушения ритма. У пациентов, получавших только медикаментозную терапию, возрастал функциональный класс стенокардии и уменьшалась продолжительность физической нагрузки. Спустя год после процедуры в группе интракоронарной инфузии отмечали выраженное улучшение качества жизни. Наибольшее улучшение происходило по индексам физического функционирования, ролевого функционирования и боли. В контрольной группе существенного увеличения данных индексов не наблюдалось, наоборот, для индекса боли отмечена обратная динамика. 

Ключевые слова

стволовые клетки, мононуклеарные клетки, стенокардия, болезнь сердца, аорто-коронарное шунтирование, ангиопластика, лечение стенокардии, продолжительность физической нагрузки, потребление нитроглицерина, опросник SF-36 

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The role of CXCL12/CXCR4-mediatedchemotaxis and homing in stromal microenvironment/leukemia interaction 

Animportant role in the interaction of tumor cells and stromal niches of bone marrow (BM) is played bythe chemokine CXCL12  (SDF-1, stromal cell-derived factor-1).The leukemia cells seek to infiltrate the BM's microscopic niches due to CXCL12/CXCR4–mediated chemotaxis, where stromal CXCL12 connects with CXC receptor 4 (CXCR4), located in the tumor cell membrane. As a result, tumor cells maintain self-renewal,their differentiation is blocked, and access to chemotherapeutic agents is hampered. This results in proliferation increasing and promotes survival leukemia cells. The blocking of CXCR4 stimulates the tumor cells to leave the bone marrow and to circulate in the patient's organism. As a result, the principal possibility of a new therapeutic strategy is opened on the basis of the influence ofthe CXCL12/CXCR4 system [10].

Currently, imatinib therapy is the major strategy for bcr-abl(+) CML.This therapy is based on targeted killing of the tyrosine kinase-expressing bcr-abl tumor cells. It was recently demonstrated [3] that tyrosine kinase p210BCR-ABL can inhibit CXCL12-signaling, interfering with thechemotaxis/homing process of leukemia cells. This leads to a release of immature myeloid cells from BM specific for CML and their circulation. Jin et al. [4] suggested that imatinib can act as an antagonist of bcr-abl, reconstructing CXCL12/CXCR4interaction, and it can force CML cells to migrate andconnect to the supporting BM microenvironment (Fig. 1). As result, the tumor cells are protected from the influence of therapeutic agents and this can be a potential causeof relapse. Thus, this therapeutic imatinib strategy can lead to the negative effect of indirect stromal resistance.

Figure 1. The influence of imatinib on CXCR4 expression, migration, and adhesion in the BM niche (see [4])

Zagrivnaja_Figure1.png

With the aim of verifying these hypotheses, Jin at al [4] investigated the influence of imatinib on CXCR4 expression, migration, and apoptose of leukemia cells in imatinib-sensitive and resistant CML cell lines, as well as in primary CML patient samples. They proved that imatinib blocks the influence of bcr-abl and stimulates the expression surface CXCR4 in conditions of co-cultivation of CML cells with mesenchymal stem cells (MSC). It increases the migration of CML cells to stromal cells of BM.

This proves that ITK imatinib can lead to indirect stroma resistance to therapy, associated with the CXCL12/CXCR4 system. It provides the possibility to conclude that ITK therapy should be added to any agent attenuating a CXCL12/CXCR4 interaction.  Research into the role of molecular inhibitors of CXCR4 in therapy CML is currently under way [1]. Dillmann et al. [1] pointed to a potential method of influencing the SDF-1/CXCR4 mechanism by using the selective CXCR4 antagonist Plerixafor, which makes bcr-abl(+) cells  more sensitive  to ITK therapy in the presence of BM stromal cells. In this way it was demonstrated that destroying the indirect CXCL12/CXCR4 interaction leads to target drug effectiveness rising. These investigations exhibit the high potential for the role of CXCR4 inhibitors in CML therapy.

Lyn–dependent drug resistance caused by the microenvironment

It is well known that Lyn-kinase of the Src-kinasefamily is one of the key components of indirect CXCL12/CXCR4 migration of normal and tumor hematopoietic cells. Lyn interacts with the CXCL12/CXCR4 system and is activated by tyrosine kinase p210 bcr-abl. CXCR4 and Lyn could be placed in lipid rafts, the mobile microdomains of cell membrane, enriched by glycosphingolipids, sphingomyelin, cholesterol, and signal molecules. TKI therapy helps CXCR4 reposition into the lipid raft, where it interacts with active phosphorylated Lyn (LynTyr396) in the CML cells. Recently,a new mechanism of drug resistance was discovered. It is based on lipid raft modulation and it includes changes of multivalent CXCR4 and Lyn complex compartmentalization (Fig. 2).

It was shown that mesenchymal stem cells (MSC), which produce CXCL12, stimulate Lyn-activation in the bcr-abl(-)AML cell line HL60. This Lyn-activation in the lipid rafts of membranes is a universal mechanism, andcould explaindrug resistance for all kinds of leukemia [7]. Lyn-associated CXCR4 reposition in lipid rafts of membranes can influence the CXCL12 / CXCR4 signal path. It activates migration and enables the survival of residual leukemia cells in BM niches.

Figure 2. Mechanisms of CXCR4 localization and Lyn activation in lipid rafts (see [8]). Imatinib causes CXCR4 clustering in lipid rafts with subsequent co-localization with active p-LynTyr396. It leads to the induction of cell migration to BM stromal cells, producing CXCL12

Zagrivnaja_Figure2.png


The discovery of activated Lyn's role in the reconstitution of CXCL12/CXCR4   signal paths during bcr-abl inhibition leads to the idea that the application of Srckinase inhibitors could diminish ITK resistance, causing a microenvironment. According to this hypothesis, the double Src/abl kinase inhibitor dasatinib induces CML cell migrations to CXCL12 at a much lower level than imatinib [8]. Investigations showed that dasatinib causes an increase in the highest level of complete cytogenetic response (46% versus 28%, p<0.0001) in CML in comparison to imatinib [5]. Thus, possible dasatinib effectiveness and lower resistance to it, is caused most probably by blockade of Lyn-dependent resistance by the microenvironment.  But this is not the complete effect. Therefore, the resistance to dasatinib is caused by another mechanism, which is different to the Lyn-activated one. Most probably it depends on the surface CXCR4 expressionincreasing [8].

Results of Fei et al. [2] showed that dasatinib therapy leads to CXCR4 expression increasing at the surface of cells in cases of p210 bcr-abl(+) acute lymphoblastic leukemia. In this case dasatinib and CXCR4-inhibitor combined therapy increases cell death. It demonstrates the usefulness of a TKI and CXCR4-inhibitor combination for CML and Ph (+)ALL therapy.

Results of Tabe et al. [8] demonstrate that lipid rafts of membranes provide key functional relays between Lyn and CXCR4. Thus, chemotaxis and homing of leukemia cells depends not only on CXCR4 inclusions in rafts, but depends on the cholesterol content in cell membranes. That is why statins, inhibiting synthesis of cholesterol, can change membrane properties, destroying rafts. Additionally, there are some data that simvastatin or lovastatin and alfa 2 β combination in CML cellsleads to inhibited cell growth [6, 9]. Thus cholesterol synthesis inhibition is a potential additional approach to CML therapy.

Conclusions

The current state of the researchprovides these conclusions:

1. It is necessary to  investigate the role of CXCR4 inhibitors more carefully, as they have a high potential for preventing stroma-mediated drug resistance.

2. Therapy using the double Src/abl kinase inhibitor dasatinib is more effective. 
This is most probably due to the influence of Lyn-kinase, which is one of the key components of indirect CXCL12/CXCR4-migration of normal and tumor hemopoietic cells.

3. It is necessary to keep in mind the potential usefulness of statin as an additional agent in CML therapy.

References

1. Dillmann F, Veldwijk MR, Laufs S, Sperandio M, Calandra G, Wenz F, Zeller J, Fruehauf S. Plerixafor inhibits chemotaxis toward SDF-1 and CXCR4-mediated stroma contact in a dose-dependent manner resulting in increased susceptibility of BCR-ABL+ cell to Imatinib and Nilotinib. Leuk Lymphoma. 2009 Oct;50(10):1676–86. doi: 10.1080/10428190903150847.

2. Fei F, Stoddart S, Müschen M, Kim YM, Groffen J, Heisterkamp N. Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia. Leukemia. 2010;24:813–820. doi: 10.1038/leu.2009.302.

3. Geay JF, Buet D, Zhang Y, Foudi A, Jarrier P, Berthebaud M, Turhan AG, Vainchenker W, Louache F. p210BCR-ABL inhibits SDF-1 chemotactic response via alteration of CXCR4 signaling and down-regulation of CXCR4 expression. Cancer Res. 2005 Apr 1;65(7):2676–83. doi: 10.1158/0008-5472.CAN-04-2152.

4. Jin L, Tabe Y, Konoplev S, Xu Y, Leysath CE, Lu H, Kimura S, Ohsaka A, Rios MB, Calvert L, Kantarjian H, Andreeff M, Konopleva M. CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma andpromotes survival of quiescent CML cells. Mol Cancer Ther. 2008 Jan;7(1):48–58. doi: 10.1158/1535-7163.MCT-07-0042.

5. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260–70.

6. Müller-Tidow C, Kiehl M, Sindermann JR, Probst M, Banger N, Zühlsdorf M, Chou TC, Berdel WE, Serve H, Koch OM. Synergistic growth inhibitory effects of interferon-alpha and lovastatin on bcr-abl positive leukemic cells. Int J Oncol. 2003;23:151–158.

7. Nakata Y, Tomkowicz B, Gewirtz AM, Ptasznik A. Integrin inhibition through Lyn-dependent cross talk from CXCR4 chemokine receptors in normal human CD34+ marrow cells. Blood. 2006; 107:4234–4239. doi: 10.1182/blood-2005-08-3343.

8. Tabe Y, Jin L, Iwabuchi K, Wang RY, Ichikawa N, Miida T, Cortes J, Andreeff M, Konopleva M. Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions inlipid rafts. Leukemia. 2011 Oct 18. doi:10.1038/leu.2011.291.

9. Yang YC, Huang WF, Chuan LM, Xiao DW, Zeng YL, Zhou DA, Xu GQ, Liu W, Huang B, Hu Q. In vitro and in vivo study of cell growth inhibition of simvastatin on chronic myelogenous leukemia cells. Chemotherapy. 2008;54:438–446. doi: 10.1159/000158663.

10. Zeng Z, Shi YX, Samudio IJ, Wang RY, Ling X, Frolova O, Levis M, Rubin JB, Negrin RR, Estey EH, Konoplev S, Andreeff M, Konopleva M. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood. 2009 Jun 11;113(24):6215–24. doi: 10.1182/blood-2008-05-158311.

" ["~DETAIL_TEXT"]=> string(11956) "

The role of CXCL12/CXCR4-mediatedchemotaxis and homing in stromal microenvironment/leukemia interaction 

Animportant role in the interaction of tumor cells and stromal niches of bone marrow (BM) is played bythe chemokine CXCL12  (SDF-1, stromal cell-derived factor-1).The leukemia cells seek to infiltrate the BM's microscopic niches due to CXCL12/CXCR4–mediated chemotaxis, where stromal CXCL12 connects with CXC receptor 4 (CXCR4), located in the tumor cell membrane. As a result, tumor cells maintain self-renewal,their differentiation is blocked, and access to chemotherapeutic agents is hampered. This results in proliferation increasing and promotes survival leukemia cells. The blocking of CXCR4 stimulates the tumor cells to leave the bone marrow and to circulate in the patient's organism. As a result, the principal possibility of a new therapeutic strategy is opened on the basis of the influence ofthe CXCL12/CXCR4 system [10].

Currently, imatinib therapy is the major strategy for bcr-abl(+) CML.This therapy is based on targeted killing of the tyrosine kinase-expressing bcr-abl tumor cells. It was recently demonstrated [3] that tyrosine kinase p210BCR-ABL can inhibit CXCL12-signaling, interfering with thechemotaxis/homing process of leukemia cells. This leads to a release of immature myeloid cells from BM specific for CML and their circulation. Jin et al. [4] suggested that imatinib can act as an antagonist of bcr-abl, reconstructing CXCL12/CXCR4interaction, and it can force CML cells to migrate andconnect to the supporting BM microenvironment (Fig. 1). As result, the tumor cells are protected from the influence of therapeutic agents and this can be a potential causeof relapse. Thus, this therapeutic imatinib strategy can lead to the negative effect of indirect stromal resistance.

Figure 1. The influence of imatinib on CXCR4 expression, migration, and adhesion in the BM niche (see [4])

Zagrivnaja_Figure1.png

With the aim of verifying these hypotheses, Jin at al [4] investigated the influence of imatinib on CXCR4 expression, migration, and apoptose of leukemia cells in imatinib-sensitive and resistant CML cell lines, as well as in primary CML patient samples. They proved that imatinib blocks the influence of bcr-abl and stimulates the expression surface CXCR4 in conditions of co-cultivation of CML cells with mesenchymal stem cells (MSC). It increases the migration of CML cells to stromal cells of BM.

This proves that ITK imatinib can lead to indirect stroma resistance to therapy, associated with the CXCL12/CXCR4 system. It provides the possibility to conclude that ITK therapy should be added to any agent attenuating a CXCL12/CXCR4 interaction.  Research into the role of molecular inhibitors of CXCR4 in therapy CML is currently under way [1]. Dillmann et al. [1] pointed to a potential method of influencing the SDF-1/CXCR4 mechanism by using the selective CXCR4 antagonist Plerixafor, which makes bcr-abl(+) cells  more sensitive  to ITK therapy in the presence of BM stromal cells. In this way it was demonstrated that destroying the indirect CXCL12/CXCR4 interaction leads to target drug effectiveness rising. These investigations exhibit the high potential for the role of CXCR4 inhibitors in CML therapy.

Lyn–dependent drug resistance caused by the microenvironment

It is well known that Lyn-kinase of the Src-kinasefamily is one of the key components of indirect CXCL12/CXCR4 migration of normal and tumor hematopoietic cells. Lyn interacts with the CXCL12/CXCR4 system and is activated by tyrosine kinase p210 bcr-abl. CXCR4 and Lyn could be placed in lipid rafts, the mobile microdomains of cell membrane, enriched by glycosphingolipids, sphingomyelin, cholesterol, and signal molecules. TKI therapy helps CXCR4 reposition into the lipid raft, where it interacts with active phosphorylated Lyn (LynTyr396) in the CML cells. Recently,a new mechanism of drug resistance was discovered. It is based on lipid raft modulation and it includes changes of multivalent CXCR4 and Lyn complex compartmentalization (Fig. 2).

It was shown that mesenchymal stem cells (MSC), which produce CXCL12, stimulate Lyn-activation in the bcr-abl(-)AML cell line HL60. This Lyn-activation in the lipid rafts of membranes is a universal mechanism, andcould explaindrug resistance for all kinds of leukemia [7]. Lyn-associated CXCR4 reposition in lipid rafts of membranes can influence the CXCL12 / CXCR4 signal path. It activates migration and enables the survival of residual leukemia cells in BM niches.

Figure 2. Mechanisms of CXCR4 localization and Lyn activation in lipid rafts (see [8]). Imatinib causes CXCR4 clustering in lipid rafts with subsequent co-localization with active p-LynTyr396. It leads to the induction of cell migration to BM stromal cells, producing CXCL12

Zagrivnaja_Figure2.png


The discovery of activated Lyn's role in the reconstitution of CXCL12/CXCR4   signal paths during bcr-abl inhibition leads to the idea that the application of Srckinase inhibitors could diminish ITK resistance, causing a microenvironment. According to this hypothesis, the double Src/abl kinase inhibitor dasatinib induces CML cell migrations to CXCL12 at a much lower level than imatinib [8]. Investigations showed that dasatinib causes an increase in the highest level of complete cytogenetic response (46% versus 28%, p<0.0001) in CML in comparison to imatinib [5]. Thus, possible dasatinib effectiveness and lower resistance to it, is caused most probably by blockade of Lyn-dependent resistance by the microenvironment.  But this is not the complete effect. Therefore, the resistance to dasatinib is caused by another mechanism, which is different to the Lyn-activated one. Most probably it depends on the surface CXCR4 expressionincreasing [8].

Results of Fei et al. [2] showed that dasatinib therapy leads to CXCR4 expression increasing at the surface of cells in cases of p210 bcr-abl(+) acute lymphoblastic leukemia. In this case dasatinib and CXCR4-inhibitor combined therapy increases cell death. It demonstrates the usefulness of a TKI and CXCR4-inhibitor combination for CML and Ph (+)ALL therapy.

Results of Tabe et al. [8] demonstrate that lipid rafts of membranes provide key functional relays between Lyn and CXCR4. Thus, chemotaxis and homing of leukemia cells depends not only on CXCR4 inclusions in rafts, but depends on the cholesterol content in cell membranes. That is why statins, inhibiting synthesis of cholesterol, can change membrane properties, destroying rafts. Additionally, there are some data that simvastatin or lovastatin and alfa 2 β combination in CML cellsleads to inhibited cell growth [6, 9]. Thus cholesterol synthesis inhibition is a potential additional approach to CML therapy.

Conclusions

The current state of the researchprovides these conclusions:

1. It is necessary to  investigate the role of CXCR4 inhibitors more carefully, as they have a high potential for preventing stroma-mediated drug resistance.

2. Therapy using the double Src/abl kinase inhibitor dasatinib is more effective. 
This is most probably due to the influence of Lyn-kinase, which is one of the key components of indirect CXCL12/CXCR4-migration of normal and tumor hemopoietic cells.

3. It is necessary to keep in mind the potential usefulness of statin as an additional agent in CML therapy.

References

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2. Fei F, Stoddart S, Müschen M, Kim YM, Groffen J, Heisterkamp N. Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia. Leukemia. 2010;24:813–820. doi: 10.1038/leu.2009.302.

3. Geay JF, Buet D, Zhang Y, Foudi A, Jarrier P, Berthebaud M, Turhan AG, Vainchenker W, Louache F. p210BCR-ABL inhibits SDF-1 chemotactic response via alteration of CXCR4 signaling and down-regulation of CXCR4 expression. Cancer Res. 2005 Apr 1;65(7):2676–83. doi: 10.1158/0008-5472.CAN-04-2152.

4. Jin L, Tabe Y, Konoplev S, Xu Y, Leysath CE, Lu H, Kimura S, Ohsaka A, Rios MB, Calvert L, Kantarjian H, Andreeff M, Konopleva M. CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma andpromotes survival of quiescent CML cells. Mol Cancer Ther. 2008 Jan;7(1):48–58. doi: 10.1158/1535-7163.MCT-07-0042.

5. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260–70.

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8. Tabe Y, Jin L, Iwabuchi K, Wang RY, Ichikawa N, Miida T, Cortes J, Andreeff M, Konopleva M. Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions inlipid rafts. Leukemia. 2011 Oct 18. doi:10.1038/leu.2011.291.

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Мария В. Загривная

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В настоящее время ведутся активные исследования ключевых механизмов взаимодействия опухолевых клеток с их микроокружением. Выявление таких механизмов и разработка лекарственных средств, которые могли бы на них воздействовать, открывает новые возможности в лечении злокачественных новообразований, в том числе лейкозов. Наибольший интерес на сегодняшний день вызывают механизмы взаимодействия между лейкозными клетками и их микроокружением с участием CXCL12/CXCR4 и Lyn-киназы

Ключевые слова

микроокружение, CXCR4, иматиниб, дазатиниб, хронические миелоидный лейкоз, лекарственная резистентность, bcr-abl, Lyn

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Maria V. Zagrivnaja

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Laboratory of transplantology and molecular hematology, R.M. Gorbacheva Memorial Institute of Pediatric Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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There are ongoing investigations on key mechanisms of interaction between tumor cells and their microenvironment. Identification of these mechanisms and development of therapeutic agents targeting them brings up new opportunities for cancer therapy, including leukemia treatment. Today there are active discussions on mechanisms of interaction between tumor cells and their microenvironment mediated by CXCL12/CXCR4 and Lyn-kinase.

Keywords

microenvironment, CXCR4, imatinib, dasatinib, chronic myeloid leukemia, drug resistance, bcr-abl, Lyn

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Maria V. Zagrivnaja

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Maria V. Zagrivnaja

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There are ongoing investigations on key mechanisms of interaction between tumor cells and their microenvironment. Identification of these mechanisms and development of therapeutic agents targeting them brings up new opportunities for cancer therapy, including leukemia treatment. Today there are active discussions on mechanisms of interaction between tumor cells and their microenvironment mediated by CXCL12/CXCR4 and Lyn-kinase.

Keywords

microenvironment, CXCR4, imatinib, dasatinib, chronic myeloid leukemia, drug resistance, bcr-abl, Lyn

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There are ongoing investigations on key mechanisms of interaction between tumor cells and their microenvironment. Identification of these mechanisms and development of therapeutic agents targeting them brings up new opportunities for cancer therapy, including leukemia treatment. Today there are active discussions on mechanisms of interaction between tumor cells and their microenvironment mediated by CXCL12/CXCR4 and Lyn-kinase.

Keywords

microenvironment, CXCR4, imatinib, dasatinib, chronic myeloid leukemia, drug resistance, bcr-abl, Lyn

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Laboratory of transplantology and molecular hematology, R.M. Gorbacheva Memorial Institute of Pediatric Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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Laboratory of transplantology and molecular hematology, R.M. Gorbacheva Memorial Institute of Pediatric Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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Мария В. Загривная

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Мария В. Загривная

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Выявление таких механизмов и разработка лекарственных средств, которые могли бы на них воздействовать, открывает новые возможности в лечении злокачественных новообразований, в том числе лейкозов. Наибольший интерес на сегодняшний день вызывают механизмы взаимодействия между лейкозными клетками и их микроокружением с участием CXCL12/CXCR4 и Lyn-киназы </p> <h3>Ключевые слова</h3> <p>микроокружение, CXCR4, иматиниб, дазатиниб, хронические миелоидный лейкоз, лекарственная резистентность, bcr-abl, Lyn </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1150) "

В настоящее время ведутся активные исследования ключевых механизмов взаимодействия опухолевых клеток с их микроокружением. Выявление таких механизмов и разработка лекарственных средств, которые могли бы на них воздействовать, открывает новые возможности в лечении злокачественных новообразований, в том числе лейкозов. Наибольший интерес на сегодняшний день вызывают механизмы взаимодействия между лейкозными клетками и их микроокружением с участием CXCL12/CXCR4 и Lyn-киназы

Ключевые слова

микроокружение, CXCR4, иматиниб, дазатиниб, хронические миелоидный лейкоз, лекарственная резистентность, bcr-abl, Lyn

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В настоящее время ведутся активные исследования ключевых механизмов взаимодействия опухолевых клеток с их микроокружением. Выявление таких механизмов и разработка лекарственных средств, которые могли бы на них воздействовать, открывает новые возможности в лечении злокачественных новообразований, в том числе лейкозов. Наибольший интерес на сегодняшний день вызывают механизмы взаимодействия между лейкозными клетками и их микроокружением с участием CXCL12/CXCR4 и Lyn-киназы

Ключевые слова

микроокружение, CXCR4, иматиниб, дазатиниб, хронические миелоидный лейкоз, лекарственная резистентность, bcr-abl, Lyn

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Introduction

Muscular dystrophies are a highly heterogeneous group of inherited disorders characterized by progressive skeletal muscle weakness and necrosis of the muscle tissue. Currently, more than 20 different monogenous disorders, inherited in autosomal recessive, autosomal dominant, and X-linked ways, are referred to as muscular dystrophies. Their incidence varies from 1 in 3000 boys for Duchenne Muscular Dystrophy (DMD) to 1 in 200 000 for LGMD2B [9, Jain Foundation Data]. The onset of the inherited muscular dystrophies, as well as their natural history also can be very different. They can start in early childhood and rapidly develop, causing death in the early twenties as happens in DMD [1], or have an average onset in the late twenties, and mildly progress, not affecting the average lifespan, as for most LGMDs. This group of diseases is easily recognized, however differential diagnosis poses some issues for a physician, as in most cases it should be based on molecular and DNA sequence data.  There is no specific treatment for any of the forms of muscular dystrophy. Physiotherapy and aerobic exercises may help to prevent contractures and maintain muscle tone, orthoses may be needed to improve quality of life in some cases, but no actual long-term therapy has been found [1]. Currently the two most promising approaches to treat muscular dystrophies in general, and DMD in particular, are gene and cell therapy or their combination. This short review highlights the key points in these fields, as well as main expectations and pitfalls in gene therapy of Duchenne myodystrophy.

Gene therapy for DMD

Muscular dystrophies, like all inherited monogenous diseases, are caused by mutations in various genes, and, thus, gene therapy is a very promising approach to their treatment. Most of the gene therapy studies in this field have been focused on Duchenne Muscular Dystrophy, one of the most widespread and fatal neuro-muscular diseases. Therefore, this particular condition is a very good model, which should help to elucidate the main issues, hopes, and pitfalls in the field.  

DMD is caused by a vast spectrum of mutations, mainly the large-span deletions of the exons in the 2.3Mb dystrophin (DMD) gene [6, 13]. The dystrophin mRNA spans nearly 1000kb and is primarily translated in the muscle tissue, where the protein of the same name plays a major role in muscle fiber contraction and maintenance. Mutations in the dystrophin gene impair normal protein synthesis, causing the consequent progressive myofiber necrosis resulting in progressive muscle weakness. Symptoms usually appear in male children before age 5 and may be visible in early infancy. Progressive proximal muscle weakness of the legs and pelvis associated with a loss of muscle mass is observed first. Eventually this weakness spreads to the arms, neck, and other areas.

Given this, the ideal vector for DMD gene therapy should be able to carry a 1000 kb of DNA and easily penetrate muscle fibers, and then effectively express functional dystrophin for an unlimited period of time. Moreover, it ought to be safe (non-mutagenic or immunogenic) and its expression should be easily regulated. But for the carried DNA size, these requirements could be applied to the ideal vector to treat any muscular dystrophy. In this connection, let’s try to evaluate the most promising vector types, taking into account the proposed criteria of safety and efficiency.

Currently all gene therapy delivery systems can be divided into two large groups: viral and non-viral. Viral vectors are the most commonly used: during the period from 1989 to 2010 they were employed in more than 60% of gene therapy clinical trials (Wiley Interscience Gene Therapy Trials Worldwide Database; Edelstein et al., 2007). Their major advantages are high effectiveness and specificity of transgene delivery. 

Amongst the viral vectors, only lentiviruses and adeno-associated viruses (AAV) can be effectively used for muscular dystrophy's gene therapy, as only they are able to efficiently penetrate the myofibers and express the transgene there. The use of lentiviruses, despite their high transgene expression efficiency and relative safety, is connected with side effects that are too serious for them to be put into clinical practice. For instance, patients who underwent such gene therapy demonstrated a HIV-positive profile [3].

The AAVs are the safest viral vectors due to their low immunogenicity, the absence of the insertional mutagenesis risk and other side effects. In addition, they are one of the most effective: stable transgene expression in primates could be detected even 18 months after injection [10]. The major issue in the use of this vector type for DMD gene therapy is the very small size of the therapeutic cassette — only 4 kb [15]. However, this has been solved by the use of a truncated version of the gene (“mini-dystrophin”) instead of the complete one. This approach efficiently helped to ameliorate the disease, but not to cure, however it successfully passed through the Phase I clinical trial [5]. Unfortunately, is inapplicable for most of the muscular dystrophies, as not all the causative genes have “mini” versions. 

Thus, none of the viral vectors, despite their efficiency and safety, fit the ideal criteria, for different reasons: the small size of the therapeutic cassette in the case of AAV, serious side effects in lentiviruses, and inefficiency of the other extensively studied viral vector types.

Non-viral vectors, such as plasmids and human artificial chromosomes (HACs), do have advantages over the viral ones, because of their safety and theoretically unlimited size of the therapeutic cassette. However, the efficiency of the plasmid-mediated transgene delivery is rather poor as well as the time of its expression [for instance, see 16], especially when it is delivered systemically. 

HACs on the other hand are able to maintain expression of genomic-sized transgenes within target cells for an unlimited time. What's more, they do not need to integrate into the host genome to maintain the transgene expression, and the latter one’s level is regulated by the intracellular mechanisms. In spite of the fact that their construction and delivery pose certain technical challenges, the recent advances in this field are very promising [4]. Moreover, the first successful results of the preclinical trial of the cell-based therapy exploiting HACs bearing DMD in mice have recently been published by Tedesco et al., 2011. The development of this strategy to treat other muscular dystrophies is a way to find the cure for this group of diseases.

So, non-viral vectors, and HACs in particular, represent the most promising direction in the DMD treatment research.

Cell therapy for muscular dystrophies

The main issue in developing an effective therapy for muscular dystrophies is that the muscle tissue is a non-dividing one, and its reparation is a very complicated and relatively rarely studied process. Even if one manages to find an effective and safe way to transfer genes to the muscle fiber and to obtain a stable transgene expression in the target cell, the results of such gene therapy aren't very promising. For instance, the presence of the transgenic dystrophin in the myofibrils will ameliorate the DMD and will prevent the disease progress, but will not help to restore them. Therefore such therapy only makes sense in the early stages of the disease.

The most effective way to solve this issue is to combine gene and cell therapy by introducing genetically modified stem cells, so that the restored myofibrils effectively express the transgene to prevent their damage and necrosis. However, not many types of stem cells fit the criteria necessary for the stem cell therapy of muscular dystrophies. Such cells should effectively fuse with the myofibers, they should be easily obtained from the patient’s tissue and then be easily expanded in vitro, and finally they must be systemically deliverable. For instance, mesoangioblasts, currently one of the most promising cell types to treat DMD are easily cultivated, effectively fuse with the myofibers and can be delivered by intravenous infusion, but can only be harvested in the very early stages of perinatal development [11]. They could be obtained from an allogenic donor, but this poses the question of their availability, as well as ethical issues. Other populations of myogenic stem cells, such as CD133+ satellite cells, are very hard to obtain, and the use of embryoniс stem cells and iPS cells raises ethical and safety issues respectively [7].

However there are two groups of the myogenic stem cells which partially suit all the criteria mentioned — these are CD133+ hematopoietic (HSC) and mesenchymal stem cells (MSC), which can be easily obtained from a patient, expanded in vitro, and have been shown to contribute to muscle regeneration [2, 14]. Currently, the therapeutic potential of these two stem cells populations are being extensively studied. 

Modification of these cell types with HACs bearing the necessary gene and their consequent transplantation to the patient via IV injection could be a very promising strategy to treat first DMD, and then muscular dystrophies in general. Thus, the use of HAC-modified autologous CD133+ HSC or MHC opens new perspectives for the treatment of the muscular dystrophies. However, much research must be done to bring this technology from paper into clinical practice. 

Acknowledgements

The author is a project manager of OJCL “Human Stem Cells Institute”, Moscow, Russian Federation.

References

1. Boland BJ, Silbert PL, Groover RV, Wollan PC, Silverstein MD. Skeletal, cardiac, and smooth muscle failure in Duchenne muscular dystrophy. Pediatr Neurol. 1996 Jan;14(1):7-12.

2. De Bari C, Dell'Accio F, Vandenabeele F, Vermeesch JR, Raymackers JM, Luyten FP. Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane. J Cell Biol. 2003 Mar 17;160(6):909-18. doi: 10.1083/jcb.200212064.

3. Escors D, Breckpot K. Lentiviral vectors in gene therapy: their current status and future potential. Arch Immunol Ther Exp (Warsz). 2010 Apr;58(2):107-19. doi:10.1007/s00005-010-0063-4.

4. Kazuki Y, Oshimura M. Human artificial chromosomes for gene delivery and the development of animal models. Mol Ther. 2011 Sep;19(9):1591-601. doi:10.1038/mt.2011.136.

5. Kornegay JN, Li J, Bogan JR, Bogan DJ, Chen C, Zheng H, Wang B, Qiao C, Howard JF Jr, Xiao X. Widespread muscle expression of an AAV9 human mini-dystrophin vector after intravenous injection in neonatal dystrophin-deficient dogs. Mol Ther. 2010 Aug;18(8):1501-8. doi: 10.1038/mt.2010.94.

6. Kunkel LM, Hejtmancik JF, Caskey CT, et al. Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy. Nature. 1986 Jul 3-9;322(6074):73-7. doi: 10.1038/322073a0.

7. Meng J, Muntoni F, Morgan JE. Stem cells to treat muscular dystrophies - where are we? Neuromuscul Disord. 2011 Jan;21(1):4-12. doi: 10.1016/j.nmd.2010.10.004.

8. Nelson, MR Pediatrics. Rehabilitation medicine quick reference. New York: Demos Medical, 2010. 268 pp. ISBN 978-1-933864-60-0.

9. Onengüt S, Kavaslar GN, et al. Deletion pattern in the dystrophin gene in Turks and a comparison with Europeans and Indians. Ann Hum Genet. 2000 Jan;64(Pt 1):33-40. doi: 10.1046/j.1469-1809.2000.6410033.x.

10. Rivera VM, Gao GP, et al. Long-term pharmacologically regulated expression of erythropoietin in primates following AAV-mediated gene transfer. Blood. 2005 Feb 15;105(4):1424-30. doi: 10.1182/blood-2004-06-2501.

11. Sampaolesi M, Torrente Y, et al. Cell therapy of alpha-sarcoglycan null dystrophic mice through intra-arterial delivery of mesoangioblasts. Science. 2003;301(5632):487-92.

12. Tedesco FS, Hoshiya H, et al. Stem cell-mediated transfer of a human artificial chromosome ameliorates muscular dystrophy. Sci. Transl. Med. 2011;3(96):96ra78. doi: 10.1126/scitranslmed.3002342.

13. Tennyson CN, Klamut HJ, Worton RG. The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced. Nature Genet. 1995;9:184-190. doi: 10.1038/ng0295-184.

14. Torrente Y, Belicchi M, et al. Human circulating AC133(+) stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle. J. Clin. Invest. 2004;114(2):182-95. doi: 10.1172/JCI20325.

15. Wu Z, Asokan A, Samulski RJ. Adeno-associated virus serotypes: vector toolkit for human gene therapy. Mol. Ther. 2006;14(3):316-327. doi: 10.1016/j.ymthe.2006.05.009.

16. Tsurumi Y, Takeshita S, et al. Direct Intramuscular Gene Transfer of Naked DNA Encoding Vascular Endothelial Growth Factor Augments Collateral Development and Tissue Perfusion. Circulation. 1996;94:3281-3290. doi: 10.1161/01.CIR.94.12.3281.

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Introduction

Muscular dystrophies are a highly heterogeneous group of inherited disorders characterized by progressive skeletal muscle weakness and necrosis of the muscle tissue. Currently, more than 20 different monogenous disorders, inherited in autosomal recessive, autosomal dominant, and X-linked ways, are referred to as muscular dystrophies. Their incidence varies from 1 in 3000 boys for Duchenne Muscular Dystrophy (DMD) to 1 in 200 000 for LGMD2B [9, Jain Foundation Data]. The onset of the inherited muscular dystrophies, as well as their natural history also can be very different. They can start in early childhood and rapidly develop, causing death in the early twenties as happens in DMD [1], or have an average onset in the late twenties, and mildly progress, not affecting the average lifespan, as for most LGMDs. This group of diseases is easily recognized, however differential diagnosis poses some issues for a physician, as in most cases it should be based on molecular and DNA sequence data.  There is no specific treatment for any of the forms of muscular dystrophy. Physiotherapy and aerobic exercises may help to prevent contractures and maintain muscle tone, orthoses may be needed to improve quality of life in some cases, but no actual long-term therapy has been found [1]. Currently the two most promising approaches to treat muscular dystrophies in general, and DMD in particular, are gene and cell therapy or their combination. This short review highlights the key points in these fields, as well as main expectations and pitfalls in gene therapy of Duchenne myodystrophy.

Gene therapy for DMD

Muscular dystrophies, like all inherited monogenous diseases, are caused by mutations in various genes, and, thus, gene therapy is a very promising approach to their treatment. Most of the gene therapy studies in this field have been focused on Duchenne Muscular Dystrophy, one of the most widespread and fatal neuro-muscular diseases. Therefore, this particular condition is a very good model, which should help to elucidate the main issues, hopes, and pitfalls in the field.  

DMD is caused by a vast spectrum of mutations, mainly the large-span deletions of the exons in the 2.3Mb dystrophin (DMD) gene [6, 13]. The dystrophin mRNA spans nearly 1000kb and is primarily translated in the muscle tissue, where the protein of the same name plays a major role in muscle fiber contraction and maintenance. Mutations in the dystrophin gene impair normal protein synthesis, causing the consequent progressive myofiber necrosis resulting in progressive muscle weakness. Symptoms usually appear in male children before age 5 and may be visible in early infancy. Progressive proximal muscle weakness of the legs and pelvis associated with a loss of muscle mass is observed first. Eventually this weakness spreads to the arms, neck, and other areas.

Given this, the ideal vector for DMD gene therapy should be able to carry a 1000 kb of DNA and easily penetrate muscle fibers, and then effectively express functional dystrophin for an unlimited period of time. Moreover, it ought to be safe (non-mutagenic or immunogenic) and its expression should be easily regulated. But for the carried DNA size, these requirements could be applied to the ideal vector to treat any muscular dystrophy. In this connection, let’s try to evaluate the most promising vector types, taking into account the proposed criteria of safety and efficiency.

Currently all gene therapy delivery systems can be divided into two large groups: viral and non-viral. Viral vectors are the most commonly used: during the period from 1989 to 2010 they were employed in more than 60% of gene therapy clinical trials (Wiley Interscience Gene Therapy Trials Worldwide Database; Edelstein et al., 2007). Their major advantages are high effectiveness and specificity of transgene delivery. 

Amongst the viral vectors, only lentiviruses and adeno-associated viruses (AAV) can be effectively used for muscular dystrophy's gene therapy, as only they are able to efficiently penetrate the myofibers and express the transgene there. The use of lentiviruses, despite their high transgene expression efficiency and relative safety, is connected with side effects that are too serious for them to be put into clinical practice. For instance, patients who underwent such gene therapy demonstrated a HIV-positive profile [3].

The AAVs are the safest viral vectors due to their low immunogenicity, the absence of the insertional mutagenesis risk and other side effects. In addition, they are one of the most effective: stable transgene expression in primates could be detected even 18 months after injection [10]. The major issue in the use of this vector type for DMD gene therapy is the very small size of the therapeutic cassette — only 4 kb [15]. However, this has been solved by the use of a truncated version of the gene (“mini-dystrophin”) instead of the complete one. This approach efficiently helped to ameliorate the disease, but not to cure, however it successfully passed through the Phase I clinical trial [5]. Unfortunately, is inapplicable for most of the muscular dystrophies, as not all the causative genes have “mini” versions. 

Thus, none of the viral vectors, despite their efficiency and safety, fit the ideal criteria, for different reasons: the small size of the therapeutic cassette in the case of AAV, serious side effects in lentiviruses, and inefficiency of the other extensively studied viral vector types.

Non-viral vectors, such as plasmids and human artificial chromosomes (HACs), do have advantages over the viral ones, because of their safety and theoretically unlimited size of the therapeutic cassette. However, the efficiency of the plasmid-mediated transgene delivery is rather poor as well as the time of its expression [for instance, see 16], especially when it is delivered systemically. 

HACs on the other hand are able to maintain expression of genomic-sized transgenes within target cells for an unlimited time. What's more, they do not need to integrate into the host genome to maintain the transgene expression, and the latter one’s level is regulated by the intracellular mechanisms. In spite of the fact that their construction and delivery pose certain technical challenges, the recent advances in this field are very promising [4]. Moreover, the first successful results of the preclinical trial of the cell-based therapy exploiting HACs bearing DMD in mice have recently been published by Tedesco et al., 2011. The development of this strategy to treat other muscular dystrophies is a way to find the cure for this group of diseases.

So, non-viral vectors, and HACs in particular, represent the most promising direction in the DMD treatment research.

Cell therapy for muscular dystrophies

The main issue in developing an effective therapy for muscular dystrophies is that the muscle tissue is a non-dividing one, and its reparation is a very complicated and relatively rarely studied process. Even if one manages to find an effective and safe way to transfer genes to the muscle fiber and to obtain a stable transgene expression in the target cell, the results of such gene therapy aren't very promising. For instance, the presence of the transgenic dystrophin in the myofibrils will ameliorate the DMD and will prevent the disease progress, but will not help to restore them. Therefore such therapy only makes sense in the early stages of the disease.

The most effective way to solve this issue is to combine gene and cell therapy by introducing genetically modified stem cells, so that the restored myofibrils effectively express the transgene to prevent their damage and necrosis. However, not many types of stem cells fit the criteria necessary for the stem cell therapy of muscular dystrophies. Such cells should effectively fuse with the myofibers, they should be easily obtained from the patient’s tissue and then be easily expanded in vitro, and finally they must be systemically deliverable. For instance, mesoangioblasts, currently one of the most promising cell types to treat DMD are easily cultivated, effectively fuse with the myofibers and can be delivered by intravenous infusion, but can only be harvested in the very early stages of perinatal development [11]. They could be obtained from an allogenic donor, but this poses the question of their availability, as well as ethical issues. Other populations of myogenic stem cells, such as CD133+ satellite cells, are very hard to obtain, and the use of embryoniс stem cells and iPS cells raises ethical and safety issues respectively [7].

However there are two groups of the myogenic stem cells which partially suit all the criteria mentioned — these are CD133+ hematopoietic (HSC) and mesenchymal stem cells (MSC), which can be easily obtained from a patient, expanded in vitro, and have been shown to contribute to muscle regeneration [2, 14]. Currently, the therapeutic potential of these two stem cells populations are being extensively studied. 

Modification of these cell types with HACs bearing the necessary gene and their consequent transplantation to the patient via IV injection could be a very promising strategy to treat first DMD, and then muscular dystrophies in general. Thus, the use of HAC-modified autologous CD133+ HSC or MHC opens new perspectives for the treatment of the muscular dystrophies. However, much research must be done to bring this technology from paper into clinical practice. 

Acknowledgements

The author is a project manager of OJCL “Human Stem Cells Institute”, Moscow, Russian Federation.

References

1. Boland BJ, Silbert PL, Groover RV, Wollan PC, Silverstein MD. Skeletal, cardiac, and smooth muscle failure in Duchenne muscular dystrophy. Pediatr Neurol. 1996 Jan;14(1):7-12.

2. De Bari C, Dell'Accio F, Vandenabeele F, Vermeesch JR, Raymackers JM, Luyten FP. Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane. J Cell Biol. 2003 Mar 17;160(6):909-18. doi: 10.1083/jcb.200212064.

3. Escors D, Breckpot K. Lentiviral vectors in gene therapy: their current status and future potential. Arch Immunol Ther Exp (Warsz). 2010 Apr;58(2):107-19. doi:10.1007/s00005-010-0063-4.

4. Kazuki Y, Oshimura M. Human artificial chromosomes for gene delivery and the development of animal models. Mol Ther. 2011 Sep;19(9):1591-601. doi:10.1038/mt.2011.136.

5. Kornegay JN, Li J, Bogan JR, Bogan DJ, Chen C, Zheng H, Wang B, Qiao C, Howard JF Jr, Xiao X. Widespread muscle expression of an AAV9 human mini-dystrophin vector after intravenous injection in neonatal dystrophin-deficient dogs. Mol Ther. 2010 Aug;18(8):1501-8. doi: 10.1038/mt.2010.94.

6. Kunkel LM, Hejtmancik JF, Caskey CT, et al. Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy. Nature. 1986 Jul 3-9;322(6074):73-7. doi: 10.1038/322073a0.

7. Meng J, Muntoni F, Morgan JE. Stem cells to treat muscular dystrophies - where are we? Neuromuscul Disord. 2011 Jan;21(1):4-12. doi: 10.1016/j.nmd.2010.10.004.

8. Nelson, MR Pediatrics. Rehabilitation medicine quick reference. New York: Demos Medical, 2010. 268 pp. ISBN 978-1-933864-60-0.

9. Onengüt S, Kavaslar GN, et al. Deletion pattern in the dystrophin gene in Turks and a comparison with Europeans and Indians. Ann Hum Genet. 2000 Jan;64(Pt 1):33-40. doi: 10.1046/j.1469-1809.2000.6410033.x.

10. Rivera VM, Gao GP, et al. Long-term pharmacologically regulated expression of erythropoietin in primates following AAV-mediated gene transfer. Blood. 2005 Feb 15;105(4):1424-30. doi: 10.1182/blood-2004-06-2501.

11. Sampaolesi M, Torrente Y, et al. Cell therapy of alpha-sarcoglycan null dystrophic mice through intra-arterial delivery of mesoangioblasts. Science. 2003;301(5632):487-92.

12. Tedesco FS, Hoshiya H, et al. Stem cell-mediated transfer of a human artificial chromosome ameliorates muscular dystrophy. Sci. Transl. Med. 2011;3(96):96ra78. doi: 10.1126/scitranslmed.3002342.

13. Tennyson CN, Klamut HJ, Worton RG. The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced. Nature Genet. 1995;9:184-190. doi: 10.1038/ng0295-184.

14. Torrente Y, Belicchi M, et al. Human circulating AC133(+) stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle. J. Clin. Invest. 2004;114(2):182-95. doi: 10.1172/JCI20325.

15. Wu Z, Asokan A, Samulski RJ. Adeno-associated virus serotypes: vector toolkit for human gene therapy. Mol. Ther. 2006;14(3):316-327. doi: 10.1016/j.ymthe.2006.05.009.

16. Tsurumi Y, Takeshita S, et al. Direct Intramuscular Gene Transfer of Naked DNA Encoding Vascular Endothelial Growth Factor Augments Collateral Development and Tissue Perfusion. Circulation. 1996;94:3281-3290. doi: 10.1161/01.CIR.94.12.3281.

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Константин Г. Шевченко

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Мышечные дистрофии представляют собой весьма гетерогенную группу наследственных заболеваний, характеризующихся прогрессирующей мышечной слабостью и некрозом мышечной ткани. В настоящее время не имеется специфического лечения для любых форм мышечной дистрофии. В этой области большинство работ по генной и клеточной терапии сконцентрировано на мышечной дистрофии Дюшенна (ДМД) – одном из наиболее частых нервно-мышечных заболеваний со смертельным исходом. В данном кратком обзоре обозначены ключевые темы в этой области, а также основные надежды и препятствия, касающиеся генной терапии ДМД.

Ключевые слова

миодистрофия Дюшенна, генная терапия, искусственные человеческие хромосомы

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Konstantin G. Shevchenko

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Human Stem Cells Institute, Moscow, Russia

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Muscular dystrophies are a highly heterogeneous group of inherited disorders characterized by progressive skeletal muscle weakness and necrosis of the muscle tissue. Currently there is no specific treatment for any of the forms of muscular dystrophy. Most of the gene and cell therapy studies in this field have focused on Duchenne Muscular Dystrophy (DMD), one of the most frequent and fatal neuro-muscular diseases. This short review highlights the key points in these field, as well as main expectations and pitfalls concerning the gene therapy of DMD.

Keywords

Duchenne, DMD, gene therapy, HAC

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Konstantin G. Shevchenko

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Muscular dystrophies are a highly heterogeneous group of inherited disorders characterized by progressive skeletal muscle weakness and necrosis of the muscle tissue. Currently there is no specific treatment for any of the forms of muscular dystrophy. Most of the gene and cell therapy studies in this field have focused on Duchenne Muscular Dystrophy (DMD), one of the most frequent and fatal neuro-muscular diseases. This short review highlights the key points in these field, as well as main expectations and pitfalls concerning the gene therapy of DMD.

Keywords

Duchenne, DMD, gene therapy, HAC

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Muscular dystrophies are a highly heterogeneous group of inherited disorders characterized by progressive skeletal muscle weakness and necrosis of the muscle tissue. Currently there is no specific treatment for any of the forms of muscular dystrophy. Most of the gene and cell therapy studies in this field have focused on Duchenne Muscular Dystrophy (DMD), one of the most frequent and fatal neuro-muscular diseases. This short review highlights the key points in these field, as well as main expectations and pitfalls concerning the gene therapy of DMD.

Keywords

Duchenne, DMD, gene therapy, HAC

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Human Stem Cells Institute, Moscow, Russia

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Константин Г. Шевченко

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Мышечные дистрофии представляют собой весьма гетерогенную группу наследственных заболеваний, характеризующихся прогрессирующей мышечной слабостью и некрозом мышечной ткани. В настоящее время не имеется специфического лечения для любых форм мышечной дистрофии. В этой области большинство работ по генной и клеточной терапии сконцентрировано на мышечной дистрофии Дюшенна (ДМД) – одном из наиболее частых нервно-мышечных заболеваний со смертельным исходом. В данном кратком обзоре обозначены ключевые темы в этой области, а также основные надежды и препятствия, касающиеся генной терапии ДМД.

Ключевые слова

миодистрофия Дюшенна, генная терапия, искусственные человеческие хромосомы

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Мышечные дистрофии представляют собой весьма гетерогенную группу наследственных заболеваний, характеризующихся прогрессирующей мышечной слабостью и некрозом мышечной ткани. В настоящее время не имеется специфического лечения для любых форм мышечной дистрофии. В этой области большинство работ по генной и клеточной терапии сконцентрировано на мышечной дистрофии Дюшенна (ДМД) – одном из наиболее частых нервно-мышечных заболеваний со смертельным исходом. В данном кратком обзоре обозначены ключевые темы в этой области, а также основные надежды и препятствия, касающиеся генной терапии ДМД.

Ключевые слова

миодистрофия Дюшенна, генная терапия, искусственные человеческие хромосомы

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Introduction

Stem cell (SC) transplantation is very topical in the fields of developmental biology and regenerative surgery. A variety of types of SC obtained from different sources are successfully used for reparation of tissues defects. The functional rehabilitation of damaged retinas in different cases of pathology with SC transplantation is a current theme in ophthalmology [1] and can be used as a model for studying cell engrafting in brain tissue [2]. Currently we have plenty of experience in SC transplantation procedures and a huge number of published works; however it is difficult to predict the effects of such transplantation in vivo due to scarce information about SC behavior in recipient tissue. In vivo studies can’t show us all changes in SC and recipient interactions after transplantation, and it is impossible to obtain enough information about transplanted cells behavior experimentally. However, many questions about the communication of transplanted cells with recipient tissue and the processes of functional contact development and mechanisms of the new microenvironment on transplanted cells still remain open. To answer these questions new adequate model systems with the ability to investigate the destiny of transplanted cells are required. That’s why it is necessary to design ex vivo models that register individual cell behavior after transplantation and clear visualization of these changes [3]. In vitro injection of xenogeny cells into 3D rat retina culture seems to be an attractive method in this case. Additionally, organotyping explant culture damaged by laser emission is used in this work.

Materials and methods

Seven-day-old rats’ retina explant culture (DMEM/F12 with 20 ng/ml FGF and EGF, 7% FCS, В12 and N2 supplements) damaged with laser Zilos-tk (300mW, 1000 mc) was used. Neuronal stem/progenitor cells (NSPC), bone marrow stromal cells (MMSC) [4], and pigment epithelium cells (PE) of С57BL/6-Tg(ACTB-EGFP)/Osb/J GFP+ mice had been transplanted in them (300-300000 cells in 0.2mkl) in vitro. AFM data were obtained from an Atomic force microscope Solver BIO Olympus with the scanning field 100х100х7mkm3. Data analysis was done with the programs Nova (НТ-МDТ) and STATISTICA 8.0. The MMSC reaction to external irritation was estimated by fluorescent dye RH 795 after electro stimulation on an ASL-1 device.

Results

Injected SC stayed alive in culture (negative stain for propidium iodide) for more than 2 months and rapidly migrated (for longer than 3000mkm in distance) from the injection point during only the first 48 hours to the laser-damaged area. Thus injected SC had good live potency, migrated for long distances and morphologically differentiated according to a new microenvironment in all our culture systems, and these culture methods were adequate and easy-to-use 3D model systems for stem cells research.

After MMSC transplantation two populations of small (≈15mkm) rapidly migrating cells and almost motionless big (≈30mkm) cells were notable among injected MMSC. On the third day after injection into intact retinas, MMSC changed their morphology by spreading long branched outgrowths but were still negative for neural and glial cell markers (β-III-tubulin and GFAP). Analogous morphology changes in transplanted MMSC in damaged retinas were observed after 24 hours (Fig. 1). MMSC injection had a noticeable neuroprotective effect on the retina. ASM assay showed significant difference (p<0.01) between glial thickness and endothelial retina cells processes and neurites and neuro-like transplanted MMSC processes. Also it was shown that MMSC form synapses up to 2.5 ±0.06mkm in diameter on the 4th day after transplantation (Fig. 2). After electrostimulation (20V, 0.5Hz, 200ms), clear depolarization of retina neurons and their processes was detected. It was shown that some GFP+ MMSC which had changed their morphology to neuro-like after transplantation into the retina explants were able to depolarize after exogenic stimulation. This means that the MMSC population is highly heterogenic. Those cells that quickly migrated and formed neurit-like processes had an ability to generate a response to stimulation. Big (>30mkm) passive migrating cells that had taken a fibroblast-like morphology did not answer to stimulation. But it was shown that many transplanted MMSC had changed their morphology but did not respond to stimulation. Because of the absence of transplanted GFP+ MMSC and retina neuron fusion detected by fluorescent DiI staining, it is reasonable to suppose that there is a small MMSC subpopulation that has the ability for neuronal transdifferentiation.

Figure 1. MMSC morphology changes at 7 days after transplantation in retina explants. Cells positive for GFP with bipolar neuromorphology were presented (E-F). Many neurite-like processes were sprouted from MMSC during their migration and differentiation (A-D)

Sergeev__Khramova_Figure1.png


Figure 2.
 AFM analysis injected MMSC surface in full contact and semi contact mode. A, C: Processes connections between transplanted MMSC and retina cells (arrows). B: MMSC surface reconstruction after morphology changes. D: 3D neurite-like processes surface reconstruction with synaptic connections

Sergeev__Khramova_Figure2_.png


NSPC quickly migrated (significantly differs (p<0.05) from the NSPC in undamaged explants) during the first 24 hours for a distance more than 3 mm from the damaged zone in the case when aggregates (1–5 thousands  cells) were transplanted, formed neuritis and connections with the retina cells, and were detected up to 50 days in damaged recipient tissue. Individual transplanted cells were associated with each other and migrated chaotically with glial differentiation. Seven days after transplantation GFP+ cells were observed at different distances (600mkm, 1000mkm, 3000mkm) populating damaged zones at a rate of 90%, 56%, and 27% respectively. NSPC migration and differentiation in cell layers of neuroretina were higher (p<0.05) than for NSPC transplanted to the explant surface. In comparison, PE cells were available for migration and proliferation activity only after photoreceptor surface transplantation. The same data were obtained after NSPC and PE cell in vivo injection in Campbell rat eyes (intravitreal, retrobulbar and suprachoroidal transplantation of 50–100 thousands cells in 2µl).

Conclusions

Therefore the obtained data indicate: an effective in vitro model of explantation culture for detecting cell migration, differentiation and communication processes in recipient tissue directly after transplantation was developed and successfully applied for NSPC and MMSC in vitro transplantation. Using this technique it is possible to observe the reparation time for damaged tissue after SC transplantation; minimal cell-migration time to the damaged area; optimal transplantation time after damage; minimal number of transplanted SC required to start the reparation process; necessity of tissue micro surrounding for SC migration and choosing the best strategy for cell injection. Using this method it is possible to optimize clinical transplantation protocols and make them more effective.

Acknowledgements

This work is a realization of the Federal program for the years 2009–2013 entitled “Scientific and science-pedagogic staff of innovation Russia”.

References

1. Bull ND, Martin KR. Using stem cells to mend the retina in ocular disease. Regen Med. 2009 Nov;4(6):855-64. doi: 10.2217/rme.09.59.

2. Johansson K, Ehinger B. Structural changes in the developing retina maintained in vitro. Vision Res. 2005 Nov;45(25-26):3235-43. doi: 10.1016/j.visres.2005.05.022.

3. Kretz A, Hermening SH, Isenmann S. A novel primary culture technique for adult retina allows for evaluation of CNS axon regeneration in rodents. J Neurosci Methods. 2004 Jul 30;136(2):207-19. doi: 10.1016/j.jneumeth.2004.01.012.

4. Schrepfer S, Deuse T, Lange C, Katzenberg R, Reichenspurner H, Robbins RC, Pelletier MP. Simplified protocol to isolate, purify, and culture expand mesenchymal stem cells. Stem Cells Dev. 2007 Feb;16(1):105-7. doi: 10.1089/scd.2006.0041.

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Introduction

Stem cell (SC) transplantation is very topical in the fields of developmental biology and regenerative surgery. A variety of types of SC obtained from different sources are successfully used for reparation of tissues defects. The functional rehabilitation of damaged retinas in different cases of pathology with SC transplantation is a current theme in ophthalmology [1] and can be used as a model for studying cell engrafting in brain tissue [2]. Currently we have plenty of experience in SC transplantation procedures and a huge number of published works; however it is difficult to predict the effects of such transplantation in vivo due to scarce information about SC behavior in recipient tissue. In vivo studies can’t show us all changes in SC and recipient interactions after transplantation, and it is impossible to obtain enough information about transplanted cells behavior experimentally. However, many questions about the communication of transplanted cells with recipient tissue and the processes of functional contact development and mechanisms of the new microenvironment on transplanted cells still remain open. To answer these questions new adequate model systems with the ability to investigate the destiny of transplanted cells are required. That’s why it is necessary to design ex vivo models that register individual cell behavior after transplantation and clear visualization of these changes [3]. In vitro injection of xenogeny cells into 3D rat retina culture seems to be an attractive method in this case. Additionally, organotyping explant culture damaged by laser emission is used in this work.

Materials and methods

Seven-day-old rats’ retina explant culture (DMEM/F12 with 20 ng/ml FGF and EGF, 7% FCS, В12 and N2 supplements) damaged with laser Zilos-tk (300mW, 1000 mc) was used. Neuronal stem/progenitor cells (NSPC), bone marrow stromal cells (MMSC) [4], and pigment epithelium cells (PE) of С57BL/6-Tg(ACTB-EGFP)/Osb/J GFP+ mice had been transplanted in them (300-300000 cells in 0.2mkl) in vitro. AFM data were obtained from an Atomic force microscope Solver BIO Olympus with the scanning field 100х100х7mkm3. Data analysis was done with the programs Nova (НТ-МDТ) and STATISTICA 8.0. The MMSC reaction to external irritation was estimated by fluorescent dye RH 795 after electro stimulation on an ASL-1 device.

Results

Injected SC stayed alive in culture (negative stain for propidium iodide) for more than 2 months and rapidly migrated (for longer than 3000mkm in distance) from the injection point during only the first 48 hours to the laser-damaged area. Thus injected SC had good live potency, migrated for long distances and morphologically differentiated according to a new microenvironment in all our culture systems, and these culture methods were adequate and easy-to-use 3D model systems for stem cells research.

After MMSC transplantation two populations of small (≈15mkm) rapidly migrating cells and almost motionless big (≈30mkm) cells were notable among injected MMSC. On the third day after injection into intact retinas, MMSC changed their morphology by spreading long branched outgrowths but were still negative for neural and glial cell markers (β-III-tubulin and GFAP). Analogous morphology changes in transplanted MMSC in damaged retinas were observed after 24 hours (Fig. 1). MMSC injection had a noticeable neuroprotective effect on the retina. ASM assay showed significant difference (p<0.01) between glial thickness and endothelial retina cells processes and neurites and neuro-like transplanted MMSC processes. Also it was shown that MMSC form synapses up to 2.5 ±0.06mkm in diameter on the 4th day after transplantation (Fig. 2). After electrostimulation (20V, 0.5Hz, 200ms), clear depolarization of retina neurons and their processes was detected. It was shown that some GFP+ MMSC which had changed their morphology to neuro-like after transplantation into the retina explants were able to depolarize after exogenic stimulation. This means that the MMSC population is highly heterogenic. Those cells that quickly migrated and formed neurit-like processes had an ability to generate a response to stimulation. Big (>30mkm) passive migrating cells that had taken a fibroblast-like morphology did not answer to stimulation. But it was shown that many transplanted MMSC had changed their morphology but did not respond to stimulation. Because of the absence of transplanted GFP+ MMSC and retina neuron fusion detected by fluorescent DiI staining, it is reasonable to suppose that there is a small MMSC subpopulation that has the ability for neuronal transdifferentiation.

Figure 1. MMSC morphology changes at 7 days after transplantation in retina explants. Cells positive for GFP with bipolar neuromorphology were presented (E-F). Many neurite-like processes were sprouted from MMSC during their migration and differentiation (A-D)

Sergeev__Khramova_Figure1.png


Figure 2.
 AFM analysis injected MMSC surface in full contact and semi contact mode. A, C: Processes connections between transplanted MMSC and retina cells (arrows). B: MMSC surface reconstruction after morphology changes. D: 3D neurite-like processes surface reconstruction with synaptic connections

Sergeev__Khramova_Figure2_.png


NSPC quickly migrated (significantly differs (p<0.05) from the NSPC in undamaged explants) during the first 24 hours for a distance more than 3 mm from the damaged zone in the case when aggregates (1–5 thousands  cells) were transplanted, formed neuritis and connections with the retina cells, and were detected up to 50 days in damaged recipient tissue. Individual transplanted cells were associated with each other and migrated chaotically with glial differentiation. Seven days after transplantation GFP+ cells were observed at different distances (600mkm, 1000mkm, 3000mkm) populating damaged zones at a rate of 90%, 56%, and 27% respectively. NSPC migration and differentiation in cell layers of neuroretina were higher (p<0.05) than for NSPC transplanted to the explant surface. In comparison, PE cells were available for migration and proliferation activity only after photoreceptor surface transplantation. The same data were obtained after NSPC and PE cell in vivo injection in Campbell rat eyes (intravitreal, retrobulbar and suprachoroidal transplantation of 50–100 thousands cells in 2µl).

Conclusions

Therefore the obtained data indicate: an effective in vitro model of explantation culture for detecting cell migration, differentiation and communication processes in recipient tissue directly after transplantation was developed and successfully applied for NSPC and MMSC in vitro transplantation. Using this technique it is possible to observe the reparation time for damaged tissue after SC transplantation; minimal cell-migration time to the damaged area; optimal transplantation time after damage; minimal number of transplanted SC required to start the reparation process; necessity of tissue micro surrounding for SC migration and choosing the best strategy for cell injection. Using this method it is possible to optimize clinical transplantation protocols and make them more effective.

Acknowledgements

This work is a realization of the Federal program for the years 2009–2013 entitled “Scientific and science-pedagogic staff of innovation Russia”.

References

1. Bull ND, Martin KR. Using stem cells to mend the retina in ocular disease. Regen Med. 2009 Nov;4(6):855-64. doi: 10.2217/rme.09.59.

2. Johansson K, Ehinger B. Structural changes in the developing retina maintained in vitro. Vision Res. 2005 Nov;45(25-26):3235-43. doi: 10.1016/j.visres.2005.05.022.

3. Kretz A, Hermening SH, Isenmann S. A novel primary culture technique for adult retina allows for evaluation of CNS axon regeneration in rodents. J Neurosci Methods. 2004 Jul 30;136(2):207-19. doi: 10.1016/j.jneumeth.2004.01.012.

4. Schrepfer S, Deuse T, Lange C, Katzenberg R, Reichenspurner H, Robbins RC, Pelletier MP. Simplified protocol to isolate, purify, and culture expand mesenchymal stem cells. Stem Cells Dev. 2007 Feb;16(1):105-7. doi: 10.1089/scd.2006.0041.

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Сергей А. Сергеев, Юлия В. Храмова

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Показана быстрая миграция трансплантированных НСПК и ММСК в эксплантатах сетчатки, поврежденных лазерным излучением (достоверно отличающаяся (p<0,05) от скорости миграции в интактных эксплантатах) в течение 24 часов, формирование ими нейритов и взаимосвязей с клетками сетчатки на протяжении 50 дней сокультивирования. Единичные клетки образовывали ассоциаты и экспрессировали GFAP. Через 7 дней после трансплантации на различных дистанциях (600, 1000, 3000мкм) от зоны повреждения детектировали 90%, 56%, 27% EGFP+ клеток соответственно. Для НСПК миграция была активней при инъекции вглубь слоев сетчатки, для ММСК достоверных отличий в миграции от способа инъекции выявлено не было.

Ключевые слова

стволовые клетки, трансплантация in vitro, органотипические культуры сетчатки 

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Sergey A. Sergeev, Yulia V. Khramova

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Lomonosov MSU, Moscow, Russia

Correspondence
Lomonosov MSU, Moscow, Russia, Leninskie gory 1/12, 119234, Moscow, Russia; Phone: +79035187482
E-mail: embryossa@spam is badgmail.com 

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Transplanted NSPC and MMSC quickly migrated in laser damaged retina explants (significantly differs (p<0.05) from the undamaged explants) during the first 24 hours, formed neuritis and connections with the retina cells, and were detected up to 50 days later in damaged recipient tissue. Individual transplanted cells were associated with each other and migrated chaotically with glial differentiation. Seven days after transplantation EGFP+ cells were observed in different distances (600 mkm, 1000 mkm, 3000 mkm) populating damaged zones in 90%, 56%, and 27% respectively. NSPC migration and differentiation in cell layers of neuroretina were higher (p<0.05) than for NSPC transplanted to the explant's surface, and no significant data was obtained for MMSC.

Keywords

Stem cells, in vitro transplantation, retina explant culture

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Sergeev, Yulia V. Khramova</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(43) "

Sergey A. Sergeev, Yulia V. Khramova

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Sergey A. Sergeev, Yulia V. Khramova

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Transplanted NSPC and MMSC quickly migrated in laser damaged retina explants (significantly differs (p<0.05) from the undamaged explants) during the first 24 hours, formed neuritis and connections with the retina cells, and were detected up to 50 days later in damaged recipient tissue. Individual transplanted cells were associated with each other and migrated chaotically with glial differentiation. Seven days after transplantation EGFP+ cells were observed in different distances (600 mkm, 1000 mkm, 3000 mkm) populating damaged zones in 90%, 56%, and 27% respectively. NSPC migration and differentiation in cell layers of neuroretina were higher (p<0.05) than for NSPC transplanted to the explant's surface, and no significant data was obtained for MMSC.

Keywords

Stem cells, in vitro transplantation, retina explant culture

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Transplanted NSPC and MMSC quickly migrated in laser damaged retina explants (significantly differs (p<0.05) from the undamaged explants) during the first 24 hours, formed neuritis and connections with the retina cells, and were detected up to 50 days later in damaged recipient tissue. Individual transplanted cells were associated with each other and migrated chaotically with glial differentiation. Seven days after transplantation EGFP+ cells were observed in different distances (600 mkm, 1000 mkm, 3000 mkm) populating damaged zones in 90%, 56%, and 27% respectively. NSPC migration and differentiation in cell layers of neuroretina were higher (p<0.05) than for NSPC transplanted to the explant's surface, and no significant data was obtained for MMSC.

Keywords

Stem cells, in vitro transplantation, retina explant culture

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Lomonosov MSU, Moscow, Russia

Correspondence
Lomonosov MSU, Moscow, Russia, Leninskie gory 1/12, 119234, Moscow, Russia; Phone: +79035187482
E-mail: embryossa@spam is badgmail.com 

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Lomonosov MSU, Moscow, Russia

Correspondence
Lomonosov MSU, Moscow, Russia, Leninskie gory 1/12, 119234, Moscow, Russia; Phone: +79035187482
E-mail: embryossa@spam is badgmail.com 

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Сергей А. Сергеев, Юлия В. Храмова

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Сергей А. Сергеев, Юлия В. Храмова

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["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19215" ["VALUE"]=> array(2) { ["TEXT"]=> string(1495) "<p class="bodytext">Показана быстрая миграция трансплантированных НСПК и ММСК в эксплантатах сетчатки, поврежденных лазерным излучением (достоверно отличающаяся (p&lt;0,05) от скорости миграции в интактных эксплантатах) в течение 24 часов, формирование ими нейритов и взаимосвязей с клетками сетчатки на протяжении 50 дней сокультивирования. Единичные клетки образовывали ассоциаты и экспрессировали GFAP. Через 7 дней после трансплантации на различных дистанциях (600, 1000, 3000мкм) от зоны повреждения детектировали 90%, 56%, 27% EGFP+ клеток соответственно. Для НСПК миграция была активней при инъекции вглубь слоев сетчатки, для ММСК достоверных отличий в миграции от способа инъекции выявлено не было. </p> <h3>Ключевые слова</h3> <p>стволовые клетки, трансплантация in vitro, органотипические культуры сетчатки  </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1445) "

Показана быстрая миграция трансплантированных НСПК и ММСК в эксплантатах сетчатки, поврежденных лазерным излучением (достоверно отличающаяся (p<0,05) от скорости миграции в интактных эксплантатах) в течение 24 часов, формирование ими нейритов и взаимосвязей с клетками сетчатки на протяжении 50 дней сокультивирования. Единичные клетки образовывали ассоциаты и экспрессировали GFAP. Через 7 дней после трансплантации на различных дистанциях (600, 1000, 3000мкм) от зоны повреждения детектировали 90%, 56%, 27% EGFP+ клеток соответственно. Для НСПК миграция была активней при инъекции вглубь слоев сетчатки, для ММСК достоверных отличий в миграции от способа инъекции выявлено не было.

Ключевые слова

стволовые клетки, трансплантация in vitro, органотипические культуры сетчатки 

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1445) "

Показана быстрая миграция трансплантированных НСПК и ММСК в эксплантатах сетчатки, поврежденных лазерным излучением (достоверно отличающаяся (p<0,05) от скорости миграции в интактных эксплантатах) в течение 24 часов, формирование ими нейритов и взаимосвязей с клетками сетчатки на протяжении 50 дней сокультивирования. Единичные клетки образовывали ассоциаты и экспрессировали GFAP. Через 7 дней после трансплантации на различных дистанциях (600, 1000, 3000мкм) от зоны повреждения детектировали 90%, 56%, 27% EGFP+ клеток соответственно. Для НСПК миграция была активней при инъекции вглубь слоев сетчатки, для ММСК достоверных отличий в миграции от способа инъекции выявлено не было.

Ключевые слова

стволовые клетки, трансплантация in vitro, органотипические культуры сетчатки 

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Introduction

Hematopoietic stem cell (HSC) transplantation is the best example of cell technology usage in clinical practice. However, the complexity associated with low HSC engraftment, the development of the "graft-versus-host disease" reaction, and infectious complications have not been eliminated so far [24]. The causes and manifestations of immunological disorders are clear in general, but low engraftment etiology remains the subject of lively debates. The subject of the development is progenitor cells, conditioning protocols, and the "destiny" of elements of bone marrow (BM) stroma transplanted along with HSCs, which specifications are necessary for the development of HSC engraftment. Our research group efforts are also focused on solving the problem. Thus this essay is directed toward systemizing the fundamental and current data of HSC engraftment and the causes of its low level in allogeneic transplantation, as well as to discuss world trends in optimization of HSC engraftment using one’s own data.

Current approaches to improve HSC engraftment

Modern solutions aimed at increasing HSC engraftment can be divided into two directions:
     a) techniques directed to the donor’s body and the graft in order to improve the quality and graft "acceptance";     
     b) methods of influence on the recipient’s body to optimize the "acceptance" of the transplanted HSCs.

The first direction is based on current data of possible HSC expansion in vitro [23], cell activation, and on studies of alternative HSC sources (cord blood, in particular) [5]. The fundamentals of the second approach are associated with studies of BM stroma, HSCs niches, and the processes occurring to stroma cellular elements forming a part of the graft into the recipient’s body. There are no comprehensive data of the processes occurring to BM stroma or bone tissue as an element of cell niches under the influence of conditioning protocols, and there is no generalized concept of the "destiny" of transplanted cellular elements of BM stroma. At the same time the necessity for such data is enormous, as it, on the one hand, helps to develop the most effective methods of HSC engraftment, and on the other hand helps to develop the technology of pathology correction of connective tissues (myelofibrosis, osteogenesis imperfecta, etc).

The concept of HSC niches is the best implementation of theoretical data on BM stroma and its role in providing hematopoiesis, and it serves for better understanding and practical application as well.

HSC niches: fundamental provisions and new vision

Generally, a cell niche is an elementary functional unit of the microenvironment. However, there is no unified, generally accepted definition of the "cell niche". The first part of the hypothetical definition, reflecting niche structure (the set of spatially organized cell elements and components of intercellular matrix) is not contested, although the functional aspect is debatable. Some authors believe that a cell niche maintains a stem cell in undifferentiated quiescent state [3]. The majority take a different view, giving a cell niche a greater role: not only the maintenance of "cellular homeostasis", but also the regulation and provision of morpho-functional activity [16].

Nowadays, scientists distinguish two types of HSCs niches: vascular (endothelial) and endosteal (osteoblastic) [22]. To my mind, this differentiation is rather conditional, since the osteoblastic line cells, forming the niches of the same name and requiring active oxygenation, are situated close to the microvasculature (the critical distance is 200–250 mkm [11]). Consequently, sinusoidal endothelial cells (EC) must be an integral component of the so-called osteoblastic niches. The main cellular elements of BM niches are osteoblasts, EC and multipotent mesenchymal stromal cells (MMSCs) [16]. Implementation of the activity of cells which form cell niches is carried out in two principal directions.

     A. Direct impact due to intercellular contacts and products of specific biologically active substances (SDF-1, SCF, TPO, interleukins, etc) [17]. Thus, spindle-shaped osteoblasts by means of tight adhesive contacts with N-cadherin/β-catenin system interact with HSCs, maintaining them in a "quiescent" state [3, 10];     

     B. Indirect impact: paracrine incentives transfer (erythropoietin, SDF-1, parathyroid hormone, etc.) from other components of the uniform functional system of hematopoiesis: kidneys, liver, spleen, endocrine glands, autonomic nervous system [25, 26].

However, the results of studies in recent years significantly extend the notion of HSC niches, particularly, HSCs that are found in adipose tissue [13], spleen [15], and placenta [12], given the description of HSC migration to extramedullary tissues, for instance, in polytrauma [1]. Taken together, the results of HSCs' persistence in extramedullary tissues indicate the presence of their niches outside the BM. In this respect, the fundamental classic works of the Russian histology school become critical again. According to the theory of "mesenchymal reserve" by A. Maximow, there are progenitor cells for the connective tissues in definitive tissues, marked by him as "stem mesenchymal cells" [19]. Later, the theory was supported by A. Zavarzin [2] and N. Khlopin [4] and has now been proven with contemporary data [6]. The presence of poorly differentiated cells (perivasculоcytes) going along with blood vessels conforming by their differentiating MMSC potency is now proven and indisputable.

Thus, there is at least a vascular HSC niche in extramedullary tissues. In light of fundamental notions and current data, the adjustment of concepts of HSC niches seems to be logical. To my mind, it is correct to speak about a uniform cell niche consisting of two components (Table 1).

Table 1. Components of HSC niches

Signs of comparison

Nonspecific component

Specific component

Cells

EC and MMSCs

Resident cells of the definitive tissues (osteoblasts of bone marrow, fibroblasts of fibrous connective tissue, etc.)

Function

 Provision of migration, transduction of regulatory incentives and regulation of non-specific functions

Provision of a specific function*

*Osteoblasts play the defining role in the regulation of hematopoietic HSC function. It is proved that osteoblasts induce proliferation and differentiation of HSCs in a greater degree than MMSCs [20]. In extramedullary tissues the specific component of cell niches incentivizes HSC homing and the implementation of other specific effects, such as participation in reparative regeneration [1].

Cell Ther Transplant2011;3:e.000095.01. doi:10.3205/ctt-2011-en-000095-table1


Such a systematic generalized concept of HSCs niche is easier and more practical.

The possibilities to restore cell niches

The practical significance of the concept of HSCs niche is in clearer comprehension of the functioning of BM stroma and the possibility of a selective approach to its restoration after conditioning. However, it is necessary to solve two problem issues to perform it in practice.
     1. What components of cell niches are damaged with different conditioning protocols, and to what degree?
     2. What way can a damaged component of a cell niche be restored?

Currently there are not enough data to give an exhaustive answer to the questions. It is established that in total irradiation the specific component of BM niches is not really damaged, thus providing a moderate level of HSC engraftment [10]. Irradiation causes marked damage to a nonspecific component: sinusoidal ES are damaged [14], and MMSCs obtain functional defects [21]. Apparently, a similar situation is typical of extramedullary HSCs niches. The influence of chemotherapy on BM niches is less studied due to the great variety of protocols. In general chemotherapy does less damage to the nonspecific component of niches [14].

However, taking into consideration the paucity of data on the damaging effect of conditioning regimens, therapeutic conditions which are aimed at restoring the two components of the niches are clear.

Our research group managed to figure out the processes to a certain extent, concerning the transplanted cellular elements of BM stroma. It has been shown with an experimental model of osteogenesis that the restoration of wholeness of mice shin bones irradiated at a dose of 7–7.5 Gy is mainly carried out due to the transplanted transgenic (GFP+) cells of allogeneic BM (Fig. 1). Moreover, even under physiological conditions the inserted components of allogeneic BM stroma planted the patches of typical location of the dispersed cambium of skeletal tissues (periosteum, endosteum, BM stroma, perivascular niches). Up to 30% of osteocytes of bone tissue were of donor origin (Fig. 2) [7]. These data are consistent with the results of other research groups and prove the possibility of the planting of recipient tissues transplanted with HSC elements of allogeneic BM stroma, as well as confirm their involvement in the implementation of reparative processes in skeletal tissues [9]. Consequently, the use of components of BM stroma (MMSCs, endothelial progenitor cells) is potentially practiced for regeneration of BM HSC niches, as well as for treatment of patients with the pathology of skeletal tissue stroma. However, the number of necessary stroma components in the whole BM is not enough (2–5×103 MMSCs/kg), and consequently only 7% of transplanted MMSCs remain for long in the stroma of a recipient’s BM [21]. At the same time the expansion of MMSCs in vitro up to the concentration in the graft (20–30×106 MMSCs per 1 kg of a recipient’s weight) significantly increases the level of stroma planting of the recipient’s BM, which are maintained over time [8]. Moreover, there are published data on the improvement of HSCs' engraftment during their co-transplantation with so-called "stromal cells of umbilical cord blood" [18].

Figure 1. Shin bone tissues of the recipient mouse: A: spongy bone tissue (1: GFP-positive cells of bone marrow and stroma, 2: endosteum with GFP-positive osteoblast, 3: bony trabeculae), magnification ×100. B: trabecula of bone and cartilage regenerate, consisting of GFP-positive cells; magnification ×400. C: isogenous group of GFP-positive chondrocytes in the bone and cartilage regenerate; magnification ×800. Confocal microscopy. Color: propidium iodide

Bozo_Figure1.png


Figure 2.
 Osteocyte in the reticular fibrous bone tissue of the regenerate, having donor origin: А: a cell nucleus, propidium iodide stained, B: cytoplasm autofluorescence; C: combined image. Magnification ×800. Confocal microscopy 

Bozo_Figure2.png


Thus, the fortification of the whole BM graft or a purified HSCs fraction with stromal cellular components in concentrations exceeding physiologic congestion is potentially effective. Furthermore, considering the important role of EC as the components of HSCs niches, transplantation of their progenitor cells in high concentrations seems to be promising, especially in combination with factors stimulating angiogenesis (for instance, medicines on the basis of VEGF). In any case, the actual clinical application of the methods requires further clinical trials.

Acknowledgements

The author wishes to thank Roman V. Deev (OJSC "Human Stem Cells Institute", Moscow, Russia), and Natalia V. Tsupkina (Institute of Cytology RAS, St. Petersburg, Russia), for qualified direction and assistance in scientific research.

References

1. Александров ВН, Сергеев ВС. Влияние тяжелой политравмы на миграцию стволовых кроветворных клеток у мышей. Клеточная трансплантология и тканевая инженерия. 2006;2(4):59-62.

2. Заварзин АА. Курс гистологической и микроскопической анатомии. Л.: Гос. из-во мед. лит-ры. 1938. 634 c.

3. Пинаев ГП. Ниши стволовых клеток (понятие «тканевой ниши» и значение белков внеклеточного матрикса для регулирования функций стволовых клеток). Материалы школы-конференции для молодых ученых «Клеточные технологии для регенеративной медицины». СПб. 17-21 окт. 2011.

4. Хлопин НГ. Общебиологические и экспериментальные основы гистологию Л.: Из-во АН СССР. 492 с.

5. Chou S, Chu P, Hwang W, Lodish H. Expansion of human cord blood hematopoietic stem cells for transplantation. Cell Stem Cell. 2010 Oct 8;7(4):427-8. doi: 10.1016/j.stem.2010.09.001.

6. Crisan M, Yap S, Casteilla L, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008 Sep 11;3(3):301-13. doi: 10.1016/j.stem.2008.07.003.

7. Deev RV, Tsupkina NV, Serikov VB, Gololobov VG, Pinaev GP. Participation of transfused bone marrow cells in reparative osteohistogenesis. Tsitologiia. 2005;47(9):755-759. In Russian.

8. Devine SM, Bartholomew AM, et al. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp Hematol. 2001 Feb;29(2):244-55.

9. Dominici M, Pritchard C, Garlits JE, Hofmann TJ, Persons DA, Horwitz EM. Hematopoietic cells and osteoblasts are derived from a common marrow progenitor after bone marrow transplantation. Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11761-6. doi: 10.1073/pnas.0404626101.

10. Dominici M, Rasini V, et al. Restoration and reversible expansion of the osteoblastic hematopoietic stem cell niche after marrow radioablation. Blood. 2009 Sep 10;114(11):2333-43. doi: 10.1182/blood-2008-10-183459.

11. Folkman J, Hochberg M. Self-regulation of growth in three dimensions. J Exp Med. 1973 Oct 1;138(4):745-53.

12. Gekas C, Dieterlen-Lièvre F, Orkin SH, Mikkola HK. The placenta is a niche for hematopoietic stem cells. Dev Cell. 2005 Mar;8(3):365-75. doi: 10.1016/j.devcel.2004.12.016.

13. Han J, Koh YJ, Moon HR, Ryoo HG, Cho CH, Kim I, Koh GY. Adipose tissue is an extramedullary reservoir for functional hematopoietic stem and progenitor cells. Blood. 2010 Feb 4;115(5):957-64. doi: 10.1182/blood-2009-05-219923.

14. Hooper AT, Butler JM, et al. Engraftment and Reconstitution of Hematopoiesis Is Dependent on VEGFR2-Mediated Regeneration of Sinusoidal Endothelial Cells. Cell Stem Cell. 2009 Mar 6;4(3):263-74. doi: 10.1016/j.stem.2009.01.006.

15. Iseki A, Morita Y, Nakauchi H, et al. Hematopoietic Stem Cells in the Mouse Spleen. Blood (ASH Annual Meeting Abstracts). 2008:112.

16. Isern J, Méndez-Ferrer S. Stem cell interactions in a bone marrow niche. Curr Osteoporos Rep. 2011 Dec;9(4):210-8.

17. Li T, Wu Y. Paracrine molecules of mesenchymal stem cells for hematopoietic stem cell niche. Bone Marrow Res. 2011;2011:353878. doi:  10.1155/2011/353878.

18. Liu Y, Yi L, Zhang X, Gao L, Zhang C, Feng YM, Chen XH. Cotransplantation of human umbilical cord blood-derived stromal cells enhances hematopoietic reconstitution and engraftment in irradiated BABL/c mice. Cancer Biol Ther. 2011 Jan 1;11(1):84-94.

19. Brodersen J, Maximow A, Schaffer J. Handbuch der mikroskopischen Anatomie des Menschen. Bd. 2., Die Gewebe; T. 1., Epithel- u. Drüsengewebe, Bindegewebe und blutbildende Gewebe, Blut. Berlin: Springer, 1927.

20. Mishima S, Nagai A, Abdullah S, Matsuda C, Taketani T, Kumakura S, Shibata H, Ishikura H, Kim SU, Masuda J. Effective ex vivo expansion of hematopoietic stem cells using osteoblast-differentiated mesenchymal stem cells is CXCL12 dependent. Eur J Haematol. 2010 Jun;84(6):538-46. doi: 10.1111/j.1600-0609.2010.01419.x.

21. Morikawa S, Mabuchi Y, et al. Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J Exp Med. 2009 Oct 26;206(11):2483-96. doi: 10.1084/jem.20091046.

22. Morrison SJ, Spradling AC. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell. 2008 Feb 22;132(4):598-611. doi: 10.1016/j.cell.2008.01.038.

23. Nishino T, Wang C, Mochizuki-Kashio M, Osawa M, Nakauchi H, Iwama A. Ex vivo expansion of human hematopoietic stem cells by garcinol, a potent inhibitor of histone acetyltransferase. PLoS One. 2011;6(9):e24298.

24. Rafeah NT, Fadilah SA. The A-B-C of haematopoietic stem cell transplantation. Med J Malaysia. 2009 Mar;64(1):94-100.

25. Rashidi N, Adams GB. The influence of parathyroid hormone on the adult hematopoietic stem cell niche. Curr Osteoporos Rep. 2009 Jul;7(2):53-7.

26. Visigalli I, Biffi A. Maintenance of a functional hematopoietic stem cell niche through galactocerebrosidase and other enzymes. Curr Opin Hematol. 2011 Jul;18(4):214-9.


" ["~DETAIL_TEXT"]=> string(22701) "

Introduction

Hematopoietic stem cell (HSC) transplantation is the best example of cell technology usage in clinical practice. However, the complexity associated with low HSC engraftment, the development of the "graft-versus-host disease" reaction, and infectious complications have not been eliminated so far [24]. The causes and manifestations of immunological disorders are clear in general, but low engraftment etiology remains the subject of lively debates. The subject of the development is progenitor cells, conditioning protocols, and the "destiny" of elements of bone marrow (BM) stroma transplanted along with HSCs, which specifications are necessary for the development of HSC engraftment. Our research group efforts are also focused on solving the problem. Thus this essay is directed toward systemizing the fundamental and current data of HSC engraftment and the causes of its low level in allogeneic transplantation, as well as to discuss world trends in optimization of HSC engraftment using one’s own data.

Current approaches to improve HSC engraftment

Modern solutions aimed at increasing HSC engraftment can be divided into two directions:
     a) techniques directed to the donor’s body and the graft in order to improve the quality and graft "acceptance";     
     b) methods of influence on the recipient’s body to optimize the "acceptance" of the transplanted HSCs.

The first direction is based on current data of possible HSC expansion in vitro [23], cell activation, and on studies of alternative HSC sources (cord blood, in particular) [5]. The fundamentals of the second approach are associated with studies of BM stroma, HSCs niches, and the processes occurring to stroma cellular elements forming a part of the graft into the recipient’s body. There are no comprehensive data of the processes occurring to BM stroma or bone tissue as an element of cell niches under the influence of conditioning protocols, and there is no generalized concept of the "destiny" of transplanted cellular elements of BM stroma. At the same time the necessity for such data is enormous, as it, on the one hand, helps to develop the most effective methods of HSC engraftment, and on the other hand helps to develop the technology of pathology correction of connective tissues (myelofibrosis, osteogenesis imperfecta, etc).

The concept of HSC niches is the best implementation of theoretical data on BM stroma and its role in providing hematopoiesis, and it serves for better understanding and practical application as well.

HSC niches: fundamental provisions and new vision

Generally, a cell niche is an elementary functional unit of the microenvironment. However, there is no unified, generally accepted definition of the "cell niche". The first part of the hypothetical definition, reflecting niche structure (the set of spatially organized cell elements and components of intercellular matrix) is not contested, although the functional aspect is debatable. Some authors believe that a cell niche maintains a stem cell in undifferentiated quiescent state [3]. The majority take a different view, giving a cell niche a greater role: not only the maintenance of "cellular homeostasis", but also the regulation and provision of morpho-functional activity [16].

Nowadays, scientists distinguish two types of HSCs niches: vascular (endothelial) and endosteal (osteoblastic) [22]. To my mind, this differentiation is rather conditional, since the osteoblastic line cells, forming the niches of the same name and requiring active oxygenation, are situated close to the microvasculature (the critical distance is 200–250 mkm [11]). Consequently, sinusoidal endothelial cells (EC) must be an integral component of the so-called osteoblastic niches. The main cellular elements of BM niches are osteoblasts, EC and multipotent mesenchymal stromal cells (MMSCs) [16]. Implementation of the activity of cells which form cell niches is carried out in two principal directions.

     A. Direct impact due to intercellular contacts and products of specific biologically active substances (SDF-1, SCF, TPO, interleukins, etc) [17]. Thus, spindle-shaped osteoblasts by means of tight adhesive contacts with N-cadherin/β-catenin system interact with HSCs, maintaining them in a "quiescent" state [3, 10];     

     B. Indirect impact: paracrine incentives transfer (erythropoietin, SDF-1, parathyroid hormone, etc.) from other components of the uniform functional system of hematopoiesis: kidneys, liver, spleen, endocrine glands, autonomic nervous system [25, 26].

However, the results of studies in recent years significantly extend the notion of HSC niches, particularly, HSCs that are found in adipose tissue [13], spleen [15], and placenta [12], given the description of HSC migration to extramedullary tissues, for instance, in polytrauma [1]. Taken together, the results of HSCs' persistence in extramedullary tissues indicate the presence of their niches outside the BM. In this respect, the fundamental classic works of the Russian histology school become critical again. According to the theory of "mesenchymal reserve" by A. Maximow, there are progenitor cells for the connective tissues in definitive tissues, marked by him as "stem mesenchymal cells" [19]. Later, the theory was supported by A. Zavarzin [2] and N. Khlopin [4] and has now been proven with contemporary data [6]. The presence of poorly differentiated cells (perivasculоcytes) going along with blood vessels conforming by their differentiating MMSC potency is now proven and indisputable.

Thus, there is at least a vascular HSC niche in extramedullary tissues. In light of fundamental notions and current data, the adjustment of concepts of HSC niches seems to be logical. To my mind, it is correct to speak about a uniform cell niche consisting of two components (Table 1).

Table 1. Components of HSC niches

Signs of comparison

Nonspecific component

Specific component

Cells

EC and MMSCs

Resident cells of the definitive tissues (osteoblasts of bone marrow, fibroblasts of fibrous connective tissue, etc.)

Function

 Provision of migration, transduction of regulatory incentives and regulation of non-specific functions

Provision of a specific function*

*Osteoblasts play the defining role in the regulation of hematopoietic HSC function. It is proved that osteoblasts induce proliferation and differentiation of HSCs in a greater degree than MMSCs [20]. In extramedullary tissues the specific component of cell niches incentivizes HSC homing and the implementation of other specific effects, such as participation in reparative regeneration [1].

Cell Ther Transplant2011;3:e.000095.01. doi:10.3205/ctt-2011-en-000095-table1


Such a systematic generalized concept of HSCs niche is easier and more practical.

The possibilities to restore cell niches

The practical significance of the concept of HSCs niche is in clearer comprehension of the functioning of BM stroma and the possibility of a selective approach to its restoration after conditioning. However, it is necessary to solve two problem issues to perform it in practice.
     1. What components of cell niches are damaged with different conditioning protocols, and to what degree?
     2. What way can a damaged component of a cell niche be restored?

Currently there are not enough data to give an exhaustive answer to the questions. It is established that in total irradiation the specific component of BM niches is not really damaged, thus providing a moderate level of HSC engraftment [10]. Irradiation causes marked damage to a nonspecific component: sinusoidal ES are damaged [14], and MMSCs obtain functional defects [21]. Apparently, a similar situation is typical of extramedullary HSCs niches. The influence of chemotherapy on BM niches is less studied due to the great variety of protocols. In general chemotherapy does less damage to the nonspecific component of niches [14].

However, taking into consideration the paucity of data on the damaging effect of conditioning regimens, therapeutic conditions which are aimed at restoring the two components of the niches are clear.

Our research group managed to figure out the processes to a certain extent, concerning the transplanted cellular elements of BM stroma. It has been shown with an experimental model of osteogenesis that the restoration of wholeness of mice shin bones irradiated at a dose of 7–7.5 Gy is mainly carried out due to the transplanted transgenic (GFP+) cells of allogeneic BM (Fig. 1). Moreover, even under physiological conditions the inserted components of allogeneic BM stroma planted the patches of typical location of the dispersed cambium of skeletal tissues (periosteum, endosteum, BM stroma, perivascular niches). Up to 30% of osteocytes of bone tissue were of donor origin (Fig. 2) [7]. These data are consistent with the results of other research groups and prove the possibility of the planting of recipient tissues transplanted with HSC elements of allogeneic BM stroma, as well as confirm their involvement in the implementation of reparative processes in skeletal tissues [9]. Consequently, the use of components of BM stroma (MMSCs, endothelial progenitor cells) is potentially practiced for regeneration of BM HSC niches, as well as for treatment of patients with the pathology of skeletal tissue stroma. However, the number of necessary stroma components in the whole BM is not enough (2–5×103 MMSCs/kg), and consequently only 7% of transplanted MMSCs remain for long in the stroma of a recipient’s BM [21]. At the same time the expansion of MMSCs in vitro up to the concentration in the graft (20–30×106 MMSCs per 1 kg of a recipient’s weight) significantly increases the level of stroma planting of the recipient’s BM, which are maintained over time [8]. Moreover, there are published data on the improvement of HSCs' engraftment during their co-transplantation with so-called "stromal cells of umbilical cord blood" [18].

Figure 1. Shin bone tissues of the recipient mouse: A: spongy bone tissue (1: GFP-positive cells of bone marrow and stroma, 2: endosteum with GFP-positive osteoblast, 3: bony trabeculae), magnification ×100. B: trabecula of bone and cartilage regenerate, consisting of GFP-positive cells; magnification ×400. C: isogenous group of GFP-positive chondrocytes in the bone and cartilage regenerate; magnification ×800. Confocal microscopy. Color: propidium iodide

Bozo_Figure1.png


Figure 2.
 Osteocyte in the reticular fibrous bone tissue of the regenerate, having donor origin: А: a cell nucleus, propidium iodide stained, B: cytoplasm autofluorescence; C: combined image. Magnification ×800. Confocal microscopy 

Bozo_Figure2.png


Thus, the fortification of the whole BM graft or a purified HSCs fraction with stromal cellular components in concentrations exceeding physiologic congestion is potentially effective. Furthermore, considering the important role of EC as the components of HSCs niches, transplantation of their progenitor cells in high concentrations seems to be promising, especially in combination with factors stimulating angiogenesis (for instance, medicines on the basis of VEGF). In any case, the actual clinical application of the methods requires further clinical trials.

Acknowledgements

The author wishes to thank Roman V. Deev (OJSC "Human Stem Cells Institute", Moscow, Russia), and Natalia V. Tsupkina (Institute of Cytology RAS, St. Petersburg, Russia), for qualified direction and assistance in scientific research.

References

1. Александров ВН, Сергеев ВС. Влияние тяжелой политравмы на миграцию стволовых кроветворных клеток у мышей. Клеточная трансплантология и тканевая инженерия. 2006;2(4):59-62.

2. Заварзин АА. Курс гистологической и микроскопической анатомии. Л.: Гос. из-во мед. лит-ры. 1938. 634 c.

3. Пинаев ГП. Ниши стволовых клеток (понятие «тканевой ниши» и значение белков внеклеточного матрикса для регулирования функций стволовых клеток). Материалы школы-конференции для молодых ученых «Клеточные технологии для регенеративной медицины». СПб. 17-21 окт. 2011.

4. Хлопин НГ. Общебиологические и экспериментальные основы гистологию Л.: Из-во АН СССР. 492 с.

5. Chou S, Chu P, Hwang W, Lodish H. Expansion of human cord blood hematopoietic stem cells for transplantation. Cell Stem Cell. 2010 Oct 8;7(4):427-8. doi: 10.1016/j.stem.2010.09.001.

6. Crisan M, Yap S, Casteilla L, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008 Sep 11;3(3):301-13. doi: 10.1016/j.stem.2008.07.003.

7. Deev RV, Tsupkina NV, Serikov VB, Gololobov VG, Pinaev GP. Participation of transfused bone marrow cells in reparative osteohistogenesis. Tsitologiia. 2005;47(9):755-759. In Russian.

8. Devine SM, Bartholomew AM, et al. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp Hematol. 2001 Feb;29(2):244-55.

9. Dominici M, Pritchard C, Garlits JE, Hofmann TJ, Persons DA, Horwitz EM. Hematopoietic cells and osteoblasts are derived from a common marrow progenitor after bone marrow transplantation. Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11761-6. doi: 10.1073/pnas.0404626101.

10. Dominici M, Rasini V, et al. Restoration and reversible expansion of the osteoblastic hematopoietic stem cell niche after marrow radioablation. Blood. 2009 Sep 10;114(11):2333-43. doi: 10.1182/blood-2008-10-183459.

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Илья Я. Бозо

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Bozo</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(20) "

Ilya Ya. Bozo

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Moscow Dental University, OJSC "Human Stem Cells Institute", Moscow, Russia

Correspondence
Ilya Ya. Bozo, Moscow Dental University, OJSC "Human Stem Cells Institute", 3/2 Gubkina str., 119991, Moscow, Russia; Phone: +7965147-12-77, Fax: +7495646-80-76
E-mail: bozo.ilya@spam is badgmail.com 

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The essay presents the problematic aspects of hematopoietic stem cell transplantation, from the position of fundamental notions about cell niches and contemporary data on the bone marrow stroma of recipient and donor, taking into account the results of one’s own research.

Keywords

hematopoietic stem cells (HSCs) transplantation, cell niches, bone marrow stroma

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В эссе представлены проблемные аспекты трансплантации гемопоэтических стволовых клеток, возможности увеличения энграфмента с позиции фундаментальных представлений о клеточных нишах и современных данных о строме костного мозга реципиента и донора с учетом результатов собственных исследований. 

Ключевые слова

трансплантация гемопоэтических стволовых клеток, клеточные ниши, строма костного мозга

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Ilya Ya. Bozo

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Ilya Ya. Bozo

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The essay presents the problematic aspects of hematopoietic stem cell transplantation, from the position of fundamental notions about cell niches and contemporary data on the bone marrow stroma of recipient and donor, taking into account the results of one’s own research.

Keywords

hematopoietic stem cells (HSCs) transplantation, cell niches, bone marrow stroma

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The essay presents the problematic aspects of hematopoietic stem cell transplantation, from the position of fundamental notions about cell niches and contemporary data on the bone marrow stroma of recipient and donor, taking into account the results of one’s own research.

Keywords

hematopoietic stem cells (HSCs) transplantation, cell niches, bone marrow stroma

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Moscow Dental University, OJSC "Human Stem Cells Institute", Moscow, Russia

Correspondence
Ilya Ya. Bozo, Moscow Dental University, OJSC "Human Stem Cells Institute", 3/2 Gubkina str., 119991, Moscow, Russia; Phone: +7965147-12-77, Fax: +7495646-80-76
E-mail: bozo.ilya@spam is badgmail.com 

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Moscow Dental University, OJSC "Human Stem Cells Institute", Moscow, Russia

Correspondence
Ilya Ya. Bozo, Moscow Dental University, OJSC "Human Stem Cells Institute", 3/2 Gubkina str., 119991, Moscow, Russia; Phone: +7965147-12-77, Fax: +7495646-80-76
E-mail: bozo.ilya@spam is badgmail.com 

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Илья Я. Бозо

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Илья Я. Бозо

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исследований.  </p> <h3>Ключевые слова</h3> <p>трансплантация гемопоэтических стволовых клеток, клеточные ниши, строма костного мозга </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(792) "

В эссе представлены проблемные аспекты трансплантации гемопоэтических стволовых клеток, возможности увеличения энграфмента с позиции фундаментальных представлений о клеточных нишах и современных данных о строме костного мозга реципиента и донора с учетом результатов собственных исследований. 

Ключевые слова

трансплантация гемопоэтических стволовых клеток, клеточные ниши, строма костного мозга

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В эссе представлены проблемные аспекты трансплантации гемопоэтических стволовых клеток, возможности увеличения энграфмента с позиции фундаментальных представлений о клеточных нишах и современных данных о строме костного мозга реципиента и донора с учетом результатов собственных исследований. 

Ключевые слова

трансплантация гемопоэтических стволовых клеток, клеточные ниши, строма костного мозга

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Introduction

Acute myeloid leukemia (AML) is a disease of malignant hematopoietic cells, which initially affect bone marrow with further suppression of its normal counterparts and infiltrate solid organs and tissues. The aims of AML patients’ treatment are the elimination of malignant cells for the further achievement of remission (complete, morphological or molecular) and the recovery of patient's bone marrow hematopoiesis. The best expected result of such treatment is the achievement of complete remission, i.e., molecular complete remission as the result of eradication of AML symptoms. The possibility of AML relapse depends upon the quality of the remission [6]. Herein, the measurement of minimal residual disease (MRD) is required for (i) the stratification of a patient’s risk and (ii) monitoring the efficiency of treatment [13].

Modern treatment regimens allow the achievement of complete morphological remission for most patients. Unfortunately, the minimal quantity of initial leukemic cells (less than 5% of nucleated cells of the bone marrow) are able to develop the relapse of AML and the further fatal outcome. 

In the primary diagnosis of AML, the quantity of leukemic cells reaches up to 1010–1012 cells. After the first course of induction therapy the number of malignant cells is reduced almost 3 times, however there are millions of leukemic cells still alive. Herein the minimal residual disease is a small population of leukemic cells, which can be detected in the bone marrow provided that there are normal peripheral blood characteristics and not any extramedullar lesion focuses in patients. Thereby the MRD of AML is a persistent number of leukemic cells in bone marrow during complete remission. 

Flow cytometry versus Polymerase Chain Reaction

There are two fundamental methods for the submorphological evaluation of MRD with a high sensitivity in clinical diagnostics – Polymerase Chain Reaction (PCR) and Flow Cytometry (FC). Both the PCR and FC were invented in 1980s and these methods are the gold standard of up-to-date routine diagnostics. Flow cytometry is based on the aberrant immunophenotype surface and/or intracellular characteristics of leukemic cells, whereas PCR is based on molecular or genetic aberrations of malignant cells such as (i) gene mutations, (ii) the over-expression of mRNA, (iii) fusion transcripts and so on. 

The PCR method is considered to be a highly specific tool with the sensitivity of one leukemic cell in 104–106 of nucleated bone marrow cells, provided that the necessary technical processes are followed [8]. The main disadvantage is a limitation in using PCR in a number of patients who do not have specific genetic aberrations. According to a number of authors, half of all patients do not have molecular – specific aberrations, so this method is difficult to use for monitoring the level of MRD in such cases [11].

Multicolor flow cytometry permits the detection of one leukemic cell in 103–104 of normal nucleated bone marrow cells. The main benefit of this method is that it  can be used for virtually all patients with AML (up to 95% of patients) for the monitoring of MRD in the dynamics of treatment [5], except in cases of promyelocytic leukemia where WHO strongly recommend using PCR to detect PML-RARa transcript or t(15;17).

MRD is difficult to evaluate because the development of myeloid cells occurs entirely in the bone marrow; therefore evaluation should be based on the detection of immunophenotypic characteristics, which will differ between normal and malignant bone marrow cells [12, 15]. Unfortunately, leukemia cells do not express any specific antigens that clearly distinguish them from healthy regenerating bone marrow cells. However, some authors report that malignant cells have a fixed aberrant expression of myeloid inhibitory c-type lectin (hMICL) and CD123 and this could be used as the immunophenotypic marker for an assessment of MRD [14].

Leukemia-associated immunophenotype of AML

There are some recommendations for the initial diagnosis of AML [4]. In the primary diagnosis of immunophenotype leukemic cells, the application of combination multicolor monoclonal antibodies can be used later in the detection of aberrations in MRD [17, 16]. The leukemia-associated immunophenotype (LAIP) of the malignant cells is detected individually for a patient. The aberration detection of surface immunophenotype can be performed as (i) an asynchronous expression in one or more antigens, (ii) a cross-lineage expression in one or more antigens, (ii) a lack of expression in one or more antigens, and (iv) an over-expression in one or more markers. The precise evaluation of MRD in patients with AML with multicolor FC depends upon many different factors including the strategy of gating (using the CD45/SS or FS/SS gating strategies) [9], a broad panel of monoclonal antibodies, instrument settings (a compensation), and the operator’s qualification (Fig. 1, Fig. 2).

Some complications arise at the diagnosis of AML during the detection of LAIP. AML in comparison with ALL is rather heterogeneous disease, and very often it produces two or more subpopulations. Some authors very actively propose using a special strategy for the measurement of LAIP. On the other hand, there are some questions such as whether we should evaluate the subpopulation of “leukemic stem” cells CD34+CD38- at diagnosis even if it appears at very low frequency (for instance, in the case of promyelocytic leukemia) and should we take into account the changes of granularity according to SS parameter in CD45/SS gating strategy at the diagnosis and during the follow-up of patients. 

Another issue is stability of the LAIPs during treatment and at the relapse of AML. This question merits additional discussion. Briefly, in concordance with a number of authors the best way to reveal alterations in LAIPs is to use a broad panel of monoclonal antibody at the primary diagnosis of AML. It increases the probability of detecting LAIPs during follow-up.

Figure 1. Detection of a LAIP at the diagnosis of AML using multicolor flow cytometry and CD45-SS gating strategies – CD45dimCD4+CD13+CD33+CD34+CD38+CD117+ with the co-expression of CD7 and CD64. The type of aberrant expression is asynchronous expression of CD4 and co-expression CD64 with early myeloid antigens

Slobodnuk_fig1.png

Slobodnuk_fig2.png

Slobodnuk_fig3.png

Slobodnuk_fig4.png

Figure 2. After induction chemotherapy and leukocyte recovery, persistent cells with LAIP are detectable at a very low frequency

Slobodnuk_fig5.png

Slobodnuk_fig6.png

Slobodnuk_fig7.png

Conclusion

There are different options to detect MRD for patients with AML. In patients with detectable molecular markers, both PCR and multicolor FC might be used for receiving more sensitive and specific information about MRD. The leukemic cells are detectable by FC with sensitivity lower than molecular aberrations by PCR, however some patients do not have such mutations. One of the main problems is standardizing procedures in diagnostic AML by both PCR and FC. There is no official protocol with comparisons between PCR and FC during a follow-up patient with AML.

The identification of LAIPs in patients with AML depends upon  (i) how broad the panel of reagents is used at diagnosis and during an evaluation of MRD, (ii) how appropriate settings are used in flow cytometer (compensation, laser stability, voltage) and (iii) the operator’s qualifications [1].

The search for new markers to distinguish normal from malignant cells after chemotherapy in bone marrow by multicolor FC is a future direction of development in clinical laboratory diagnostics, and the possibility to identify new target treatment with AML patients [7].

Acknowledgements

The author wish to thank Yekaterina Ye. Zueva (Center for laboratory diagnostics, Pavlov Medical University of St. Petersburg, Russia) for providing the supervision.

References

1. Al-Mawali A, Gillis D, Lewis I. The role of multiparameter flow cytometry for detection of minimal residual disease in acute myeloid leukemia. Am J Clin Pathol. 2009 Jan;131(1):16-26. doi: 10.1309/AJCP5TSD3DZXFLCX.

2. Arnoulet C, Béné MC, Durrieu F, Feuillard J, Fossat C, Husson B, Jouault H, Maynadié M, Lacombe F. Four- and five-color flow cytometry analysis of leukocyte differentiation pathways in normal bone marrow: a reference document based on a systematic approach by the GTLLF and GEIL. Cytometry B Clin Cytom. 2010 Jan;78(1):4-10. doi: 10.1002/cyto.b.20484.

3. Bacher U, Haferlach T, Fehse B, Schnittger S, Kröger N. Minimal residual disease diagnostics and chimerism in the post-transplant period in acute myeloid leukemia. ScientificWorldJournal. 2011 Feb 3;11:310-9. doi: 10.1100/tsw.2011.16.

4. Campana D. Progress of minimal residual disease studies in childhood acute leukemia. Curr Hematol Malig Rep. 2010 Jul;5(3):169-7. doi: 10.1007/s11899-010-0056-8.

5. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Journal of Clinical Oncology. 2003;21(24):4642-9.

6. Chung NG, Buxhofer-Ausch V, Radich JP. The detection and significance of minimal residual disease in acute and chronic leukemia. Tissue Antigens. 2006 Nov;68(5):371-85. doi: 10.1111/j.1399-0039.2006.00714.x.

7. Herrmann H, Cerny-Reiterer S, Gleixner KV, Blatt K, Herndlhofer S, Rabitsch W, Jager E, Mitterbauer-Hohendanner G, Streubel B, Selzer E, Schwarzinger I, Sperr WR, Valent P. CD34+/CD38- stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin. Haematologica. 2011; Oct 11. doi: 10.3324/haematol.2010.035006.

8. Hokland P, Ommen HB. Towards individualized follow-up in adult acute myeloid leukemia in remission. Blood. 2011 Mar 3;117(9):2577-84. doi: 10.1182/blood-2010-09-303685.

9. Kern W, Voskova D, Schnittger S, Schoch C, Hiddemann W, Haferlach T. Four-fold staining including CD45 gating improves the sensitivity of multiparameter flow cytometric assessment of minimal residual disease in patients with acute myeloid leukemia. Hematol J. 2004;5(5):410-8.

10. Kern W, Voskova D, Schoch C, Hiddemann W, Schnittger S, Haferlach T. Determination of relapse risk based on assessment of minimal residual disease during complete remission by multiparameter flow cytometry in unselected patients with acute myeloid leukemia. Blood. 2004 Nov 15;104(10):3078-85. doi: 10.1182/blood-2004-03-1036.

11. Kern W, Bacher U, Haferlach C, Schnittger S, Haferlach T. The role of multiparameter flow cytometry for disease monitoring in AML. Best Pract Res Clin Haematol. 2010 Sep;23(3):379-90. doi: 10.1016/j.beha.2010.06.007.

12. Kern W, Schoch C, Haferlach T, Schnittger S. Monitoring of minimal residual disease in acute myeloid leukemia. Crit Rev Oncol Hematol. 2005 Nov;56(2):283-309. doi: 10.1016/j.critrevonc.2004.06.004.

13. Shook D, Coustan-Smith E, Ribeiro RC, Rubnitz JE, Campana D. Minimal residual disease quantitation in acute myeloid leukemia. Clin Lymphoma Myeloma. 2009;9 Suppl 3:S281-5. doi: 10.3816/CLM.2009.s.024.

14. Sperr WR, Valent P. Novel developments in AML – ASH 2010. ASH report. Memo 2011;4:106-9.

15. Voskova D, Schnittger S, Schoch C, Haferlach T, Kern W. Use of five-color staining improves the sensitivity of multiparameter flow cytomeric assessment of minimal residual disease in patients with acute myeloid leukemia. Leuk Lymphoma 2007;48(1):80-8. doi: 10.1080/10428190600886164.

16. Inoue D, Maruoka H, Takahashi T. Clinical analysis and optimization of postremission therapy for acute myeloid leukemia patients with minimal residual disease as determined by flow cytometry. Mediterr J Hematol Infect Dis. 2010; 2(2):e2010020. doi: 10.4084/MJHID.2010.020.

17. Peters JM, Ansari MQ. Multiparameter flow cytometry in the diagnosis and management of acute leukemia. Arch Pathol Lab Med. 2011;135(1):44-54. Review.

" ["~DETAIL_TEXT"]=> string(16098) "

Introduction

Acute myeloid leukemia (AML) is a disease of malignant hematopoietic cells, which initially affect bone marrow with further suppression of its normal counterparts and infiltrate solid organs and tissues. The aims of AML patients’ treatment are the elimination of malignant cells for the further achievement of remission (complete, morphological or molecular) and the recovery of patient's bone marrow hematopoiesis. The best expected result of such treatment is the achievement of complete remission, i.e., molecular complete remission as the result of eradication of AML symptoms. The possibility of AML relapse depends upon the quality of the remission [6]. Herein, the measurement of minimal residual disease (MRD) is required for (i) the stratification of a patient’s risk and (ii) monitoring the efficiency of treatment [13].

Modern treatment regimens allow the achievement of complete morphological remission for most patients. Unfortunately, the minimal quantity of initial leukemic cells (less than 5% of nucleated cells of the bone marrow) are able to develop the relapse of AML and the further fatal outcome. 

In the primary diagnosis of AML, the quantity of leukemic cells reaches up to 1010–1012 cells. After the first course of induction therapy the number of malignant cells is reduced almost 3 times, however there are millions of leukemic cells still alive. Herein the minimal residual disease is a small population of leukemic cells, which can be detected in the bone marrow provided that there are normal peripheral blood characteristics and not any extramedullar lesion focuses in patients. Thereby the MRD of AML is a persistent number of leukemic cells in bone marrow during complete remission. 

Flow cytometry versus Polymerase Chain Reaction

There are two fundamental methods for the submorphological evaluation of MRD with a high sensitivity in clinical diagnostics – Polymerase Chain Reaction (PCR) and Flow Cytometry (FC). Both the PCR and FC were invented in 1980s and these methods are the gold standard of up-to-date routine diagnostics. Flow cytometry is based on the aberrant immunophenotype surface and/or intracellular characteristics of leukemic cells, whereas PCR is based on molecular or genetic aberrations of malignant cells such as (i) gene mutations, (ii) the over-expression of mRNA, (iii) fusion transcripts and so on. 

The PCR method is considered to be a highly specific tool with the sensitivity of one leukemic cell in 104–106 of nucleated bone marrow cells, provided that the necessary technical processes are followed [8]. The main disadvantage is a limitation in using PCR in a number of patients who do not have specific genetic aberrations. According to a number of authors, half of all patients do not have molecular – specific aberrations, so this method is difficult to use for monitoring the level of MRD in such cases [11].

Multicolor flow cytometry permits the detection of one leukemic cell in 103–104 of normal nucleated bone marrow cells. The main benefit of this method is that it  can be used for virtually all patients with AML (up to 95% of patients) for the monitoring of MRD in the dynamics of treatment [5], except in cases of promyelocytic leukemia where WHO strongly recommend using PCR to detect PML-RARa transcript or t(15;17).

MRD is difficult to evaluate because the development of myeloid cells occurs entirely in the bone marrow; therefore evaluation should be based on the detection of immunophenotypic characteristics, which will differ between normal and malignant bone marrow cells [12, 15]. Unfortunately, leukemia cells do not express any specific antigens that clearly distinguish them from healthy regenerating bone marrow cells. However, some authors report that malignant cells have a fixed aberrant expression of myeloid inhibitory c-type lectin (hMICL) and CD123 and this could be used as the immunophenotypic marker for an assessment of MRD [14].

Leukemia-associated immunophenotype of AML

There are some recommendations for the initial diagnosis of AML [4]. In the primary diagnosis of immunophenotype leukemic cells, the application of combination multicolor monoclonal antibodies can be used later in the detection of aberrations in MRD [17, 16]. The leukemia-associated immunophenotype (LAIP) of the malignant cells is detected individually for a patient. The aberration detection of surface immunophenotype can be performed as (i) an asynchronous expression in one or more antigens, (ii) a cross-lineage expression in one or more antigens, (ii) a lack of expression in one or more antigens, and (iv) an over-expression in one or more markers. The precise evaluation of MRD in patients with AML with multicolor FC depends upon many different factors including the strategy of gating (using the CD45/SS or FS/SS gating strategies) [9], a broad panel of monoclonal antibodies, instrument settings (a compensation), and the operator’s qualification (Fig. 1, Fig. 2).

Some complications arise at the diagnosis of AML during the detection of LAIP. AML in comparison with ALL is rather heterogeneous disease, and very often it produces two or more subpopulations. Some authors very actively propose using a special strategy for the measurement of LAIP. On the other hand, there are some questions such as whether we should evaluate the subpopulation of “leukemic stem” cells CD34+CD38- at diagnosis even if it appears at very low frequency (for instance, in the case of promyelocytic leukemia) and should we take into account the changes of granularity according to SS parameter in CD45/SS gating strategy at the diagnosis and during the follow-up of patients. 

Another issue is stability of the LAIPs during treatment and at the relapse of AML. This question merits additional discussion. Briefly, in concordance with a number of authors the best way to reveal alterations in LAIPs is to use a broad panel of monoclonal antibody at the primary diagnosis of AML. It increases the probability of detecting LAIPs during follow-up.

Figure 1. Detection of a LAIP at the diagnosis of AML using multicolor flow cytometry and CD45-SS gating strategies – CD45dimCD4+CD13+CD33+CD34+CD38+CD117+ with the co-expression of CD7 and CD64. The type of aberrant expression is asynchronous expression of CD4 and co-expression CD64 with early myeloid antigens

Slobodnuk_fig1.png

Slobodnuk_fig2.png

Slobodnuk_fig3.png

Slobodnuk_fig4.png

Figure 2. After induction chemotherapy and leukocyte recovery, persistent cells with LAIP are detectable at a very low frequency

Slobodnuk_fig5.png

Slobodnuk_fig6.png

Slobodnuk_fig7.png

Conclusion

There are different options to detect MRD for patients with AML. In patients with detectable molecular markers, both PCR and multicolor FC might be used for receiving more sensitive and specific information about MRD. The leukemic cells are detectable by FC with sensitivity lower than molecular aberrations by PCR, however some patients do not have such mutations. One of the main problems is standardizing procedures in diagnostic AML by both PCR and FC. There is no official protocol with comparisons between PCR and FC during a follow-up patient with AML.

The identification of LAIPs in patients with AML depends upon  (i) how broad the panel of reagents is used at diagnosis and during an evaluation of MRD, (ii) how appropriate settings are used in flow cytometer (compensation, laser stability, voltage) and (iii) the operator’s qualifications [1].

The search for new markers to distinguish normal from malignant cells after chemotherapy in bone marrow by multicolor FC is a future direction of development in clinical laboratory diagnostics, and the possibility to identify new target treatment with AML patients [7].

Acknowledgements

The author wish to thank Yekaterina Ye. Zueva (Center for laboratory diagnostics, Pavlov Medical University of St. Petersburg, Russia) for providing the supervision.

References

1. Al-Mawali A, Gillis D, Lewis I. The role of multiparameter flow cytometry for detection of minimal residual disease in acute myeloid leukemia. Am J Clin Pathol. 2009 Jan;131(1):16-26. doi: 10.1309/AJCP5TSD3DZXFLCX.

2. Arnoulet C, Béné MC, Durrieu F, Feuillard J, Fossat C, Husson B, Jouault H, Maynadié M, Lacombe F. Four- and five-color flow cytometry analysis of leukocyte differentiation pathways in normal bone marrow: a reference document based on a systematic approach by the GTLLF and GEIL. Cytometry B Clin Cytom. 2010 Jan;78(1):4-10. doi: 10.1002/cyto.b.20484.

3. Bacher U, Haferlach T, Fehse B, Schnittger S, Kröger N. Minimal residual disease diagnostics and chimerism in the post-transplant period in acute myeloid leukemia. ScientificWorldJournal. 2011 Feb 3;11:310-9. doi: 10.1100/tsw.2011.16.

4. Campana D. Progress of minimal residual disease studies in childhood acute leukemia. Curr Hematol Malig Rep. 2010 Jul;5(3):169-7. doi: 10.1007/s11899-010-0056-8.

5. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Journal of Clinical Oncology. 2003;21(24):4642-9.

6. Chung NG, Buxhofer-Ausch V, Radich JP. The detection and significance of minimal residual disease in acute and chronic leukemia. Tissue Antigens. 2006 Nov;68(5):371-85. doi: 10.1111/j.1399-0039.2006.00714.x.

7. Herrmann H, Cerny-Reiterer S, Gleixner KV, Blatt K, Herndlhofer S, Rabitsch W, Jager E, Mitterbauer-Hohendanner G, Streubel B, Selzer E, Schwarzinger I, Sperr WR, Valent P. CD34+/CD38- stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin. Haematologica. 2011; Oct 11. doi: 10.3324/haematol.2010.035006.

8. Hokland P, Ommen HB. Towards individualized follow-up in adult acute myeloid leukemia in remission. Blood. 2011 Mar 3;117(9):2577-84. doi: 10.1182/blood-2010-09-303685.

9. Kern W, Voskova D, Schnittger S, Schoch C, Hiddemann W, Haferlach T. Four-fold staining including CD45 gating improves the sensitivity of multiparameter flow cytometric assessment of minimal residual disease in patients with acute myeloid leukemia. Hematol J. 2004;5(5):410-8.

10. Kern W, Voskova D, Schoch C, Hiddemann W, Schnittger S, Haferlach T. Determination of relapse risk based on assessment of minimal residual disease during complete remission by multiparameter flow cytometry in unselected patients with acute myeloid leukemia. Blood. 2004 Nov 15;104(10):3078-85. doi: 10.1182/blood-2004-03-1036.

11. Kern W, Bacher U, Haferlach C, Schnittger S, Haferlach T. The role of multiparameter flow cytometry for disease monitoring in AML. Best Pract Res Clin Haematol. 2010 Sep;23(3):379-90. doi: 10.1016/j.beha.2010.06.007.

12. Kern W, Schoch C, Haferlach T, Schnittger S. Monitoring of minimal residual disease in acute myeloid leukemia. Crit Rev Oncol Hematol. 2005 Nov;56(2):283-309. doi: 10.1016/j.critrevonc.2004.06.004.

13. Shook D, Coustan-Smith E, Ribeiro RC, Rubnitz JE, Campana D. Minimal residual disease quantitation in acute myeloid leukemia. Clin Lymphoma Myeloma. 2009;9 Suppl 3:S281-5. doi: 10.3816/CLM.2009.s.024.

14. Sperr WR, Valent P. Novel developments in AML – ASH 2010. ASH report. Memo 2011;4:106-9.

15. Voskova D, Schnittger S, Schoch C, Haferlach T, Kern W. Use of five-color staining improves the sensitivity of multiparameter flow cytomeric assessment of minimal residual disease in patients with acute myeloid leukemia. Leuk Lymphoma 2007;48(1):80-8. doi: 10.1080/10428190600886164.

16. Inoue D, Maruoka H, Takahashi T. Clinical analysis and optimization of postremission therapy for acute myeloid leukemia patients with minimal residual disease as determined by flow cytometry. Mediterr J Hematol Infect Dis. 2010; 2(2):e2010020. doi: 10.4084/MJHID.2010.020.

17. Peters JM, Ansari MQ. Multiparameter flow cytometry in the diagnosis and management of acute leukemia. Arch Pathol Lab Med. 2011;135(1):44-54. Review.

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string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(1) { [0]=> string(5) "19316" } ["VALUE"]=> array(1) { [0]=> string(4) "1077" } ["DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(1) { [0]=> string(4) "1077" } ["~DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19309" ["VALUE"]=> array(2) { ["TEXT"]=> string(62) "<p>Константин У. Слободнюк</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(50) "

Константин У. Слободнюк

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19310" ["VALUE"]=> array(2) { ["TEXT"]=> string(1526) "<p class="bodytext">Минимальная остаточная болезнь (МОД) у больных с диагнозом острого миелобластного лейкоза (ОМЛ) может выявляться различными методами. Знание уровней МОД весьма важно для (1) стратификации больных по группамриска, и (2) для мониторинга эффективности лечения. Разработаны процедуры проточной цитометрии для идентификации поверхностных и внутриклеточных антигенов в клетках. Они стали исключительно полезным способом определения клеток костного мозга,  с иммунофенотипом, ассоциированным с лейкозом, и они осществимы практически у всех больных с ОМЛ. Данное краткое сообщение касается, в основном, оценки МОД при ОМЛ с помощью многоцветной проточной цитометрии. </p> <h3>Ключевые слова</h3> <p>острый миелобластный лейкоз, многоцветная проточная цитометрия, иммунофенотип, ассоциация с лейкозом </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1480) "

Минимальная остаточная болезнь (МОД) у больных с диагнозом острого миелобластного лейкоза (ОМЛ) может выявляться различными методами. Знание уровней МОД весьма важно для (1) стратификации больных по группамриска, и (2) для мониторинга эффективности лечения. Разработаны процедуры проточной цитометрии для идентификации поверхностных и внутриклеточных антигенов в клетках. Они стали исключительно полезным способом определения клеток костного мозга,  с иммунофенотипом, ассоциированным с лейкозом, и они осществимы практически у всех больных с ОМЛ. Данное краткое сообщение касается, в основном, оценки МОД при ОМЛ с помощью многоцветной проточной цитометрии.

Ключевые слова

острый миелобластный лейкоз, многоцветная проточная цитометрия, иммунофенотип, ассоциация с лейкозом

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19306" ["VALUE"]=> string(29) "10.3205/ctt-2012-en-000099.01" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(29) "10.3205/ctt-2012-en-000099.01" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19312" ["VALUE"]=> array(2) { ["TEXT"]=> string(43) "<p>Konstantin U. Slobodnyuk</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(31) "

Konstantin U. Slobodnyuk

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19313" ["VALUE"]=> array(2) { ["TEXT"]=> string(607) "<p>Center for laboratory diagnostics, Pavlov State Medical University, St. Petersburg, Russia</p> <p class="bodytext"><b>Correspondence</b><br> Konstantin U. Slobodnyuk, Center for laboratory diagnostics, Pavlov State Medical University, 6/8 Lev Tolstoy Str., St. Petersburg, 199022, Russia <br>E-mail: <a href="javascript:linkTo_UnCryptMailto('qempxs.o2wpsfshrcyoDkqemp2gsq');">k.slobodnyuk@<span style="display:none;">spam is bad</span>gmail.com</a> <sup><br /></sup> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(487) "

Center for laboratory diagnostics, Pavlov State Medical University, St. Petersburg, Russia

Correspondence
Konstantin U. Slobodnyuk, Center for laboratory diagnostics, Pavlov State Medical University, 6/8 Lev Tolstoy Str., St. Petersburg, 199022, Russia
E-mail: k.slobodnyuk@spam is badgmail.com 

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Minimal residual disease (MRD) in patients diagnosed with acute myeloid leukemia (AML) can be detected by different methods. Knowing the MRD value is highly important for (i) stratification of patients in to risk groups and (ii) monitoring treatment's efficiency. Flow cytometry procedures have been developed to identify surface and intracellular antigens in cells. It has become an extremely useful tool for detecting the leukemia-associated immunophenotype of leukemia cells in bone marrow and it can be provided to virtually all patients with acute myeloid leukemia. This short report focuses on the assessment of AML MRD with multicolor flow cytometry. 

Keywords

acute myeloid leukemia, multicolor flow cytometry, leukemia-associated immunophenotype

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Slobodnyuk</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(31) "

Konstantin U. Slobodnyuk

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Konstantin U. Slobodnyuk

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Minimal residual disease (MRD) in patients diagnosed with acute myeloid leukemia (AML) can be detected by different methods. Knowing the MRD value is highly important for (i) stratification of patients in to risk groups and (ii) monitoring treatment's efficiency. Flow cytometry procedures have been developed to identify surface and intracellular antigens in cells. It has become an extremely useful tool for detecting the leukemia-associated immunophenotype of leukemia cells in bone marrow and it can be provided to virtually all patients with acute myeloid leukemia. This short report focuses on the assessment of AML MRD with multicolor flow cytometry. 

Keywords

acute myeloid leukemia, multicolor flow cytometry, leukemia-associated immunophenotype

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Minimal residual disease (MRD) in patients diagnosed with acute myeloid leukemia (AML) can be detected by different methods. Knowing the MRD value is highly important for (i) stratification of patients in to risk groups and (ii) monitoring treatment's efficiency. Flow cytometry procedures have been developed to identify surface and intracellular antigens in cells. It has become an extremely useful tool for detecting the leukemia-associated immunophenotype of leukemia cells in bone marrow and it can be provided to virtually all patients with acute myeloid leukemia. This short report focuses on the assessment of AML MRD with multicolor flow cytometry. 

Keywords

acute myeloid leukemia, multicolor flow cytometry, leukemia-associated immunophenotype

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Center for laboratory diagnostics, Pavlov State Medical University, St. Petersburg, Russia

Correspondence
Konstantin U. Slobodnyuk, Center for laboratory diagnostics, Pavlov State Medical University, 6/8 Lev Tolstoy Str., St. Petersburg, 199022, Russia
E-mail: k.slobodnyuk@spam is badgmail.com 

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Center for laboratory diagnostics, Pavlov State Medical University, St. Petersburg, Russia

Correspondence
Konstantin U. Slobodnyuk, Center for laboratory diagnostics, Pavlov State Medical University, 6/8 Lev Tolstoy Str., St. Petersburg, 199022, Russia
E-mail: k.slobodnyuk@spam is badgmail.com 

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Константин У. Слободнюк

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Знание уровней МОД весьма важно для (1) стратификации больных по группамриска, и (2) для мониторинга эффективности лечения. Разработаны процедуры проточной цитометрии для идентификации поверхностных и внутриклеточных антигенов в клетках. Они стали исключительно полезным способом определения клеток костного мозга,  с иммунофенотипом, ассоциированным с лейкозом, и они осществимы практически у всех больных с ОМЛ. Данное краткое сообщение касается, в основном, оценки МОД при ОМЛ с помощью многоцветной проточной цитометрии. </p> <h3>Ключевые слова</h3> <p>острый миелобластный лейкоз, многоцветная проточная цитометрия, иммунофенотип, ассоциация с лейкозом </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1480) "

Минимальная остаточная болезнь (МОД) у больных с диагнозом острого миелобластного лейкоза (ОМЛ) может выявляться различными методами. Знание уровней МОД весьма важно для (1) стратификации больных по группамриска, и (2) для мониторинга эффективности лечения. Разработаны процедуры проточной цитометрии для идентификации поверхностных и внутриклеточных антигенов в клетках. Они стали исключительно полезным способом определения клеток костного мозга,  с иммунофенотипом, ассоциированным с лейкозом, и они осществимы практически у всех больных с ОМЛ. Данное краткое сообщение касается, в основном, оценки МОД при ОМЛ с помощью многоцветной проточной цитометрии.

Ключевые слова

острый миелобластный лейкоз, многоцветная проточная цитометрия, иммунофенотип, ассоциация с лейкозом

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Минимальная остаточная болезнь (МОД) у больных с диагнозом острого миелобластного лейкоза (ОМЛ) может выявляться различными методами. Знание уровней МОД весьма важно для (1) стратификации больных по группамриска, и (2) для мониторинга эффективности лечения. Разработаны процедуры проточной цитометрии для идентификации поверхностных и внутриклеточных антигенов в клетках. Они стали исключительно полезным способом определения клеток костного мозга,  с иммунофенотипом, ассоциированным с лейкозом, и они осществимы практически у всех больных с ОМЛ. Данное краткое сообщение касается, в основном, оценки МОД при ОМЛ с помощью многоцветной проточной цитометрии.

Ключевые слова

острый миелобластный лейкоз, многоцветная проточная цитометрия, иммунофенотип, ассоциация с лейкозом

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Introduction

The first allogeneic bone marrow transplantation (BMT) in the People's Republic of China (P.R.C.) was successfully performed in an acute leukemia patient at Peking University People’s Hospital by D-P Lu in 1981. Since then the number of hematopoietic stem cell transplantations (HSCT) in China has increased gradually, especially since the late 1990s. Now, more than 2000 HSCTs per year including 1000 allogeneic HSCTs (allo-HSCTs), have been performed in recent years in more than 50 BMT units in mainland China [1]. As the one child policy has been in effect in China for 30 years, unrelated donors (URD) represent one of the common alternative sources of stem cells for allo-HSCT.

1. Sources of unrelated donors

Unrelated donors for allo-HSCT in the P.R.C. are from the Chinese Marrow Donor Program (CMDP) and the Taiwan Tzu Chi Stem Cell Center. The Taiwan Tzu Chi Stem Cell Center was established in 1993, and the first stem cell donation to mainland China was carried out in 1997. As the CMDP only started service for the public in 2001, before 2001 unrelated donors for allo-HSCT in mainland China were mainly from the Taiwan Tzu Chi Stem Cell Center. By the end of June 2010, the number of donors had risen to 333,798 and 927 stem cells had been successfully donated to mainland China. The primary three BMT units in mainland China, ordered by the number of stem cell donations received from the Taiwan Tzu Chi Stem Cell Center, are the First Affiliated Hospital of Zhejiang University School of Medicine (215 cases), Guangzhou Nanfang Hospital (145 cases), and Beijing Daopei Hospital (66 cases) [2].

The CMDP was established in 1992 and started service for the public in 2001. The CMDP is responsible for organization and mobilization of volunteers, searching for donors, standardization of HLA typing, and the promotion of research on clinical transplantation in China. At the end of 2009, the CMDP comprised 31 branch registries, 31 HLA-typing laboratories, five high-resolution laboratories and one quality control laboratory [3]. 

The first search requests for donors from the CMDP were processed in 1996 and the first transplant was facilitated successfully in September 1996. The total number of donor registrations has increased dramatically since 2002. In 2002, the CMDP only had 6,000 donors. By the end of May 2010, the number of donors had risen to 1,130,566, and 1,662 stem cell donations and 16,659 search requests had been carried out [3]. The CMDP is currently the largest donor pool among the nine Asian countries/regions and the third largest register of unrelated donors in the world. It is expected that the number of donor registrations in the CMDP will reach 2,000,000 in 2015. There are more than 200 search requests per month with a 60% preliminary matching rate. The processing of HLA data systems has made significant enhancements for more efficient and accurate alternative donor searches, and the median time to identify a suitable URD is now about 2 months. The CMDP also cooperates with the major cord blood banks in mainland China. There are over 30,000 units of cord blood available for search requests in the CMDP [4]. The CMDP is actively involved in international cooperations. More than 300 preliminary searches from more than 20 countries have been carried out. Stem cells from the CMDP have been successfully donated to the United States, Singapore, Switzerland, Korea, and the United Kingdom.

2. Current URD-HSCT activity

2.1. Number of URD-HSCTs

The number of URD-HSCTs has been increasing in China since 2000. A survey of 16 BMT units in mainland China from 1986 to 2005 indicates that the predominant types of transplantation performed are identical sibling (36%), related mismatched/ haploidentical (11.2%), unrelated (7.5%), and autologous (44.5%) [5]. The report from the Asia-Pacific Blood and Marrow Transplantation Group showed that of 352 HSCTs performed in mainland China in 2006, 60% were identical sibling and related mismatched/haploidentical, 20% were unrelated, and 20% were autologous [6]. The data submitted to the Chinese Hematopoietic Stem Cell Transplantation Committee from 30 BMT units from June 2007 to June 2008 indicated that of 1099 allo-HSCTs, 533 (48.5%) were identical sibling, 345 (31.4%) were related haploidentical, 207 (18.8%) were unrelated, and 14 (1.3%) were cord blood.

2.2. Disease indication

The most common indication for URD-HSCT is hematological malignancies. Follow-up surveys were completed on 822 CMDP stem cell recipients between 1996 and 2007. The distribution of disease entities and prevalent diseases being transplanted is CML (35.9%), ALL (29.2%), AML (18.6%), MPD (3.3%), and lymphoid malignancy (2.9%) [4]. The number of transplants for CML has decreased in most Asia countries/regions since 2000, excluding China and Iran [6]. Allo-HSCT is still the main therapy for 15% or more of current patients in China [7]. Wang J.X. et al [8] analyzed 1,824 CML patients from 15 hospitals throughout China in the whole year of 2005 and 22.72% received allo-HSCT. The reasons may be the following factors: CML in China tends to afflict a younger population than in Western countries, due to restriction of financial support, only one third of CML patients were treated with imatinib, and the majority of those treated were not monitored in time. 

2.3. Clinical outcomes of URD-HSCT

With advances in HLA-typing techniques, transplant techniques, and supporting care, the clinical outcome of URD-HSCT has been improved. The data from the CMDP showed the 1-year overall survival (OS) of stem cell recipients was 53% in 2004, 60% in 2005, 65% in 2006, and 71% in 2007 [4]. Follow-up surveys of 182 patients receiving URD-HSCT at the Beijing Daopei Hospital from September 2003 to February 2010 indicated the 5-year OS was 72.2%, and the disease free survival (DFS) was 64.9% [9]. 

3. Advances in URD-HSCT

Despite the improvements in transplant procedures, URD-HSCT is still associated with a higher treatment-related mortality (TRM) due to the toxicity of conditioning regimens, severe GVHD, and infectious complications. Non-relapse mortality (NRM) rates over 50% are commonly reported in patients over 40 years old [10]. 

3.1. Conditioning regimens 

 The main myeloablative conditioning regimens used in URD-HSCT in China are busulfan/cyclophosphamide (BuCy) or BuCy combined with cytarabine without total body irradiation. A significant trend has been an increase in the numbers of transplants in patients over the age of 50 years because of the introduction of reduced intensity conditioning (RIC) regimens. From 1996 to 2007, 4% (34 of 822 transplants) of CMDP stem cell recipients were ≥50 years old [4]. RIC regimens were predominantly fludarabine-based combinations without irradiation. 

The BMT Center of the First Affiliated Hospital of Zhejiang University School of Medicine [11] first performed RIC URD-HSCT combined with imatinib in 18 CML patients in the first chronic phase (CP1). The conditioning regimen included Flu, Bu and antithymocyte globulin (ATG). Imatinib was administered for 3–6 months before transplantation to reduce leukemia burden and after transplantation to treat relapsed disease or graft failure. Prophylactic imatinib was commenced on day +100 in engrafted patients to prevent relapse and was discontinued 12 months after transplantation. Overall survival was 82.1% and complete molecular remission was 91.3%. The results suggested that RIC allo-SCT combined with imatinib was well tolerated in CML patients with a low-risk of GVHD. Imatinib changed the kinetics of disease relapse after RIC allo-SCT and the anti-leukemic immunological function of RIC could provide a definite cure for CML.

3.2. Prophylaxis regimens for aGVHD

Acute GVHD remains a significant cause of transplant-related mortality and morbidity following allo-HSCT, and especially following URD-HSCT. The combination of calcineurin inhibitor (cyclosporine) and methotrexate is the standard prophylaxis regimen for GVHD. Many BMT units in China add ATG to this standard prophylaxis regimen in URD-HSCT. Due to a high incidence of infection in prophylaxis with ATG, Huang H et al [12] firstly used a combination of cyclosporine, methotrexate and low-dose, short-course mycophenolate mofetil (MMF) for GVHD prophylaxis in 12 patients receiving URD-HSCT, including 8 patients with HLA-A, B,DRB1 matched, 3 patients with one mismatched allele and one patient with two mismatched alleles. Only one patient developed grade IV aGVHD and two patients developed grade II aGVHD, who achieved complete remission after being treated with the combination of MMF, methylprednisolone and CsA. They used this prophylaxis regimen in 138 URD-HSCT recipients from January 2001 to March 2009, the cumulative incidences of severe (grade III–IV) aGVHD, chronic GVHD (cGVHD) and extensive cGVHD were 10.9%, 32.6%, and 15.9% [13]. The cumulative incidences of severe aGVHD, cGVHD, and extensive cGVHD were 8.6%, 32.9%, and 13.7% in URD-HSCT recipients receiving cyclosporine, methotrexate, and ATG for GVHD prophylaxis in the Institute of Hematology of People’s Hospital of Peking University from September 2002 to April 2008 [14]. The two regimens are similar in reducing GVHD, which suggests that MMF could be used effectively and safely for prevention of aGVHD in URD-HSCT.

4. Trends and perspective for HSCT in China

The Asia-Pacific Blood and Marrow Transplantation Group [6] surveyed HSCT activity in nine Asian countries/regions from 1986 to 2006. The results showed the most significant increases in the past 10 years were observed in Iran and China. The ratio of the reported numbers of HSCTs in year 2006 and in year 1996 was 10.2 in Iran and 9.8 in China. However, even in countries/regions within the high-income group (Hong Kong, Japan, Korea, and Singapore) the number of HSCTs performed has been consistently increasing in the study period and is not likely to reach a plateau any time soon. This suggests that the demand for HSCTs has not been fulfilled in any of these countries.

The significant effect of the economic strength of individual countries on HSCT activity was reported by Gratwohl et al [15]. Recently, a retrospective survey study of HSCTs for the year 2006 collected by 1,327 centers in 71 participating countries of the Worldwide Network for Blood and Marrow Transplantation showed the gross national income per capita was found to have the highest associations with HSCT rates. The median HSCT rates (total numbers of HSCTs per 10 million population) varied between regions and countries: 184 (range, 0.6–488.5) in Asia, and 268.9 (range, 5.7–792.1) in Europe. Their results suggested HSCT is used for a broad spectrum of indications worldwide, but most frequently in countries with higher gross national incomes, higher governmental health care expenditures, and higher team densities [16].

According to the World Bank’s income category based on the Gross National Income per capita, China is a lower-middle-income country. The data from Asia-Pacific Blood and Marrow Transplantation Group indicated numbers of transplant institutes per 100 million population was 1 in China and the highest was 279 in Japan; numbers of reported HSCTs per 100 million population was 3 in China and the highest was 301 in Japan [6]. With rapid economic development in China, there will be much development potential for HSCT, especially in some economic high-income areas.

References

1. Lu DP. Blood and marrow transplantation in mainland China. Hong Kong Med. 2009;15(Supple3):9-12.

2. Data from Buddhist Tzu Chi Stem Cells Center, Available at: http://www.tzuchi.org.tw/. Accessed on July 1, 2010.

3. Data from China Marrow Donor Program, Available at: http://www.cmdp.com.cn/. Accessed on July 1, 2010.

4. Hong JL. A brief introduction of the Chinese Marrow Donor Program. Hong Kong Med. 2009;15(Suppl. 3):45-47.

5. Wu T and Lu DP. Blood and marrow transplantation in the People's Republic of China. Bone Marrow Transplant. 2008;42:72-75. doi:10.1038/bmt.2008.123

6. Yoshimi A, Suzuki R, Atsuta Y, et al. Hematopoietic SCT activity in Asia: a report from the Asia-Pacific Blood and Marrow Transplantation Group. Bone Marrow Transplant. 1 March 2010. Epub. doi: 10.1038/bmt.2010.34

7. Kim DW, Banavali SD, Bunworasate U, et al. Chronic myeloid leukemia in the Asia-Pacific region: current practice, challenges and opportunities in the targeted therapy era. Leu Res. 29 April 2010. Epub. doi:10.1016/j.leukres.2010.03.033

8. Wang JX, Huang XJ, Wu DP, et al. Overview of chronic myelogenous leukemia and its current diagnosis and treatment patterns in 15 hospitals in China. 中华血液学杂志 [Zhonghua Xue Ye Xue Za Zhi, Chinese Journal of Hematology]. 2009;30(11):721-725. Chinese. doi:10.3760/cma.j.issn.0253-2727.2009.11.001

9. Lu DP. Abstract of oral presentation in 2010 annual meeting of China Marrow Donor Program in Wuhan.

10. Huang H, Lai XY. Unrelated donor haematopoietic stem cell transplantation for adult patients with haematological malignancies. Hong Kong Med. 2009;15 (Suppl. 3):22-26.

11. Luo Y, Lai XY, Tan YM, et al. Reduced-intensity allogeneic transplantation combined with imatinib mesylate for chronic myeloid leukemia in first chronic phase. Leukemia. 2009;23(6):1171-1174. doi:10.1038/leu.2008.401

12. Huang H, Lin MF, Meng HT, et al. Combination of mycophenolate mofetil with cyclosporine A and methotrexate as acute GVHD prophylaxis after unrelated donor allogeneic bone marrow transplantation. 中华血液学杂志 [Zhonghua Xue Ye Xue Za Zhi, Chinese Journal of Hematology]. 2001;22:76-78. Chinese.

13. Xiao H, Cao W, Lai X, et al. Immunosuppressive cytokine gene polymorphisms and outcome after related and unrelated hematopoietic cell transplantation in Chinese population. Biol Bone Marrow Transplantation, 7 May 2010. Epub. doi: 10.1016/j.bbmt.2010.04.013

14. Liu KY. Abstract of oral presentation in 2010 annual meeting of China Marrow Donor Program in Wuhan.

15. Gratwohl A, Passweg J, Baldomero H, et al. Economics, health care systems and utilization of haematopoietic stem cell transplants in Europe. Br J Haematol. 2002;117:451–468.

16. Gratwohl A, Baldomero H, Aljurf M, et al. Hematopoietic stem cell transplantation: a global perspective. JAMA. 2010;303(16):1617-1624.

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Introduction

The first allogeneic bone marrow transplantation (BMT) in the People's Republic of China (P.R.C.) was successfully performed in an acute leukemia patient at Peking University People’s Hospital by D-P Lu in 1981. Since then the number of hematopoietic stem cell transplantations (HSCT) in China has increased gradually, especially since the late 1990s. Now, more than 2000 HSCTs per year including 1000 allogeneic HSCTs (allo-HSCTs), have been performed in recent years in more than 50 BMT units in mainland China [1]. As the one child policy has been in effect in China for 30 years, unrelated donors (URD) represent one of the common alternative sources of stem cells for allo-HSCT.

1. Sources of unrelated donors

Unrelated donors for allo-HSCT in the P.R.C. are from the Chinese Marrow Donor Program (CMDP) and the Taiwan Tzu Chi Stem Cell Center. The Taiwan Tzu Chi Stem Cell Center was established in 1993, and the first stem cell donation to mainland China was carried out in 1997. As the CMDP only started service for the public in 2001, before 2001 unrelated donors for allo-HSCT in mainland China were mainly from the Taiwan Tzu Chi Stem Cell Center. By the end of June 2010, the number of donors had risen to 333,798 and 927 stem cells had been successfully donated to mainland China. The primary three BMT units in mainland China, ordered by the number of stem cell donations received from the Taiwan Tzu Chi Stem Cell Center, are the First Affiliated Hospital of Zhejiang University School of Medicine (215 cases), Guangzhou Nanfang Hospital (145 cases), and Beijing Daopei Hospital (66 cases) [2].

The CMDP was established in 1992 and started service for the public in 2001. The CMDP is responsible for organization and mobilization of volunteers, searching for donors, standardization of HLA typing, and the promotion of research on clinical transplantation in China. At the end of 2009, the CMDP comprised 31 branch registries, 31 HLA-typing laboratories, five high-resolution laboratories and one quality control laboratory [3]. 

The first search requests for donors from the CMDP were processed in 1996 and the first transplant was facilitated successfully in September 1996. The total number of donor registrations has increased dramatically since 2002. In 2002, the CMDP only had 6,000 donors. By the end of May 2010, the number of donors had risen to 1,130,566, and 1,662 stem cell donations and 16,659 search requests had been carried out [3]. The CMDP is currently the largest donor pool among the nine Asian countries/regions and the third largest register of unrelated donors in the world. It is expected that the number of donor registrations in the CMDP will reach 2,000,000 in 2015. There are more than 200 search requests per month with a 60% preliminary matching rate. The processing of HLA data systems has made significant enhancements for more efficient and accurate alternative donor searches, and the median time to identify a suitable URD is now about 2 months. The CMDP also cooperates with the major cord blood banks in mainland China. There are over 30,000 units of cord blood available for search requests in the CMDP [4]. The CMDP is actively involved in international cooperations. More than 300 preliminary searches from more than 20 countries have been carried out. Stem cells from the CMDP have been successfully donated to the United States, Singapore, Switzerland, Korea, and the United Kingdom.

2. Current URD-HSCT activity

2.1. Number of URD-HSCTs

The number of URD-HSCTs has been increasing in China since 2000. A survey of 16 BMT units in mainland China from 1986 to 2005 indicates that the predominant types of transplantation performed are identical sibling (36%), related mismatched/ haploidentical (11.2%), unrelated (7.5%), and autologous (44.5%) [5]. The report from the Asia-Pacific Blood and Marrow Transplantation Group showed that of 352 HSCTs performed in mainland China in 2006, 60% were identical sibling and related mismatched/haploidentical, 20% were unrelated, and 20% were autologous [6]. The data submitted to the Chinese Hematopoietic Stem Cell Transplantation Committee from 30 BMT units from June 2007 to June 2008 indicated that of 1099 allo-HSCTs, 533 (48.5%) were identical sibling, 345 (31.4%) were related haploidentical, 207 (18.8%) were unrelated, and 14 (1.3%) were cord blood.

2.2. Disease indication

The most common indication for URD-HSCT is hematological malignancies. Follow-up surveys were completed on 822 CMDP stem cell recipients between 1996 and 2007. The distribution of disease entities and prevalent diseases being transplanted is CML (35.9%), ALL (29.2%), AML (18.6%), MPD (3.3%), and lymphoid malignancy (2.9%) [4]. The number of transplants for CML has decreased in most Asia countries/regions since 2000, excluding China and Iran [6]. Allo-HSCT is still the main therapy for 15% or more of current patients in China [7]. Wang J.X. et al [8] analyzed 1,824 CML patients from 15 hospitals throughout China in the whole year of 2005 and 22.72% received allo-HSCT. The reasons may be the following factors: CML in China tends to afflict a younger population than in Western countries, due to restriction of financial support, only one third of CML patients were treated with imatinib, and the majority of those treated were not monitored in time. 

2.3. Clinical outcomes of URD-HSCT

With advances in HLA-typing techniques, transplant techniques, and supporting care, the clinical outcome of URD-HSCT has been improved. The data from the CMDP showed the 1-year overall survival (OS) of stem cell recipients was 53% in 2004, 60% in 2005, 65% in 2006, and 71% in 2007 [4]. Follow-up surveys of 182 patients receiving URD-HSCT at the Beijing Daopei Hospital from September 2003 to February 2010 indicated the 5-year OS was 72.2%, and the disease free survival (DFS) was 64.9% [9]. 

3. Advances in URD-HSCT

Despite the improvements in transplant procedures, URD-HSCT is still associated with a higher treatment-related mortality (TRM) due to the toxicity of conditioning regimens, severe GVHD, and infectious complications. Non-relapse mortality (NRM) rates over 50% are commonly reported in patients over 40 years old [10]. 

3.1. Conditioning regimens 

 The main myeloablative conditioning regimens used in URD-HSCT in China are busulfan/cyclophosphamide (BuCy) or BuCy combined with cytarabine without total body irradiation. A significant trend has been an increase in the numbers of transplants in patients over the age of 50 years because of the introduction of reduced intensity conditioning (RIC) regimens. From 1996 to 2007, 4% (34 of 822 transplants) of CMDP stem cell recipients were ≥50 years old [4]. RIC regimens were predominantly fludarabine-based combinations without irradiation. 

The BMT Center of the First Affiliated Hospital of Zhejiang University School of Medicine [11] first performed RIC URD-HSCT combined with imatinib in 18 CML patients in the first chronic phase (CP1). The conditioning regimen included Flu, Bu and antithymocyte globulin (ATG). Imatinib was administered for 3–6 months before transplantation to reduce leukemia burden and after transplantation to treat relapsed disease or graft failure. Prophylactic imatinib was commenced on day +100 in engrafted patients to prevent relapse and was discontinued 12 months after transplantation. Overall survival was 82.1% and complete molecular remission was 91.3%. The results suggested that RIC allo-SCT combined with imatinib was well tolerated in CML patients with a low-risk of GVHD. Imatinib changed the kinetics of disease relapse after RIC allo-SCT and the anti-leukemic immunological function of RIC could provide a definite cure for CML.

3.2. Prophylaxis regimens for aGVHD

Acute GVHD remains a significant cause of transplant-related mortality and morbidity following allo-HSCT, and especially following URD-HSCT. The combination of calcineurin inhibitor (cyclosporine) and methotrexate is the standard prophylaxis regimen for GVHD. Many BMT units in China add ATG to this standard prophylaxis regimen in URD-HSCT. Due to a high incidence of infection in prophylaxis with ATG, Huang H et al [12] firstly used a combination of cyclosporine, methotrexate and low-dose, short-course mycophenolate mofetil (MMF) for GVHD prophylaxis in 12 patients receiving URD-HSCT, including 8 patients with HLA-A, B,DRB1 matched, 3 patients with one mismatched allele and one patient with two mismatched alleles. Only one patient developed grade IV aGVHD and two patients developed grade II aGVHD, who achieved complete remission after being treated with the combination of MMF, methylprednisolone and CsA. They used this prophylaxis regimen in 138 URD-HSCT recipients from January 2001 to March 2009, the cumulative incidences of severe (grade III–IV) aGVHD, chronic GVHD (cGVHD) and extensive cGVHD were 10.9%, 32.6%, and 15.9% [13]. The cumulative incidences of severe aGVHD, cGVHD, and extensive cGVHD were 8.6%, 32.9%, and 13.7% in URD-HSCT recipients receiving cyclosporine, methotrexate, and ATG for GVHD prophylaxis in the Institute of Hematology of People’s Hospital of Peking University from September 2002 to April 2008 [14]. The two regimens are similar in reducing GVHD, which suggests that MMF could be used effectively and safely for prevention of aGVHD in URD-HSCT.

4. Trends and perspective for HSCT in China

The Asia-Pacific Blood and Marrow Transplantation Group [6] surveyed HSCT activity in nine Asian countries/regions from 1986 to 2006. The results showed the most significant increases in the past 10 years were observed in Iran and China. The ratio of the reported numbers of HSCTs in year 2006 and in year 1996 was 10.2 in Iran and 9.8 in China. However, even in countries/regions within the high-income group (Hong Kong, Japan, Korea, and Singapore) the number of HSCTs performed has been consistently increasing in the study period and is not likely to reach a plateau any time soon. This suggests that the demand for HSCTs has not been fulfilled in any of these countries.

The significant effect of the economic strength of individual countries on HSCT activity was reported by Gratwohl et al [15]. Recently, a retrospective survey study of HSCTs for the year 2006 collected by 1,327 centers in 71 participating countries of the Worldwide Network for Blood and Marrow Transplantation showed the gross national income per capita was found to have the highest associations with HSCT rates. The median HSCT rates (total numbers of HSCTs per 10 million population) varied between regions and countries: 184 (range, 0.6–488.5) in Asia, and 268.9 (range, 5.7–792.1) in Europe. Their results suggested HSCT is used for a broad spectrum of indications worldwide, but most frequently in countries with higher gross national incomes, higher governmental health care expenditures, and higher team densities [16].

According to the World Bank’s income category based on the Gross National Income per capita, China is a lower-middle-income country. The data from Asia-Pacific Blood and Marrow Transplantation Group indicated numbers of transplant institutes per 100 million population was 1 in China and the highest was 279 in Japan; numbers of reported HSCTs per 100 million population was 3 in China and the highest was 301 in Japan [6]. With rapid economic development in China, there will be much development potential for HSCT, especially in some economic high-income areas.

References

1. Lu DP. Blood and marrow transplantation in mainland China. Hong Kong Med. 2009;15(Supple3):9-12.

2. Data from Buddhist Tzu Chi Stem Cells Center, Available at: http://www.tzuchi.org.tw/. Accessed on July 1, 2010.

3. Data from China Marrow Donor Program, Available at: http://www.cmdp.com.cn/. Accessed on July 1, 2010.

4. Hong JL. A brief introduction of the Chinese Marrow Donor Program. Hong Kong Med. 2009;15(Suppl. 3):45-47.

5. Wu T and Lu DP. Blood and marrow transplantation in the People's Republic of China. Bone Marrow Transplant. 2008;42:72-75. doi:10.1038/bmt.2008.123

6. Yoshimi A, Suzuki R, Atsuta Y, et al. Hematopoietic SCT activity in Asia: a report from the Asia-Pacific Blood and Marrow Transplantation Group. Bone Marrow Transplant. 1 March 2010. Epub. doi: 10.1038/bmt.2010.34

7. Kim DW, Banavali SD, Bunworasate U, et al. Chronic myeloid leukemia in the Asia-Pacific region: current practice, challenges and opportunities in the targeted therapy era. Leu Res. 29 April 2010. Epub. doi:10.1016/j.leukres.2010.03.033

8. Wang JX, Huang XJ, Wu DP, et al. Overview of chronic myelogenous leukemia and its current diagnosis and treatment patterns in 15 hospitals in China. 中华血液学杂志 [Zhonghua Xue Ye Xue Za Zhi, Chinese Journal of Hematology]. 2009;30(11):721-725. Chinese. doi:10.3760/cma.j.issn.0253-2727.2009.11.001

9. Lu DP. Abstract of oral presentation in 2010 annual meeting of China Marrow Donor Program in Wuhan.

10. Huang H, Lai XY. Unrelated donor haematopoietic stem cell transplantation for adult patients with haematological malignancies. Hong Kong Med. 2009;15 (Suppl. 3):22-26.

11. Luo Y, Lai XY, Tan YM, et al. Reduced-intensity allogeneic transplantation combined with imatinib mesylate for chronic myeloid leukemia in first chronic phase. Leukemia. 2009;23(6):1171-1174. doi:10.1038/leu.2008.401

12. Huang H, Lin MF, Meng HT, et al. Combination of mycophenolate mofetil with cyclosporine A and methotrexate as acute GVHD prophylaxis after unrelated donor allogeneic bone marrow transplantation. 中华血液学杂志 [Zhonghua Xue Ye Xue Za Zhi, Chinese Journal of Hematology]. 2001;22:76-78. Chinese.

13. Xiao H, Cao W, Lai X, et al. Immunosuppressive cytokine gene polymorphisms and outcome after related and unrelated hematopoietic cell transplantation in Chinese population. Biol Bone Marrow Transplantation, 7 May 2010. Epub. doi: 10.1016/j.bbmt.2010.04.013

14. Liu KY. Abstract of oral presentation in 2010 annual meeting of China Marrow Donor Program in Wuhan.

15. Gratwohl A, Passweg J, Baldomero H, et al. Economics, health care systems and utilization of haematopoietic stem cell transplants in Europe. Br J Haematol. 2002;117:451–468.

16. Gratwohl A, Baldomero H, Aljurf M, et al. Hematopoietic stem cell transplantation: a global perspective. JAMA. 2010;303(16):1617-1624.

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Хе Хуанг, Хаовен Сяо, Хуалюй Фу

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Число трансплантаций гемопоэтических стволовых клеток (ТГСК) в Китае резко возросло, особенно по сравнению с концом 90-х годов. Поскольку в Китае введена политика "одна семья-один ребенок", все больше альтернативных доноров, например, неродственных (НРД), привлекаются для лечения больных, требующих трансплантации и не имеющих HLA-идентичного донора из числа сибсов. Значительное возрастание числа неродственных ТГСК, проводимых в Китае, отмечено после того, как в 2001 году было официально начато обслуживание по китайской Программе доноров костного мозга, что привело к быстрому росту пула доноров. Наиболее частым показанием для неродственной ТГСК являются онкогематологические заболевания. Успехи в технологии HLA-типирования, сниженние интенсивности режимов кондиционирования и стратегии профилактики РТПХ в большой мере улучшили исходы и расширили пригодность неродственной ТГСК для пациентов. По мере быстрого экономического развития Китая, будет больше возможностей для развития потенциала ТГСК.

Ключевые слова

трансплантация гемопоэтических стволовых клеток, ТГСК, неродственные доноры, Китай" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19343" ["VALUE"]=> string(29) "10.3205/ctt-2010-en-000083.01" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(29) "10.3205/ctt-2010-en-000083.01" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19350" ["VALUE"]=> array(2) { ["TEXT"]=> string(125) "<p>He Huang<sup>1</sup>, Haowen Xiao<sup>1,2</sup>, Huarui Fu<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(77) "

He Huang1, Haowen Xiao1,2, Huarui Fu1

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19351" ["VALUE"]=> array(2) { ["TEXT"]=> string(353) "<p class="bodytext"><sup>1</sup>Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, P R China; <br> <sup>2</sup>Department of Haematology, Guangzhou Liuhuaqiao Hospital, Guangzhou, Guangdong province, P R China </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(301) "

1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, P R China;
2Department of Haematology, Guangzhou Liuhuaqiao Hospital, Guangzhou, Guangdong province, P R China

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The number of hematopoietic stem cell transplantations (HSCT) in China has increased dramatically, especially since the late 1990s. As the one child policy has been implemented in China, more and more alternative donors such as unrelated donors (URD) have been used for patients who need transplantation without a human leukocyte antigen (HLA) identical sibling donor. A dramatic increase in the number of URD-HSCTs performed in China was observed after the Chinese Marrow Donor Program started servicing the public in 2001, resulting in the rapid expansion of the donor pool. The most common indication is hematological malignancies in URD-HSCT. Advances in HLA-typing techniques, a reduced intensity conditioning regimen, and prophylaxis strategy for GVHD have greatly improved the outcome and expanded patient eligibility for URD-HSCT. With rapid the economic development in China there will be much development potential for HSCT.

Keywords

hematopoietic stem cell transplantation, HSCT, unrelated donor, China

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He Huang1, Haowen Xiao1,2, Huarui Fu1

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He Huang1, Haowen Xiao1,2, Huarui Fu1

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The number of hematopoietic stem cell transplantations (HSCT) in China has increased dramatically, especially since the late 1990s. As the one child policy has been implemented in China, more and more alternative donors such as unrelated donors (URD) have been used for patients who need transplantation without a human leukocyte antigen (HLA) identical sibling donor. A dramatic increase in the number of URD-HSCTs performed in China was observed after the Chinese Marrow Donor Program started servicing the public in 2001, resulting in the rapid expansion of the donor pool. The most common indication is hematological malignancies in URD-HSCT. Advances in HLA-typing techniques, a reduced intensity conditioning regimen, and prophylaxis strategy for GVHD have greatly improved the outcome and expanded patient eligibility for URD-HSCT. With rapid the economic development in China there will be much development potential for HSCT.

Keywords

hematopoietic stem cell transplantation, HSCT, unrelated donor, China

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The number of hematopoietic stem cell transplantations (HSCT) in China has increased dramatically, especially since the late 1990s. As the one child policy has been implemented in China, more and more alternative donors such as unrelated donors (URD) have been used for patients who need transplantation without a human leukocyte antigen (HLA) identical sibling donor. A dramatic increase in the number of URD-HSCTs performed in China was observed after the Chinese Marrow Donor Program started servicing the public in 2001, resulting in the rapid expansion of the donor pool. The most common indication is hematological malignancies in URD-HSCT. Advances in HLA-typing techniques, a reduced intensity conditioning regimen, and prophylaxis strategy for GVHD have greatly improved the outcome and expanded patient eligibility for URD-HSCT. With rapid the economic development in China there will be much development potential for HSCT.

Keywords

hematopoietic stem cell transplantation, HSCT, unrelated donor, China

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1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, P R China;
2Department of Haematology, Guangzhou Liuhuaqiao Hospital, Guangzhou, Guangdong province, P R China

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1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, P R China;
2Department of Haematology, Guangzhou Liuhuaqiao Hospital, Guangzhou, Guangdong province, P R China

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Поскольку в Китае введена политика &quot;одна семья-один ребенок&quot;, все больше альтернативных доноров, например, неродственных (НРД), привлекаются для лечения больных, требующих трансплантации и не имеющих HLA-идентичного донора из числа сибсов. Значительное возрастание числа неродственных ТГСК, проводимых в Китае, отмечено после того, как в 2001 году было официально начато обслуживание по китайской Программе доноров костного мозга, что привело к быстрому росту пула доноров. Наиболее частым показанием для неродственной ТГСК являются онкогематологические заболевания. Успехи в технологии HLA-типирования, сниженние интенсивности режимов кондиционирования и стратегии профилактики РТПХ в большой мере улучшили исходы и расширили пригодность неродственной ТГСК для пациентов. По мере быстрого экономического развития Китая, будет больше возможностей для развития потенциала ТГСК. </p> <h3>Ключевые слова</h3> <p>трансплантация гемопоэтических стволовых клеток, ТГСК, неродственные доноры, Китай" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2078) "

Число трансплантаций гемопоэтических стволовых клеток (ТГСК) в Китае резко возросло, особенно по сравнению с концом 90-х годов. Поскольку в Китае введена политика "одна семья-один ребенок", все больше альтернативных доноров, например, неродственных (НРД), привлекаются для лечения больных, требующих трансплантации и не имеющих HLA-идентичного донора из числа сибсов. Значительное возрастание числа неродственных ТГСК, проводимых в Китае, отмечено после того, как в 2001 году было официально начато обслуживание по китайской Программе доноров костного мозга, что привело к быстрому росту пула доноров. Наиболее частым показанием для неродственной ТГСК являются онкогематологические заболевания. Успехи в технологии HLA-типирования, сниженние интенсивности режимов кондиционирования и стратегии профилактики РТПХ в большой мере улучшили исходы и расширили пригодность неродственной ТГСК для пациентов. По мере быстрого экономического развития Китая, будет больше возможностей для развития потенциала ТГСК.

Ключевые слова

трансплантация гемопоэтических стволовых клеток, ТГСК, неродственные доноры, Китай" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2078) "

Число трансплантаций гемопоэтических стволовых клеток (ТГСК) в Китае резко возросло, особенно по сравнению с концом 90-х годов. Поскольку в Китае введена политика "одна семья-один ребенок", все больше альтернативных доноров, например, неродственных (НРД), привлекаются для лечения больных, требующих трансплантации и не имеющих HLA-идентичного донора из числа сибсов. Значительное возрастание числа неродственных ТГСК, проводимых в Китае, отмечено после того, как в 2001 году было официально начато обслуживание по китайской Программе доноров костного мозга, что привело к быстрому росту пула доноров. Наиболее частым показанием для неродственной ТГСК являются онкогематологические заболевания. Успехи в технологии HLA-типирования, сниженние интенсивности режимов кондиционирования и стратегии профилактики РТПХ в большой мере улучшили исходы и расширили пригодность неродственной ТГСК для пациентов. По мере быстрого экономического развития Китая, будет больше возможностей для развития потенциала ТГСК.

Ключевые слова

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Introduction

With damage to the nervous system, the activation of immune system and immune-mediated inflammatory reactions profoundly affect the ability of neurons to survive and to regenerate damaged axons. The role of inflammation, comprised mostly of macrophages, is controversial. Macrophages can cause neuronal and glial toxicity through the proinflammatory cytokines, free radicals, eicosanoids and proteases [9, 23]. However, recent studies have demonstrated that macrophages can enhance neuroprotection and promote long-distance axon growth, sprouting, and remyelination [20, 33]. The positive effects of macrophages in CNS repair are considered to be mediated through the several mechanisms including phagocytosis and clearance of cell debris and inhibitory molecules [3, 8]; limiting of glutamate-mediated excitotoxicity [31]; production of cytokines and growth factors with neuroprotective and regenerative activity [10, 14, 19, 26]; attraction and activation of stem cells and neural precursors [21, 38, 1], and recruitment of T-cells capable of local production of neurotrophic factors and regulating glial cells [17, 24]. The opposite effects of macrophages on CNS repair may be conditioned by the macrophage functional type. Thus, classical pro-inflammatory macrophages (M1) are tissue destructive, while anti-inflammatory (M2) macrophages mediate tissue repair [25, 15, 22, 20]. In addition, M2 macrophages predominantly induce the Th2 response, which is particularly beneficial in the CNS repair [16]. Therefore, M2-like macrophages may be prospective candidates for cell therapy of brain injuries [7].

Cerebral palsy (CP) is defined as a chronic non-progressive motor impairment syndrome due to a problem in the developing brain [28]. CP is manifested with spastic paralysis often in combination with epileptic seizures and/or mental impairment, caused by damage to the frontal cortical (mainly motor) area of the developing brain, mostly during pregnancy [29]. Sigmund Freud was the first who hypothesized that cerebral palsy may be closely associated with natal development. However, brain development continues during the first two years of life, so CP can result from brain injury occurring during the prenatal, perinatal, or postnatal periods. CP affects at least 2 in 1000 children, leading to more than 1 million chronic patients under the age of 21 [36]. Since this disease does not substantially reduce the lifespan, cerebral palsy is an important social and economic problem.

No evidence exists that the brain damage can be reversed; however, maturational and adaptive processes may change the clinical picture of the child over time. Treatment for cerebral palsy, therefore, has the goal not to cure or to achieve healthy subject states but to increase functionality, improve capabilities, and sustain health in terms of locomotion, cognitive functions, social interaction, and independence. Most children with cerebral palsy require lifelong medical and physical care, including physical, occupational, and speech/swallowing therapy.

At the moment there is no cure for CP, so currently available treatments for patients suffering from CP are only supportive, not curative [27]. This forces the search for new therapeutic approaches in the field of brain pathology. In this context cell transplantation has become a promising therapeutic option for CP treatment, and macrophages are considered to be prospective candidates for cell therapy.

Using growth factor deficiency conditions we have generated M2-like macrophages that had low antigen-presenting and proinflammatory activity and possessed considerable regenerative potential (in particular, produced high amounts of IGF-1 and VEGF) [7]. We hypothesized such macrophages may be useful in CNS repair, so evaluated the safety and therapeutic efficacy of endolumbar introduction of autological macrophages in treatment of children with cerebral palsy.

Patients and methods

Study design

This was a phase I/II non-randomized open-labeled clinical study of chronic children who had severe cerebral palsy and received transplantation of autologous M2-like macrophage. Treatment of CP children using autologous M2-like macrophages transplantation and all studies were performed in accordance with study protocols after obtaining written informed consent from patients’ parents. The clinical trial protocols and consent form were approved by the Institutional Academic Board and Institutional Review Board (Local Ethics Committee). The purpose of this study was to assess the safety and therapeutic efficacy of M2-like macrophages for treatment of CP patients. The families of all eligible patients were properly informed about the nature of the study.

Patients and selection criteria
   
Sixteen severely brain-injured, cerebral palsy children (n=16, 10 boys and 6 girls) were examined and subjected to cell transplantation therapy. Cerebral palsy was diagnosed in these children at 12 months. The age of the patients varied from 2 to 8 years (median 4.5 years). The time from diagnosis of CP to cell therapy ranged from 1 to 7 years. According to the developed protocol, generated macrophages were injected via lumbar puncture. All patients were followed up for the following 9 months after cell therapy. The inclusion criteria were: 1) age ≥ 12 months and ≤ 8 years; 2) diagnosis: spastic cerebral palsy with quadriplegia; 3) performance status: Gross Motor Function Classification System at level IV–V; and 4) parental consent. The exclusion criteria were: 1) autism and autistic spectrum disorders without motor disability; 2) progressive neurologic disease; 3) HIV or uncontrolled bacterial, fungal, or viral infections; 4) impaired renal or liver function (as determined by serum creatinine >1.5mg/dL and/or total bilirubin >1.3mg/dL); 5) genetic disease or phenotypic evidence of a genetic disease on physical examination; 6) requires ventilatory support; 7) unable to obtain parental consent.

Macrophage generation and assessment

Human peripheral blood mononuclear cells (PBMCs) were obtained through density gradient centrifugation (Ficoll-Paque, Sigma-Aldrich, Germany) of heparinized whole blood samples. For monocyte separation PBMCs were plated at 3–5 x106/ml in tissue culture dishes (TPP, Switzerland) in RPMI-1640 (Sigma-Aldrich, Germany) with 5% FCS (Biolot, Russia) for 18 h and then washed to remove non-adherent residual lymphocytes. The percentage of CD14-positive cells was demonstrated by flow cytometry to be greater than 90–93% of the total cells recovered. The generation of macrophages from plastic-adherent cells was performed according previously developed protocol [7]. In brief, adherent cells were cultured in RPMI-1640 with supplements at 37°C with 5% CO2. To receive M2-like macrophages we used recombinant human GM-CSF (rhGM-CSF, 50 ng/ml, R&D Systems, USA) and serum deprivation conditions (low percent of autologous plasma). In 7 days the macrophages were harvested by using EDTA in Hanks' balanced salt solution, washed and counted. Then the generated M2-like macrophages were resuspended in 2 ml sodium chloride 0.9 % and infused into the spinal cord fluid of the patient.

For evaluation of the phenotype, cell suspensions were incubated for 20 min at 4°C with FITC- or PE-conjugated antibodies specific for human CD14, CD86, and HLA-DR or isotype controls (all from BD Biosciences, USA). Then cells were washed with PBS/ 0.1% sodium azide/ 0.1% bovine serum albumin, and analyzed with a FACSCalibur using CellQuest software (BD Biosciences).

The antigen-presenting/allostimulatory activity of the macrophages was determined by measuring macrophage capacity to induce T -cell proliferation in the mixed lymphocyte culture (MLC). Briefly, 1x104 macrophages were plated in complete RPMI-1640 with 1x105 allogeneic responder PBMCs for 5 days. Cell proliferation was measured by [3H]thymidine incorporation (1 μCi/well for 18 h). The stimulatory capacity of macrophages in MLC was expressed by the stimulation index (SI) = cpm in MLC (PBMCs+macrophages) / cpm in control culture (PBMCs alone). Th1, Th17 and Th2 - stimulatory activity was assessed by measuring of IFN-γ, IL-17 and IL-4/IL-10 in supernatants of MLC induced by macrophages. The stimulation index (SI) was calculated as ratio of cytokine level in MLC to spontaneous cytokine production in PBMCs alone.

The CP children’s serum samples obtained before and after macrophage introduction were collected and frozen at –80°C until the measurement. The concentration of secreted cytokines and growth factors was determined using ELISA following the instructions of manufacturers: IFN-γ, IL-17, IL-4 (all from Protein Contour, St-Petersburg, Russia), brain-derived neurotrophic factor (BDNF; R&D Systems, USA) and vascular endothelial growth factor (VEGF; Invitrogen Corp., USA).

Measurement of safety and efficacy

All patients were evaluated according to a protocol by 3 independent experts including a neurologist, a neurosurgeon and one child's parents. Study evaluations consisted of thorough physical and neurological examinations and evaluations of adverse effects. The time from macrophage introduction to response was 3 months. The primary measure of efficacy was the improvement of motor functions of CP patients. To assess patients’ motor abilities we used the Gross Motor Function Measure (an 88-item GMFM test), a criterion-referenced observational measure that was developed and validated to assess children with cerebral palsy [32]. The GMFM test includes evaluation of 88 items divided into 5 sections: 1, lying and rolling; 2, sitting; 3, crawling and kneeling; 4, standing; and 5, walking, running, and jumping. It evaluates the skills of the child in the individual items by using a 4-point scale on a quantitative basis. A secondary objective was to determine the effects on spasticity and muscle strength as well as mental faculties in these children. The five-point Ashworth scale was used for evaluating the degree of spasticity, and the six-point Medical Research Council Weakness Scale (MRC) served for muscle strength estimation.

In addition, we monitored the immediate reactions possibly related to the endolumbar introduction of autologous M2-like macrophages, which included allergic reactions (tachycardia, fever, skin eruption, leukocytosis) and local complications (hematoma or local infection).

Statistical analysis

The data were expressed as means ± SE. Statistica 6.0 software for Windows, StatSoft Inc. USA was used for analysis of data. Mean differences between groups were compared by a sign test. Additionally, the Mann–Whitney U test was used to compare nonparametric values.

Results

As shown in Table 1, the majority of children were diagnosed with severe spastic cerebral palsy, which can be considered the hallmark of our investigation. We did not have even a single child with a mild form of CP (when the use of both hands and/or gait is clumsy) and only one patient was diagnosed with a moderate degree of disease (characterized by the ability to use the affected hand in bimanual activities and/or impaired gait) [18]. It is evident from Table 1 that the examined children formed quite a homogenous group presumably with spastic forms of cerebral palsy (spastic quadriplegia was revealed in 14/16 children). The GMFM-88 score at entry was 12.1 ± 9.0. The majority of CP children had the fifth level of movement abnormalities, wher the child did not hold ,his head and back, all motor functions were limited, and these movement defects were not compensated by additional means.

Evaluating the degree of spasticity based on the Ashworth scale evidenced a considerable (4–5 point) increase in muscle tone in 14 out of 16 (87.5%) of CP children with an average Ashworth score of 3.9 ± 0.2. In two children even passive movements were hampered, and spasticity achieved 5 points. The MRC weakness score reflecting muscle strength in forearms was 1.8 ± 0.15, which indicated a marked reduction in muscle strength in all children at baseline. More than one third of CP children (6/16) had epileptic seizures. Mental faculties were impaired in virtually all patients. In fact, 14 out of 16 children had no capacity to speak, and 9 out of 16 did not understand addressed speech.

Table 1. Patients’ characteristics

Number

16

Gender (Boy/Girl)

10/6

Age (median), years

4.5 (2-8)

CP forms:
      -    spastic
      -    dystonic
      -    atonia-ataxia
      -    mixed


12 (75%)
1 (6.2%)
2 (12.5%)
1 (6.2%)

Motor dysfunctions
(according to Gross Motor Function Classification System):
      -    level IV
      -    level V



2 (12.5%)
14 (87.5%)

Degree of spasticity (based on Ashworth scale):
      -    level I–III
      -    level IV
      -    level V 


12.5%
75 %
12.5%

Muscle strength (points, MRC):
      -    1 point
      -    2 points
      -    3 points


37.5%
50%
12.5%

Epileptic seizures

6 (37.5%)

Mental deficiency
      -    non-understanding of addressed speech
      -    non-speaking


9 (56%)
14 (88%)

Cell Ther Transplant. 2011;3:e.000092.01. doi:10.3205/ctt-2011-en-000092-table1


Each of sixteen trial patients received one grafting of autologous macrophages generated from their own peripheral blood according to our protocol (see Patients and methods). The motor and mental faculties of these CP children were evaluated at 3 months after the cell transplantation by 3 independent experts including a neurologist, a neurosurgeon and one child's parents. It is of great importance that their opinions practically coincided and the difference in their assessments was minimal.

First, we proved the principle possibility of generating M2-like macrophages in children with CP. Mean cell yield of macrophages was 77.1 ± 13.4x103 from 1x106 peripheral blood mononuclear cells. On average 0.8 ± 0.15 x 106/kg M2-like macrophages (0.18–2.58 x 106/kg) were used for the introduction (Table 2). The viability of the obtained cells in all cases was more than 90%.

Table 2. Macrophage characteristic and cell therapy safety

Macrophage characteristic

Macrophage yield (from 1x106 MNCs)

77.1 ± 13.4x103

Number of macrophages х106/kg (M ± m, median)

0.8 ± 0.15 (0.6)

Cell viability

> 90%

Immunophenotype (% positive cells, min-max):
     HLA-DR
     CD14
     CD86


22–87
47–90
11–20

The ability to induce allo-T-cell response in MLC
(stimulation index, SI)


0.36 – 1.46

Cell therapy safety

Febrile temperature ± 1–2 fold vomiting in the first two days

10 (62.5%)

Subfebrile temperature without vomiting

1 (6.25%)

Local inflammatory or allergic reactions

0

Meningism

0

Local or systemic infections

0

Exacerbation of comorbidity
- Atopic dermatitis


1 (6.25%)

Cell Ther Transplant. 2011;3:e.000092.01. doi:10.3205/ctt-2011-en-000092-table2


Moreover, evaluation of these M2-like cells to stimulate various T–helper cells revealed that M2-like cells similar to M1 macrophages induce T lymphocytes to produce IL-4 and presumably IL-10, but in contrast to M1 did not induce secretion of Th1 (IFN-γ) and Th17 (IL-17) cytokines. In M1-stimulated cultures, a pronounced stimulation of IFN-γ and IL-17 was observed: 344 ± 104 pg/ml (SI 32.6 ± 11.1) and 402 ± 167 pg/ml (SI 80 ± 33), respectively. In marked contrast, M2-like macrophages did not induce nor IFN-γ (32 ± 21 pg/ml; SI 3.2 ± 2.1), or IL-17 (11 ± 4 pg/ml; SI 2.2 ± 0.76). At the same time both M1 and M2-like macrophages stimulated an equal production of Th2 cytokines (IL-4 and IL-10) in MLC: 115 ± 39 and 78 ± 38 pg/ml for IL-10 as well as 109 ± 24 and 97 ± 15 pg/ml for IL-4.

Endolumbar administration of M2-like cells was accompanied by fever and 1–2 fold vomiting in 10 out of 16 children (63%). These cell-therapy-related reactions never lasted longer than one or two days and were easily abrogated by the use of Dexasone and Cerucal. We did not observe any local or systemic immediate hypersensitivity reactions, local hematoma, or infection complications due to cell transplantation. However, one child demonstrated the exacerbation of atopic dermatitis.

As shown in Table 3, three months after cell therapy a significant decrease in spasticity was revealed. In the lower extremities of the CP children Ashworth scores decreased from 3.9 ± 0.2 to 3.1 ± 0.2 (p<0.01) while the muscle strength in the forearms was enhanced from 1.8 ± 0.15 to 2.9 ± 0.22 (p<0.05). The Gross Motor Function Measure test improved significantly from 12.1 ± 9.0 to 60 ± 19 points (p <0.01).

Table 3. Neurological improvement at three months after macrophage introduction

Parameters

Before cell therapy

After cell therapy

Degree of spasticity (Ashworth scale)

3.9 ± 0.2

3.1 ± 0.2**

Muscle strength in the forearms (MRC)

1.8 ± 0.15

2.9 ± 0.2*

Motor dysfunctions (GMFM-88)

12.1 ± 9.0

60  ± 19**

Note: * - p<0.05 and ** - p<0.01; sign test was used to determine the significance

Cell Ther Transplant. 2011;3:e.000092.01. doi:10.3205/ctt-2011-en-000092-table3


Apparent clinical improvements were noted in 11 out of sixteen cell-grafted CP children (68.8%; responding group). With the cell-based therapy, two-thirds of CP children (11/16) initially unable to retain their head in the vertical position independently became able to consistently execute this function. Among 15 children who initially failed to sit, after cell therapy 9 could sit without assistance. The majority of CP children involved in our investigation had no capacity to crawl. Only one boy could crawl on his abdomen, and two from 16 children could crawl/move on their backs by pushing their feet. With M2-therapy, eight children (43%) became able to crawl/move on their backs. Three of six children with seizure syndrome experienced seizures arrest, which persisted after the discontinuation of anticonvulsants.

Cell therapy significantly influenced mental functions. We observed a decrease in aggression (63%) and improvement of contact with outsiders (69%). Four children improved mental functions; they became able to understand or understand better the addressed speech (2/9) and showed the appearance of a meaning-bearing speech (2/14).

It should be noted that improvement of motor functions and mental abilities once registered  at 3 months following cell administration persisted without reversion during the whole period of observation (until one year in some children).

Comparing children responding and not responding to cell therapy, we found some trends. First, the CP children with improved motor and/or mental functions were younger (4.6 ± 0.6 vs 6.4 ± 0.8 years; pU >0.05). Second, they received higher number of input cells (0.74 ± 0.15 vs 0.59 ± 0.17 х 106/kg; pU >0.05). And, finally, the development of cytokine reactions in children who responded to cell therapy was observed twice as often (in 82% vs. 40%) as in the non-responsived group.

Analysis of some cytokines and growth factor levels in the serum of CP children showed that the macrophage introduction was not accompanied by an increase of IFN- γ, IL-17, and IL-4. At the same time, such a therapy resulted in significant enhancement of brain-derived neurotrophic factor (BDNF; from 695 ± 60 to 1183 ± 153 pg/ml; pU =0.015) and strong tendency to an increase of vascular endothelial growth factor (VEGF; from 190 ± 41 to 240 ± 40 pg/ml; pU =0.07). It is of great importance that these changes were the most pronounced in the responder group.

Table 4. Cytokine and growth factor levels in the serum

Cytokine/growth factor (pg/ml)

Before cell therapy

After cell therapy

M ± m

BDNF

695 ± 60

1183 ± 153 *

VEGF

190 ± 41

240 ± 40

IFN-γ

1.0 ± 0.6

1.0 ± 0.4

IL-17

<OOR

1.0 ±1.0

IL-4

14 ± 4.1

10.0 ± 2.7

Note: < OOR out of range (the minimum detectable dose of IL-17 is 5ng/ml)

Cell Ther Transplant. 2011;3:e.000092.01. doi:10.3205/ctt-2011-en-000092-table4


Some examples of applying the cell transplantation therapy for cerebral palsy are described below.

The 2-year-old boy N. was evaluated for developmental delay at the age of 2 years. He was born as a result of premature delivery at 28 weeks, weighing 1200 g. The boy was from the second pregnancy (the first childbirth) with danger of fetus wastage. He stayed in the Intensive Care Unit for 16 days and in the Department of Newborn Pathology for 1 month.

On admission all motor and mental functions were profoundly defective. The patient demonstrated global developmental delay. The boy was incapable of turning from abdomen to back, holding a toy in his hand, sitting, standing, and walking. He kept his head in an upright position with great difficulty. He was incapable of tracking a toy with his eyes, speaking, and understanding addressed speech. Epileptic seizures occurred up to 6 times a day. The GMFM-88 score was 0, degree of spasticity according to the Ashworth scale was 4, and muscle strength in the forearms was reduced, at only 2 points.

The treatment included endolumbar administration of generated autologous M2-like macrophages (total dose 3.1x106; 0.22x x106/kg). Cell introduction was accompanied by subfebrile fever and one episode of vomiting. Three months later the patient could turn from abdomen to back, hold a toy in his hands, sit, stand with support and retain his head in a vertical position. His epileptic seizures have completely stopped. The GMFM-88 score increased up to 164 and muscle strength in the forearms enhanced up to 4, while spasticity decreased to 2 points.

At 6 months after therapy the boy could understand addressed speech. The child gained weight. He is without anticonvulsant therapy for 1 year.

The 5-year-old boy G.
with cerebral palsy was from the fourth pregnancy with danger of fetus wastage. The childbirth was the second, premature at 32 weeks, as a result of Cesarean section. The newborn child had a weight of 2025 g. Prematurity II. He stayed in the Department of Newborn Pathology for 1 month. At one year, following a detailed assessment, the child was assigned a diagnosis of moderately severe spastic quadriplegia cerebral palsy. 

On admission the patient could crawl, sit, stand with assistance, understood addressed speech and spoke.  At the same time the boy was unable to walk without assistance and could not retain his head in a vertical position. Intelligence was unaffected. The GMFM-88 score was 158, degree of spasticity according to the Ashworth scale was 4, and muscle strength in the forearms was reduced, at 2 points. The treatment included endolumbar administration of generated autologous M2-like macrophages (5.2x106; 0.31x x106/kg). Three months later the patient could walk without support and retain his head in a vertical position. The boy could make attempts to run with wide-set legs and walk up the stairs without support. The GMFM-88 score increased to 217 and muscle strength in the forearms was enhanced to 4, while spasticity decreased to 2 points.

Discussion

The brain possesses a limited capacity for endogenous regeneration after various insults, including perinatal hypoxia/ischemia. Therefore, the treatment of cerebral palsy as neurologic sequelae of hypoxia/ischemia-induced damage demands regenerative strategies. Recent studies have demonstrated that macrophages can enhance neuroprotection and promote axon growth, sprouting and remyelination [11]. Moreover, promotion of neuroregeneration was shown to be mediated predominantly by M2 anti-inflammatory macrophages [33, 20]. The present study provides the first evidence for the possible application of M2-like macrophages for the treatment of cerebral palsy.

The evaluation of macrophage capacity to activate various types of T-helper cells as the first step of the present study revealed that generated M2-like macrophages did not stimulate T cells to produce IFN-γ and IL-17. This can be considered as the basic difference between the two types of macrophages investigated in our study, since classical M1 macrophages did induce substantial Th1 and Th17 cytokine production. With regard to Th2-stimulatory activity, M2-like macrophages did not differ from the M1 analogue as both stimulate detectable levels of IL-4 and IL-10. The last data are of great importance since Th2 cells are known to support neuron survival better than Th1 cells and in contrast to Th1 significantly stimulate axonal outgrowth. Namely, Th2 cells stimulate glial cells to produce neurotrophic factors without inducing inflammation[16]. Therefore, Th2-stimulatory activity of M2-like macrophages constituted an additional reason for the application of these cells for CNS repair.

In our study, we have shown that M2-like macrophages may be successfully generated in children with CP, and macrophage yields and functions in these cases are compared with that of adult healthy individuals [7]. Moreover, we first demonstrated that the introduction of M2-like macrophages via lumbar puncture in children with CP was safe, well tolerated and did not induce serious adverse reactions. Fever following macrophage administration observed in more than half of the patients was simply stopped with medication. There was no evidence of local immediate hypersensitivity reactions, hematoma, or infection at the site of the cell injection, and any serious infection complications related to the cell transplantation. Aggravation of atopic dermatitis registered in one person suggested the capacity of generated macrophages to activate Th2 response in vivo. This fact calls for a careful examination of patients for allergic diseases and may be exclusion criteria for M2 macrophage application in children with severe and diffuse forms of atopic pathology. On the other hand, exacerbation of atopic dermatitis in only one out of 16 cases evidenced that endolumbar application of macrophages obviously did not induce systemic activation of the Th2 response. This suggestion is confirmed by the results of IL-4 measurements of the serum of treated children. Indeed, we did not observe any enhancement of IL-4 serum levels after the introduction of M2-like macrophages.

Despite our clinical trial enrolling children with severe impairment of motor functions (predominantly V level of Gross Motor Function Classification System), cell therapy was accompanied by significant decreases in spasticity, increased muscle strength and enhancement of GMFM scores. Along with the increase in motor functions, more than half of the children displayed a decrease in aggressiveness and an improvement in communication with strangers. Enhancement of mental functions was also confirmed by appearance of the capacity to understand in two children and to speak in another two participants. In addition, three of six persons experienced full arrest of their seizure syndrome. Current therapeutic strategies of CP management are aimed at preventing brain damage, but at present there are no effective means to repair the brain once damage has occurred. From this point of view, our data are of significant importance. Similar results have been described recently by Chen L. et al. after introduction of olfactory ensheathing cells (OECs). These authors showed that OECs derived from aborted fetal tissue and injected into the bilateral corona radiata in the frontal lobes resulted in a significant increase of GMFM-88 score and improvement of mental functions in CP, according to the Caregiver Questionnaire Scale score [6]. 

The mechanisms underlying the clinical effects of M2-like macrophages in CP patients are not quite clear. We would like to point out some of them. As we have shown previously, М2-like macrophages are capable of spontaneous production of BDNF, IFG-1, EGF, bFGF, G-CSF, erythropoietin and VEGF, which possess neuroprotective activity and stimulate CNS regeneration [7]. Stimulation of CNS repair in ischemic brain damage may also be the result of increased angiogenesis and vasculogenesis [2, 37]. In this connection an increase in serum levels of BDNF and VEGF following cell therapy indicate that clinical effects may be mediated by growth factors produced by macrophages or other paracrine-activated cells. Finally, recent findings showed that monocytes/macrophages are able to differentiate into endothelium-like cells and function as precursors of endothelial cells [30] and thus participate in the repair of the vascular barrier after brain injury [12].
  
At the same time it should be emphasized that macrophage injection via lumbar puncture was not accompanied by an increase of serum IFN-γ or IL-17. Proinflammatory cytokines IFN-γ and IL-17 are known to have marked destructive effects on the nervous system [34, 35]. From this point of view, the data that M2-like macrophages lack Th1- and Th17-stimulatory activity in vitro and in vivo are additional arguments evidencing the safety of their application. However, to better define the therapeutic effects of these cells in CP, randomized, controlled prospective trials and long-term follow-up are required.

Acknowledgments

We are grateful to the parents of the CP children for their courage, perseverance, and faith in us. 
Competing interests: The authors have declared that no competing interests exist.

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Introduction

With damage to the nervous system, the activation of immune system and immune-mediated inflammatory reactions profoundly affect the ability of neurons to survive and to regenerate damaged axons. The role of inflammation, comprised mostly of macrophages, is controversial. Macrophages can cause neuronal and glial toxicity through the proinflammatory cytokines, free radicals, eicosanoids and proteases [9, 23]. However, recent studies have demonstrated that macrophages can enhance neuroprotection and promote long-distance axon growth, sprouting, and remyelination [20, 33]. The positive effects of macrophages in CNS repair are considered to be mediated through the several mechanisms including phagocytosis and clearance of cell debris and inhibitory molecules [3, 8]; limiting of glutamate-mediated excitotoxicity [31]; production of cytokines and growth factors with neuroprotective and regenerative activity [10, 14, 19, 26]; attraction and activation of stem cells and neural precursors [21, 38, 1], and recruitment of T-cells capable of local production of neurotrophic factors and regulating glial cells [17, 24]. The opposite effects of macrophages on CNS repair may be conditioned by the macrophage functional type. Thus, classical pro-inflammatory macrophages (M1) are tissue destructive, while anti-inflammatory (M2) macrophages mediate tissue repair [25, 15, 22, 20]. In addition, M2 macrophages predominantly induce the Th2 response, which is particularly beneficial in the CNS repair [16]. Therefore, M2-like macrophages may be prospective candidates for cell therapy of brain injuries [7].

Cerebral palsy (CP) is defined as a chronic non-progressive motor impairment syndrome due to a problem in the developing brain [28]. CP is manifested with spastic paralysis often in combination with epileptic seizures and/or mental impairment, caused by damage to the frontal cortical (mainly motor) area of the developing brain, mostly during pregnancy [29]. Sigmund Freud was the first who hypothesized that cerebral palsy may be closely associated with natal development. However, brain development continues during the first two years of life, so CP can result from brain injury occurring during the prenatal, perinatal, or postnatal periods. CP affects at least 2 in 1000 children, leading to more than 1 million chronic patients under the age of 21 [36]. Since this disease does not substantially reduce the lifespan, cerebral palsy is an important social and economic problem.

No evidence exists that the brain damage can be reversed; however, maturational and adaptive processes may change the clinical picture of the child over time. Treatment for cerebral palsy, therefore, has the goal not to cure or to achieve healthy subject states but to increase functionality, improve capabilities, and sustain health in terms of locomotion, cognitive functions, social interaction, and independence. Most children with cerebral palsy require lifelong medical and physical care, including physical, occupational, and speech/swallowing therapy.

At the moment there is no cure for CP, so currently available treatments for patients suffering from CP are only supportive, not curative [27]. This forces the search for new therapeutic approaches in the field of brain pathology. In this context cell transplantation has become a promising therapeutic option for CP treatment, and macrophages are considered to be prospective candidates for cell therapy.

Using growth factor deficiency conditions we have generated M2-like macrophages that had low antigen-presenting and proinflammatory activity and possessed considerable regenerative potential (in particular, produced high amounts of IGF-1 and VEGF) [7]. We hypothesized such macrophages may be useful in CNS repair, so evaluated the safety and therapeutic efficacy of endolumbar introduction of autological macrophages in treatment of children with cerebral palsy.

Patients and methods

Study design

This was a phase I/II non-randomized open-labeled clinical study of chronic children who had severe cerebral palsy and received transplantation of autologous M2-like macrophage. Treatment of CP children using autologous M2-like macrophages transplantation and all studies were performed in accordance with study protocols after obtaining written informed consent from patients’ parents. The clinical trial protocols and consent form were approved by the Institutional Academic Board and Institutional Review Board (Local Ethics Committee). The purpose of this study was to assess the safety and therapeutic efficacy of M2-like macrophages for treatment of CP patients. The families of all eligible patients were properly informed about the nature of the study.

Patients and selection criteria
   
Sixteen severely brain-injured, cerebral palsy children (n=16, 10 boys and 6 girls) were examined and subjected to cell transplantation therapy. Cerebral palsy was diagnosed in these children at 12 months. The age of the patients varied from 2 to 8 years (median 4.5 years). The time from diagnosis of CP to cell therapy ranged from 1 to 7 years. According to the developed protocol, generated macrophages were injected via lumbar puncture. All patients were followed up for the following 9 months after cell therapy. The inclusion criteria were: 1) age ≥ 12 months and ≤ 8 years; 2) diagnosis: spastic cerebral palsy with quadriplegia; 3) performance status: Gross Motor Function Classification System at level IV–V; and 4) parental consent. The exclusion criteria were: 1) autism and autistic spectrum disorders without motor disability; 2) progressive neurologic disease; 3) HIV or uncontrolled bacterial, fungal, or viral infections; 4) impaired renal or liver function (as determined by serum creatinine >1.5mg/dL and/or total bilirubin >1.3mg/dL); 5) genetic disease or phenotypic evidence of a genetic disease on physical examination; 6) requires ventilatory support; 7) unable to obtain parental consent.

Macrophage generation and assessment

Human peripheral blood mononuclear cells (PBMCs) were obtained through density gradient centrifugation (Ficoll-Paque, Sigma-Aldrich, Germany) of heparinized whole blood samples. For monocyte separation PBMCs were plated at 3–5 x106/ml in tissue culture dishes (TPP, Switzerland) in RPMI-1640 (Sigma-Aldrich, Germany) with 5% FCS (Biolot, Russia) for 18 h and then washed to remove non-adherent residual lymphocytes. The percentage of CD14-positive cells was demonstrated by flow cytometry to be greater than 90–93% of the total cells recovered. The generation of macrophages from plastic-adherent cells was performed according previously developed protocol [7]. In brief, adherent cells were cultured in RPMI-1640 with supplements at 37°C with 5% CO2. To receive M2-like macrophages we used recombinant human GM-CSF (rhGM-CSF, 50 ng/ml, R&D Systems, USA) and serum deprivation conditions (low percent of autologous plasma). In 7 days the macrophages were harvested by using EDTA in Hanks' balanced salt solution, washed and counted. Then the generated M2-like macrophages were resuspended in 2 ml sodium chloride 0.9 % and infused into the spinal cord fluid of the patient.

For evaluation of the phenotype, cell suspensions were incubated for 20 min at 4°C with FITC- or PE-conjugated antibodies specific for human CD14, CD86, and HLA-DR or isotype controls (all from BD Biosciences, USA). Then cells were washed with PBS/ 0.1% sodium azide/ 0.1% bovine serum albumin, and analyzed with a FACSCalibur using CellQuest software (BD Biosciences).

The antigen-presenting/allostimulatory activity of the macrophages was determined by measuring macrophage capacity to induce T -cell proliferation in the mixed lymphocyte culture (MLC). Briefly, 1x104 macrophages were plated in complete RPMI-1640 with 1x105 allogeneic responder PBMCs for 5 days. Cell proliferation was measured by [3H]thymidine incorporation (1 μCi/well for 18 h). The stimulatory capacity of macrophages in MLC was expressed by the stimulation index (SI) = cpm in MLC (PBMCs+macrophages) / cpm in control culture (PBMCs alone). Th1, Th17 and Th2 - stimulatory activity was assessed by measuring of IFN-γ, IL-17 and IL-4/IL-10 in supernatants of MLC induced by macrophages. The stimulation index (SI) was calculated as ratio of cytokine level in MLC to spontaneous cytokine production in PBMCs alone.

The CP children’s serum samples obtained before and after macrophage introduction were collected and frozen at –80°C until the measurement. The concentration of secreted cytokines and growth factors was determined using ELISA following the instructions of manufacturers: IFN-γ, IL-17, IL-4 (all from Protein Contour, St-Petersburg, Russia), brain-derived neurotrophic factor (BDNF; R&D Systems, USA) and vascular endothelial growth factor (VEGF; Invitrogen Corp., USA).

Measurement of safety and efficacy

All patients were evaluated according to a protocol by 3 independent experts including a neurologist, a neurosurgeon and one child's parents. Study evaluations consisted of thorough physical and neurological examinations and evaluations of adverse effects. The time from macrophage introduction to response was 3 months. The primary measure of efficacy was the improvement of motor functions of CP patients. To assess patients’ motor abilities we used the Gross Motor Function Measure (an 88-item GMFM test), a criterion-referenced observational measure that was developed and validated to assess children with cerebral palsy [32]. The GMFM test includes evaluation of 88 items divided into 5 sections: 1, lying and rolling; 2, sitting; 3, crawling and kneeling; 4, standing; and 5, walking, running, and jumping. It evaluates the skills of the child in the individual items by using a 4-point scale on a quantitative basis. A secondary objective was to determine the effects on spasticity and muscle strength as well as mental faculties in these children. The five-point Ashworth scale was used for evaluating the degree of spasticity, and the six-point Medical Research Council Weakness Scale (MRC) served for muscle strength estimation.

In addition, we monitored the immediate reactions possibly related to the endolumbar introduction of autologous M2-like macrophages, which included allergic reactions (tachycardia, fever, skin eruption, leukocytosis) and local complications (hematoma or local infection).

Statistical analysis

The data were expressed as means ± SE. Statistica 6.0 software for Windows, StatSoft Inc. USA was used for analysis of data. Mean differences between groups were compared by a sign test. Additionally, the Mann–Whitney U test was used to compare nonparametric values.

Results

As shown in Table 1, the majority of children were diagnosed with severe spastic cerebral palsy, which can be considered the hallmark of our investigation. We did not have even a single child with a mild form of CP (when the use of both hands and/or gait is clumsy) and only one patient was diagnosed with a moderate degree of disease (characterized by the ability to use the affected hand in bimanual activities and/or impaired gait) [18]. It is evident from Table 1 that the examined children formed quite a homogenous group presumably with spastic forms of cerebral palsy (spastic quadriplegia was revealed in 14/16 children). The GMFM-88 score at entry was 12.1 ± 9.0. The majority of CP children had the fifth level of movement abnormalities, wher the child did not hold ,his head and back, all motor functions were limited, and these movement defects were not compensated by additional means.

Evaluating the degree of spasticity based on the Ashworth scale evidenced a considerable (4–5 point) increase in muscle tone in 14 out of 16 (87.5%) of CP children with an average Ashworth score of 3.9 ± 0.2. In two children even passive movements were hampered, and spasticity achieved 5 points. The MRC weakness score reflecting muscle strength in forearms was 1.8 ± 0.15, which indicated a marked reduction in muscle strength in all children at baseline. More than one third of CP children (6/16) had epileptic seizures. Mental faculties were impaired in virtually all patients. In fact, 14 out of 16 children had no capacity to speak, and 9 out of 16 did not understand addressed speech.

Table 1. Patients’ characteristics

Number

16

Gender (Boy/Girl)

10/6

Age (median), years

4.5 (2-8)

CP forms:
      -    spastic
      -    dystonic
      -    atonia-ataxia
      -    mixed


12 (75%)
1 (6.2%)
2 (12.5%)
1 (6.2%)

Motor dysfunctions
(according to Gross Motor Function Classification System):
      -    level IV
      -    level V



2 (12.5%)
14 (87.5%)

Degree of spasticity (based on Ashworth scale):
      -    level I–III
      -    level IV
      -    level V 


12.5%
75 %
12.5%

Muscle strength (points, MRC):
      -    1 point
      -    2 points
      -    3 points


37.5%
50%
12.5%

Epileptic seizures

6 (37.5%)

Mental deficiency
      -    non-understanding of addressed speech
      -    non-speaking


9 (56%)
14 (88%)

Cell Ther Transplant. 2011;3:e.000092.01. doi:10.3205/ctt-2011-en-000092-table1


Each of sixteen trial patients received one grafting of autologous macrophages generated from their own peripheral blood according to our protocol (see Patients and methods). The motor and mental faculties of these CP children were evaluated at 3 months after the cell transplantation by 3 independent experts including a neurologist, a neurosurgeon and one child's parents. It is of great importance that their opinions practically coincided and the difference in their assessments was minimal.

First, we proved the principle possibility of generating M2-like macrophages in children with CP. Mean cell yield of macrophages was 77.1 ± 13.4x103 from 1x106 peripheral blood mononuclear cells. On average 0.8 ± 0.15 x 106/kg M2-like macrophages (0.18–2.58 x 106/kg) were used for the introduction (Table 2). The viability of the obtained cells in all cases was more than 90%.

Table 2. Macrophage characteristic and cell therapy safety

Macrophage characteristic

Macrophage yield (from 1x106 MNCs)

77.1 ± 13.4x103

Number of macrophages х106/kg (M ± m, median)

0.8 ± 0.15 (0.6)

Cell viability

> 90%

Immunophenotype (% positive cells, min-max):
     HLA-DR
     CD14
     CD86


22–87
47–90
11–20

The ability to induce allo-T-cell response in MLC
(stimulation index, SI)


0.36 – 1.46

Cell therapy safety

Febrile temperature ± 1–2 fold vomiting in the first two days

10 (62.5%)

Subfebrile temperature without vomiting

1 (6.25%)

Local inflammatory or allergic reactions

0

Meningism

0

Local or systemic infections

0

Exacerbation of comorbidity
- Atopic dermatitis


1 (6.25%)

Cell Ther Transplant. 2011;3:e.000092.01. doi:10.3205/ctt-2011-en-000092-table2


Moreover, evaluation of these M2-like cells to stimulate various T–helper cells revealed that M2-like cells similar to M1 macrophages induce T lymphocytes to produce IL-4 and presumably IL-10, but in contrast to M1 did not induce secretion of Th1 (IFN-γ) and Th17 (IL-17) cytokines. In M1-stimulated cultures, a pronounced stimulation of IFN-γ and IL-17 was observed: 344 ± 104 pg/ml (SI 32.6 ± 11.1) and 402 ± 167 pg/ml (SI 80 ± 33), respectively. In marked contrast, M2-like macrophages did not induce nor IFN-γ (32 ± 21 pg/ml; SI 3.2 ± 2.1), or IL-17 (11 ± 4 pg/ml; SI 2.2 ± 0.76). At the same time both M1 and M2-like macrophages stimulated an equal production of Th2 cytokines (IL-4 and IL-10) in MLC: 115 ± 39 and 78 ± 38 pg/ml for IL-10 as well as 109 ± 24 and 97 ± 15 pg/ml for IL-4.

Endolumbar administration of M2-like cells was accompanied by fever and 1–2 fold vomiting in 10 out of 16 children (63%). These cell-therapy-related reactions never lasted longer than one or two days and were easily abrogated by the use of Dexasone and Cerucal. We did not observe any local or systemic immediate hypersensitivity reactions, local hematoma, or infection complications due to cell transplantation. However, one child demonstrated the exacerbation of atopic dermatitis.

As shown in Table 3, three months after cell therapy a significant decrease in spasticity was revealed. In the lower extremities of the CP children Ashworth scores decreased from 3.9 ± 0.2 to 3.1 ± 0.2 (p<0.01) while the muscle strength in the forearms was enhanced from 1.8 ± 0.15 to 2.9 ± 0.22 (p<0.05). The Gross Motor Function Measure test improved significantly from 12.1 ± 9.0 to 60 ± 19 points (p <0.01).

Table 3. Neurological improvement at three months after macrophage introduction

Parameters

Before cell therapy

After cell therapy

Degree of spasticity (Ashworth scale)

3.9 ± 0.2

3.1 ± 0.2**

Muscle strength in the forearms (MRC)

1.8 ± 0.15

2.9 ± 0.2*

Motor dysfunctions (GMFM-88)

12.1 ± 9.0

60  ± 19**

Note: * - p<0.05 and ** - p<0.01; sign test was used to determine the significance

Cell Ther Transplant. 2011;3:e.000092.01. doi:10.3205/ctt-2011-en-000092-table3


Apparent clinical improvements were noted in 11 out of sixteen cell-grafted CP children (68.8%; responding group). With the cell-based therapy, two-thirds of CP children (11/16) initially unable to retain their head in the vertical position independently became able to consistently execute this function. Among 15 children who initially failed to sit, after cell therapy 9 could sit without assistance. The majority of CP children involved in our investigation had no capacity to crawl. Only one boy could crawl on his abdomen, and two from 16 children could crawl/move on their backs by pushing their feet. With M2-therapy, eight children (43%) became able to crawl/move on their backs. Three of six children with seizure syndrome experienced seizures arrest, which persisted after the discontinuation of anticonvulsants.

Cell therapy significantly influenced mental functions. We observed a decrease in aggression (63%) and improvement of contact with outsiders (69%). Four children improved mental functions; they became able to understand or understand better the addressed speech (2/9) and showed the appearance of a meaning-bearing speech (2/14).

It should be noted that improvement of motor functions and mental abilities once registered  at 3 months following cell administration persisted without reversion during the whole period of observation (until one year in some children).

Comparing children responding and not responding to cell therapy, we found some trends. First, the CP children with improved motor and/or mental functions were younger (4.6 ± 0.6 vs 6.4 ± 0.8 years; pU >0.05). Second, they received higher number of input cells (0.74 ± 0.15 vs 0.59 ± 0.17 х 106/kg; pU >0.05). And, finally, the development of cytokine reactions in children who responded to cell therapy was observed twice as often (in 82% vs. 40%) as in the non-responsived group.

Analysis of some cytokines and growth factor levels in the serum of CP children showed that the macrophage introduction was not accompanied by an increase of IFN- γ, IL-17, and IL-4. At the same time, such a therapy resulted in significant enhancement of brain-derived neurotrophic factor (BDNF; from 695 ± 60 to 1183 ± 153 pg/ml; pU =0.015) and strong tendency to an increase of vascular endothelial growth factor (VEGF; from 190 ± 41 to 240 ± 40 pg/ml; pU =0.07). It is of great importance that these changes were the most pronounced in the responder group.

Table 4. Cytokine and growth factor levels in the serum

Cytokine/growth factor (pg/ml)

Before cell therapy

After cell therapy

M ± m

BDNF

695 ± 60

1183 ± 153 *

VEGF

190 ± 41

240 ± 40

IFN-γ

1.0 ± 0.6

1.0 ± 0.4

IL-17

<OOR

1.0 ±1.0

IL-4

14 ± 4.1

10.0 ± 2.7

Note: < OOR out of range (the minimum detectable dose of IL-17 is 5ng/ml)

Cell Ther Transplant. 2011;3:e.000092.01. doi:10.3205/ctt-2011-en-000092-table4


Some examples of applying the cell transplantation therapy for cerebral palsy are described below.

The 2-year-old boy N. was evaluated for developmental delay at the age of 2 years. He was born as a result of premature delivery at 28 weeks, weighing 1200 g. The boy was from the second pregnancy (the first childbirth) with danger of fetus wastage. He stayed in the Intensive Care Unit for 16 days and in the Department of Newborn Pathology for 1 month.

On admission all motor and mental functions were profoundly defective. The patient demonstrated global developmental delay. The boy was incapable of turning from abdomen to back, holding a toy in his hand, sitting, standing, and walking. He kept his head in an upright position with great difficulty. He was incapable of tracking a toy with his eyes, speaking, and understanding addressed speech. Epileptic seizures occurred up to 6 times a day. The GMFM-88 score was 0, degree of spasticity according to the Ashworth scale was 4, and muscle strength in the forearms was reduced, at only 2 points.

The treatment included endolumbar administration of generated autologous M2-like macrophages (total dose 3.1x106; 0.22x x106/kg). Cell introduction was accompanied by subfebrile fever and one episode of vomiting. Three months later the patient could turn from abdomen to back, hold a toy in his hands, sit, stand with support and retain his head in a vertical position. His epileptic seizures have completely stopped. The GMFM-88 score increased up to 164 and muscle strength in the forearms enhanced up to 4, while spasticity decreased to 2 points.

At 6 months after therapy the boy could understand addressed speech. The child gained weight. He is without anticonvulsant therapy for 1 year.

The 5-year-old boy G.
with cerebral palsy was from the fourth pregnancy with danger of fetus wastage. The childbirth was the second, premature at 32 weeks, as a result of Cesarean section. The newborn child had a weight of 2025 g. Prematurity II. He stayed in the Department of Newborn Pathology for 1 month. At one year, following a detailed assessment, the child was assigned a diagnosis of moderately severe spastic quadriplegia cerebral palsy. 

On admission the patient could crawl, sit, stand with assistance, understood addressed speech and spoke.  At the same time the boy was unable to walk without assistance and could not retain his head in a vertical position. Intelligence was unaffected. The GMFM-88 score was 158, degree of spasticity according to the Ashworth scale was 4, and muscle strength in the forearms was reduced, at 2 points. The treatment included endolumbar administration of generated autologous M2-like macrophages (5.2x106; 0.31x x106/kg). Three months later the patient could walk without support and retain his head in a vertical position. The boy could make attempts to run with wide-set legs and walk up the stairs without support. The GMFM-88 score increased to 217 and muscle strength in the forearms was enhanced to 4, while spasticity decreased to 2 points.

Discussion

The brain possesses a limited capacity for endogenous regeneration after various insults, including perinatal hypoxia/ischemia. Therefore, the treatment of cerebral palsy as neurologic sequelae of hypoxia/ischemia-induced damage demands regenerative strategies. Recent studies have demonstrated that macrophages can enhance neuroprotection and promote axon growth, sprouting and remyelination [11]. Moreover, promotion of neuroregeneration was shown to be mediated predominantly by M2 anti-inflammatory macrophages [33, 20]. The present study provides the first evidence for the possible application of M2-like macrophages for the treatment of cerebral palsy.

The evaluation of macrophage capacity to activate various types of T-helper cells as the first step of the present study revealed that generated M2-like macrophages did not stimulate T cells to produce IFN-γ and IL-17. This can be considered as the basic difference between the two types of macrophages investigated in our study, since classical M1 macrophages did induce substantial Th1 and Th17 cytokine production. With regard to Th2-stimulatory activity, M2-like macrophages did not differ from the M1 analogue as both stimulate detectable levels of IL-4 and IL-10. The last data are of great importance since Th2 cells are known to support neuron survival better than Th1 cells and in contrast to Th1 significantly stimulate axonal outgrowth. Namely, Th2 cells stimulate glial cells to produce neurotrophic factors without inducing inflammation[16]. Therefore, Th2-stimulatory activity of M2-like macrophages constituted an additional reason for the application of these cells for CNS repair.

In our study, we have shown that M2-like macrophages may be successfully generated in children with CP, and macrophage yields and functions in these cases are compared with that of adult healthy individuals [7]. Moreover, we first demonstrated that the introduction of M2-like macrophages via lumbar puncture in children with CP was safe, well tolerated and did not induce serious adverse reactions. Fever following macrophage administration observed in more than half of the patients was simply stopped with medication. There was no evidence of local immediate hypersensitivity reactions, hematoma, or infection at the site of the cell injection, and any serious infection complications related to the cell transplantation. Aggravation of atopic dermatitis registered in one person suggested the capacity of generated macrophages to activate Th2 response in vivo. This fact calls for a careful examination of patients for allergic diseases and may be exclusion criteria for M2 macrophage application in children with severe and diffuse forms of atopic pathology. On the other hand, exacerbation of atopic dermatitis in only one out of 16 cases evidenced that endolumbar application of macrophages obviously did not induce systemic activation of the Th2 response. This suggestion is confirmed by the results of IL-4 measurements of the serum of treated children. Indeed, we did not observe any enhancement of IL-4 serum levels after the introduction of M2-like macrophages.

Despite our clinical trial enrolling children with severe impairment of motor functions (predominantly V level of Gross Motor Function Classification System), cell therapy was accompanied by significant decreases in spasticity, increased muscle strength and enhancement of GMFM scores. Along with the increase in motor functions, more than half of the children displayed a decrease in aggressiveness and an improvement in communication with strangers. Enhancement of mental functions was also confirmed by appearance of the capacity to understand in two children and to speak in another two participants. In addition, three of six persons experienced full arrest of their seizure syndrome. Current therapeutic strategies of CP management are aimed at preventing brain damage, but at present there are no effective means to repair the brain once damage has occurred. From this point of view, our data are of significant importance. Similar results have been described recently by Chen L. et al. after introduction of olfactory ensheathing cells (OECs). These authors showed that OECs derived from aborted fetal tissue and injected into the bilateral corona radiata in the frontal lobes resulted in a significant increase of GMFM-88 score and improvement of mental functions in CP, according to the Caregiver Questionnaire Scale score [6]. 

The mechanisms underlying the clinical effects of M2-like macrophages in CP patients are not quite clear. We would like to point out some of them. As we have shown previously, М2-like macrophages are capable of spontaneous production of BDNF, IFG-1, EGF, bFGF, G-CSF, erythropoietin and VEGF, which possess neuroprotective activity and stimulate CNS regeneration [7]. Stimulation of CNS repair in ischemic brain damage may also be the result of increased angiogenesis and vasculogenesis [2, 37]. In this connection an increase in serum levels of BDNF and VEGF following cell therapy indicate that clinical effects may be mediated by growth factors produced by macrophages or other paracrine-activated cells. Finally, recent findings showed that monocytes/macrophages are able to differentiate into endothelium-like cells and function as precursors of endothelial cells [30] and thus participate in the repair of the vascular barrier after brain injury [12].
  
At the same time it should be emphasized that macrophage injection via lumbar puncture was not accompanied by an increase of serum IFN-γ or IL-17. Proinflammatory cytokines IFN-γ and IL-17 are known to have marked destructive effects on the nervous system [34, 35]. From this point of view, the data that M2-like macrophages lack Th1- and Th17-stimulatory activity in vitro and in vivo are additional arguments evidencing the safety of their application. However, to better define the therapeutic effects of these cells in CP, randomized, controlled prospective trials and long-term follow-up are required.

Acknowledgments

We are grateful to the parents of the CP children for their courage, perseverance, and faith in us. 
Competing interests: The authors have declared that no competing interests exist.

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Роль воспаления, индуцированного  главным образом макрофагами, противоречива,  поскольку макрофаги могут проявлять как нейротоксическую активность в отношении нейронов и клеток глии, так и способствовать репарации нервной ткани. Оппозитные эффекты макрофагов могут быть обусловлены их функциональной гетерогенностью. Так классические провоспалительные макрофаги (М1) являются тканедеструктивными, а противовоспалительные макрофаги (М2) участвуют в репарации тканей. Кроме того, М2 макрофаги индуцируют преимущественно Th2 ответ, который  в наибольшей степени способствует восстановлению ЦНС. Используя культуральные условия  с дефицитом ростовых факторов, мы разработали метод получения М2-подобных макрофагов и исследовали безопасность и клиническую эффективность эндолюмбального введения  этих клеток в лечении детей с церебральным параличом (ЦП).  <br /> <br />В исследование были отобраны 9 детей в возрасте от 2 до 8 лет с тяжелыми формами ЦП. Эндолюмбальное введение М2-подобных макрофагов  сопровождалось развитием цитокиновых реакций у 10 (62,5%) детей. Локальных или системных аллергических реакций немедленного типа, а также гематом или инфекционных осложнений, связанных  с введением клеток, не отмечалось. Через три месяца после лечения уровень спастичности в нижних конечностях (балл по шкале Эшворта) снизился с 3,9 ± 0,2 до 3,1 ± 0,2 (p&lt;0,01). Уровень двигательной активности по шкале GMFM (Gross Motor Function Measure) возрос с 12,1 ± 9,0 до 60 ± 19 баллов (p&lt;0,01). У трех из шести детей было отмечено полное прекращение судорожного синдрома, у четырех детей отмечено улучшение ментальных функций (способность понимать обращенную речь и говорить). Трансплантация М2-подобных макрофагов путем люмбальной пункции не сопровождалась возрастанием  уровня интерлейкина-17 и интерферона-γ в сыворотке крови, однако приводила к достоверному увеличению  нейроторофического фактора головного мозга (с 695 ± 60 до 1183 ± 153 пг/мл; p<sub>U</sub>=0,015) и выраженной тенденции к возрастанию концентрации фактора роста эндотелия сосудов (с 190 ± 41 до 240 ± 40 pg/ml; p<sub>U</sub>=0,07). <br /> <br />Полученные нами данные свидетельствуют о том, что эндолюмбальное ведение М2-подобных макрофагов является безопасным и улучшает неврологический статус у детей с ЦП. 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Черных, Марина Ю. Кафанова, Екатерина Я. Шевела, Елена И. Адонина, Людмила В. Сахно, Марина А. Тихонова, Александр А. Останин</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(242) "

Елена Р. Черных, Марина Ю. Кафанова, Екатерина Я. Шевела, Елена И. Адонина, Людмила В. Сахно, Марина А. Тихонова, Александр А. Останин

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19565" ["VALUE"]=> array(2) { ["TEXT"]=> string(5154) "<p class="bodytext">Повреждение центральной нервной системы (ЦНС) сопровождается развитием иммуноопосредованных воспалительных реакций, которые оказывают существенное влияние на выживаемость и регенерацию нервных клеток. Роль воспаления, индуцированного  главным образом макрофагами, противоречива,  поскольку макрофаги могут проявлять как нейротоксическую активность в отношении нейронов и клеток глии, так и способствовать репарации нервной ткани. Оппозитные эффекты макрофагов могут быть обусловлены их функциональной гетерогенностью. Так классические провоспалительные макрофаги (М1) являются тканедеструктивными, а противовоспалительные макрофаги (М2) участвуют в репарации тканей. Кроме того, М2 макрофаги индуцируют преимущественно Th2 ответ, который  в наибольшей степени способствует восстановлению ЦНС. Используя культуральные условия  с дефицитом ростовых факторов, мы разработали метод получения М2-подобных макрофагов и исследовали безопасность и клиническую эффективность эндолюмбального введения  этих клеток в лечении детей с церебральным параличом (ЦП).  <br /> <br />В исследование были отобраны 9 детей в возрасте от 2 до 8 лет с тяжелыми формами ЦП. Эндолюмбальное введение М2-подобных макрофагов  сопровождалось развитием цитокиновых реакций у 10 (62,5%) детей. Локальных или системных аллергических реакций немедленного типа, а также гематом или инфекционных осложнений, связанных  с введением клеток, не отмечалось. Через три месяца после лечения уровень спастичности в нижних конечностях (балл по шкале Эшворта) снизился с 3,9 ± 0,2 до 3,1 ± 0,2 (p&lt;0,01). Уровень двигательной активности по шкале GMFM (Gross Motor Function Measure) возрос с 12,1 ± 9,0 до 60 ± 19 баллов (p&lt;0,01). У трех из шести детей было отмечено полное прекращение судорожного синдрома, у четырех детей отмечено улучшение ментальных функций (способность понимать обращенную речь и говорить). Трансплантация М2-подобных макрофагов путем люмбальной пункции не сопровождалась возрастанием  уровня интерлейкина-17 и интерферона-γ в сыворотке крови, однако приводила к достоверному увеличению  нейроторофического фактора головного мозга (с 695 ± 60 до 1183 ± 153 пг/мл; p<sub>U</sub>=0,015) и выраженной тенденции к возрастанию концентрации фактора роста эндотелия сосудов (с 190 ± 41 до 240 ± 40 pg/ml; p<sub>U</sub>=0,07). <br /> <br />Полученные нами данные свидетельствуют о том, что эндолюмбальное ведение М2-подобных макрофагов является безопасным и улучшает неврологический статус у детей с ЦП. Однако для более полной оценки терапевтического потенциала этих клеток у детей с ЦП необходимы дальнейшие рандомизированные контролируемые проспективные исследования с оценкой отдаленных эффектов. </p> <h3>Ключевые слова</h3> <p>М2-макрофаги, церебральный паралич, цитокины, нейротрофические фактор </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5052) "

Повреждение центральной нервной системы (ЦНС) сопровождается развитием иммуноопосредованных воспалительных реакций, которые оказывают существенное влияние на выживаемость и регенерацию нервных клеток. Роль воспаления, индуцированного  главным образом макрофагами, противоречива,  поскольку макрофаги могут проявлять как нейротоксическую активность в отношении нейронов и клеток глии, так и способствовать репарации нервной ткани. Оппозитные эффекты макрофагов могут быть обусловлены их функциональной гетерогенностью. Так классические провоспалительные макрофаги (М1) являются тканедеструктивными, а противовоспалительные макрофаги (М2) участвуют в репарации тканей. Кроме того, М2 макрофаги индуцируют преимущественно Th2 ответ, который  в наибольшей степени способствует восстановлению ЦНС. Используя культуральные условия  с дефицитом ростовых факторов, мы разработали метод получения М2-подобных макрофагов и исследовали безопасность и клиническую эффективность эндолюмбального введения  этих клеток в лечении детей с церебральным параличом (ЦП). 

В исследование были отобраны 9 детей в возрасте от 2 до 8 лет с тяжелыми формами ЦП. Эндолюмбальное введение М2-подобных макрофагов  сопровождалось развитием цитокиновых реакций у 10 (62,5%) детей. Локальных или системных аллергических реакций немедленного типа, а также гематом или инфекционных осложнений, связанных  с введением клеток, не отмечалось. Через три месяца после лечения уровень спастичности в нижних конечностях (балл по шкале Эшворта) снизился с 3,9 ± 0,2 до 3,1 ± 0,2 (p<0,01). Уровень двигательной активности по шкале GMFM (Gross Motor Function Measure) возрос с 12,1 ± 9,0 до 60 ± 19 баллов (p<0,01). У трех из шести детей было отмечено полное прекращение судорожного синдрома, у четырех детей отмечено улучшение ментальных функций (способность понимать обращенную речь и говорить). Трансплантация М2-подобных макрофагов путем люмбальной пункции не сопровождалась возрастанием  уровня интерлейкина-17 и интерферона-γ в сыворотке крови, однако приводила к достоверному увеличению  нейроторофического фактора головного мозга (с 695 ± 60 до 1183 ± 153 пг/мл; pU=0,015) и выраженной тенденции к возрастанию концентрации фактора роста эндотелия сосудов (с 190 ± 41 до 240 ± 40 pg/ml; pU=0,07).

Полученные нами данные свидетельствуют о том, что эндолюмбальное ведение М2-подобных макрофагов является безопасным и улучшает неврологический статус у детей с ЦП. Однако для более полной оценки терапевтического потенциала этих клеток у детей с ЦП необходимы дальнейшие рандомизированные контролируемые проспективные исследования с оценкой отдаленных эффектов.

Ключевые слова

М2-макрофаги, церебральный паралич, цитокины, нейротрофические фактор

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Elena R. Chernykh, Marina Yu. Kafanova, Ekaterina Ya. Shevela, Elena I. Adonina, Lyudmila V. Sakhno, Marina A. Tikhonova, Alexander A. Ostanin

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19575" ["VALUE"]=> array(2) { ["TEXT"]=> string(720) "<p class="bodytext">Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology of Russian Academy on Medical Sciences, Siberian Branch, Novosibirsk, 630099, Russia </p> <br> <p class="bodytext"><b>Correspondence</b><br> Elena Chernykh, Head of Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology RAMS SB, Yadrintsevskaya str., 14, Novosibirsk, 630099, Russia <br> Phone: +7(383)2360329, Fax: +7(383)2227028 <br> E-mail: <a href="javascript:linkTo_UnCryptMailto('qempxs.gx_pefDqemp2vy');">ct_lab@<span style="display:none;">spam is bad</span>mail.ru</a> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(596) "

Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology of Russian Academy on Medical Sciences, Siberian Branch, Novosibirsk, 630099, Russia


Correspondence
Elena Chernykh, Head of Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology RAMS SB, Yadrintsevskaya str., 14, Novosibirsk, 630099, Russia
Phone: +7(383)2360329, Fax: +7(383)2227028
E-mail: ct_lab@spam is badmail.ru

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Following injury to the central nervous system (CNS), immune-mediated inflammation profoundly affects the ability of neural cells to survive and to regenerate. The role of inflammation, comprises mostly of macrophages, is controversial, since macrophages can both induce neuronal and glial toxicity and promote tissue repair. The opposite effects of macrophages may be conditioned by their functional heterogeneity. Thus, classical pro-inflammatory macrophages (M1) are tissue-destructive, while anti-inflammatory (M2) macrophages mediate tissue repair. In addition, M2 macrophages predominantly induce the Th2 response, which is particularly beneficial in CNS repair. Using growth factor deficiency conditions we have generated M2-like macrophages and evaluated the safety and clinical efficacy of endolumbar introduction of these cells in treatment of children with cerebral palsy (CP). Sixteen children from 2.0 to 8.0 years old with severe forms of CP were enrolled in this trial. Endolumbar administration of M2-like cells was accompanied by cytokine reactions in 10 (62.5%) persons. There was no evidence of local and systemic immediate hypersensitivity reactions, hematoma or infection complications related to cell transplantation. At 3 months after therapy the average Ashworth score decreased from 3.9 ± 0.2 to 3.1 ± 0.2 in the lower extremities (p<0.01). Gross Motor Function Measure (GMFM) test improved from 12.1 ± 9.0 to 60 ± 19 points (p<0.01). Three of six children experienced seizures arrest, and four children improved mental functions (improvement of speech and understanding). M2-like macrophage introduction was not accompanied by an increase of serum levels of interferon-gamma and interleukin-17, but resulted in significant enhancement of brain-derived neurotrophic factor (from 695 ± 60 to 1183 ± 153 pg/ml; pU=0.015) and a strong tendency to enlargement of vascular endothelial growth factor (from 190 ± 41 to 240 ± 40 pg/ml; pU=0.07). Our data indicate that transplantation of M2-like macrophages via lumbar puncture is safe and improves neurological status in children with CP. However, to better define the therapeutic effect of these cells in CP, randomized controlled prospective trials and long-term follow-up are required.

Keywords

M2-macrophages, cerebral palsy, cytokines, neurotrophic factors

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Chernykh, Marina Yu. Kafanova, Ekaterina Ya. Shevela, Elena I. Adonina, Lyudmila V. Sakhno, Marina A. Tikhonova, Alexander A. Ostanin</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(149) "

Elena R. Chernykh, Marina Yu. Kafanova, Ekaterina Ya. Shevela, Elena I. Adonina, Lyudmila V. Sakhno, Marina A. Tikhonova, Alexander A. Ostanin

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Elena R. Chernykh, Marina Yu. Kafanova, Ekaterina Ya. Shevela, Elena I. Adonina, Lyudmila V. Sakhno, Marina A. Tikhonova, Alexander A. Ostanin

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Following injury to the central nervous system (CNS), immune-mediated inflammation profoundly affects the ability of neural cells to survive and to regenerate. The role of inflammation, comprises mostly of macrophages, is controversial, since macrophages can both induce neuronal and glial toxicity and promote tissue repair. The opposite effects of macrophages may be conditioned by their functional heterogeneity. Thus, classical pro-inflammatory macrophages (M1) are tissue-destructive, while anti-inflammatory (M2) macrophages mediate tissue repair. In addition, M2 macrophages predominantly induce the Th2 response, which is particularly beneficial in CNS repair. Using growth factor deficiency conditions we have generated M2-like macrophages and evaluated the safety and clinical efficacy of endolumbar introduction of these cells in treatment of children with cerebral palsy (CP). Sixteen children from 2.0 to 8.0 years old with severe forms of CP were enrolled in this trial. Endolumbar administration of M2-like cells was accompanied by cytokine reactions in 10 (62.5%) persons. There was no evidence of local and systemic immediate hypersensitivity reactions, hematoma or infection complications related to cell transplantation. At 3 months after therapy the average Ashworth score decreased from 3.9 ± 0.2 to 3.1 ± 0.2 in the lower extremities (p<0.01). Gross Motor Function Measure (GMFM) test improved from 12.1 ± 9.0 to 60 ± 19 points (p<0.01). Three of six children experienced seizures arrest, and four children improved mental functions (improvement of speech and understanding). M2-like macrophage introduction was not accompanied by an increase of serum levels of interferon-gamma and interleukin-17, but resulted in significant enhancement of brain-derived neurotrophic factor (from 695 ± 60 to 1183 ± 153 pg/ml; pU=0.015) and a strong tendency to enlargement of vascular endothelial growth factor (from 190 ± 41 to 240 ± 40 pg/ml; pU=0.07). Our data indicate that transplantation of M2-like macrophages via lumbar puncture is safe and improves neurological status in children with CP. However, to better define the therapeutic effect of these cells in CP, randomized controlled prospective trials and long-term follow-up are required.

Keywords

M2-macrophages, cerebral palsy, cytokines, neurotrophic factors

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Following injury to the central nervous system (CNS), immune-mediated inflammation profoundly affects the ability of neural cells to survive and to regenerate. The role of inflammation, comprises mostly of macrophages, is controversial, since macrophages can both induce neuronal and glial toxicity and promote tissue repair. The opposite effects of macrophages may be conditioned by their functional heterogeneity. Thus, classical pro-inflammatory macrophages (M1) are tissue-destructive, while anti-inflammatory (M2) macrophages mediate tissue repair. In addition, M2 macrophages predominantly induce the Th2 response, which is particularly beneficial in CNS repair. Using growth factor deficiency conditions we have generated M2-like macrophages and evaluated the safety and clinical efficacy of endolumbar introduction of these cells in treatment of children with cerebral palsy (CP). Sixteen children from 2.0 to 8.0 years old with severe forms of CP were enrolled in this trial. Endolumbar administration of M2-like cells was accompanied by cytokine reactions in 10 (62.5%) persons. There was no evidence of local and systemic immediate hypersensitivity reactions, hematoma or infection complications related to cell transplantation. At 3 months after therapy the average Ashworth score decreased from 3.9 ± 0.2 to 3.1 ± 0.2 in the lower extremities (p<0.01). Gross Motor Function Measure (GMFM) test improved from 12.1 ± 9.0 to 60 ± 19 points (p<0.01). Three of six children experienced seizures arrest, and four children improved mental functions (improvement of speech and understanding). M2-like macrophage introduction was not accompanied by an increase of serum levels of interferon-gamma and interleukin-17, but resulted in significant enhancement of brain-derived neurotrophic factor (from 695 ± 60 to 1183 ± 153 pg/ml; pU=0.015) and a strong tendency to enlargement of vascular endothelial growth factor (from 190 ± 41 to 240 ± 40 pg/ml; pU=0.07). Our data indicate that transplantation of M2-like macrophages via lumbar puncture is safe and improves neurological status in children with CP. However, to better define the therapeutic effect of these cells in CP, randomized controlled prospective trials and long-term follow-up are required.

Keywords

M2-macrophages, cerebral palsy, cytokines, neurotrophic factors

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Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology of Russian Academy on Medical Sciences, Siberian Branch, Novosibirsk, 630099, Russia


Correspondence
Elena Chernykh, Head of Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology RAMS SB, Yadrintsevskaya str., 14, Novosibirsk, 630099, Russia
Phone: +7(383)2360329, Fax: +7(383)2227028
E-mail: ct_lab@spam is badmail.ru

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Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology of Russian Academy on Medical Sciences, Siberian Branch, Novosibirsk, 630099, Russia


Correspondence
Elena Chernykh, Head of Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology RAMS SB, Yadrintsevskaya str., 14, Novosibirsk, 630099, Russia
Phone: +7(383)2360329, Fax: +7(383)2227028
E-mail: ct_lab@spam is badmail.ru

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Елена Р. Черных, Марина Ю. Кафанова, Екатерина Я. Шевела, Елена И. Адонина, Людмила В. Сахно, Марина А. Тихонова, Александр А. Останин

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Елена Р. Черных, Марина Ю. Кафанова, Екатерина Я. Шевела, Елена И. Адонина, Людмила В. Сахно, Марина А. Тихонова, Александр А. Останин

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Роль воспаления, индуцированного  главным образом макрофагами, противоречива,  поскольку макрофаги могут проявлять как нейротоксическую активность в отношении нейронов и клеток глии, так и способствовать репарации нервной ткани. Оппозитные эффекты макрофагов могут быть обусловлены их функциональной гетерогенностью. Так классические провоспалительные макрофаги (М1) являются тканедеструктивными, а противовоспалительные макрофаги (М2) участвуют в репарации тканей. Кроме того, М2 макрофаги индуцируют преимущественно Th2 ответ, который  в наибольшей степени способствует восстановлению ЦНС. Используя культуральные условия  с дефицитом ростовых факторов, мы разработали метод получения М2-подобных макрофагов и исследовали безопасность и клиническую эффективность эндолюмбального введения  этих клеток в лечении детей с церебральным параличом (ЦП).  <br /> <br />В исследование были отобраны 9 детей в возрасте от 2 до 8 лет с тяжелыми формами ЦП. Эндолюмбальное введение М2-подобных макрофагов  сопровождалось развитием цитокиновых реакций у 10 (62,5%) детей. Локальных или системных аллергических реакций немедленного типа, а также гематом или инфекционных осложнений, связанных  с введением клеток, не отмечалось. Через три месяца после лечения уровень спастичности в нижних конечностях (балл по шкале Эшворта) снизился с 3,9 ± 0,2 до 3,1 ± 0,2 (p&lt;0,01). Уровень двигательной активности по шкале GMFM (Gross Motor Function Measure) возрос с 12,1 ± 9,0 до 60 ± 19 баллов (p&lt;0,01). У трех из шести детей было отмечено полное прекращение судорожного синдрома, у четырех детей отмечено улучшение ментальных функций (способность понимать обращенную речь и говорить). Трансплантация М2-подобных макрофагов путем люмбальной пункции не сопровождалась возрастанием  уровня интерлейкина-17 и интерферона-γ в сыворотке крови, однако приводила к достоверному увеличению  нейроторофического фактора головного мозга (с 695 ± 60 до 1183 ± 153 пг/мл; p<sub>U</sub>=0,015) и выраженной тенденции к возрастанию концентрации фактора роста эндотелия сосудов (с 190 ± 41 до 240 ± 40 pg/ml; p<sub>U</sub>=0,07). <br /> <br />Полученные нами данные свидетельствуют о том, что эндолюмбальное ведение М2-подобных макрофагов является безопасным и улучшает неврологический статус у детей с ЦП. Однако для более полной оценки терапевтического потенциала этих клеток у детей с ЦП необходимы дальнейшие рандомизированные контролируемые проспективные исследования с оценкой отдаленных эффектов. </p> <h3>Ключевые слова</h3> <p>М2-макрофаги, церебральный паралич, цитокины, нейротрофические фактор </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5052) "

Повреждение центральной нервной системы (ЦНС) сопровождается развитием иммуноопосредованных воспалительных реакций, которые оказывают существенное влияние на выживаемость и регенерацию нервных клеток. Роль воспаления, индуцированного  главным образом макрофагами, противоречива,  поскольку макрофаги могут проявлять как нейротоксическую активность в отношении нейронов и клеток глии, так и способствовать репарации нервной ткани. Оппозитные эффекты макрофагов могут быть обусловлены их функциональной гетерогенностью. Так классические провоспалительные макрофаги (М1) являются тканедеструктивными, а противовоспалительные макрофаги (М2) участвуют в репарации тканей. Кроме того, М2 макрофаги индуцируют преимущественно Th2 ответ, который  в наибольшей степени способствует восстановлению ЦНС. Используя культуральные условия  с дефицитом ростовых факторов, мы разработали метод получения М2-подобных макрофагов и исследовали безопасность и клиническую эффективность эндолюмбального введения  этих клеток в лечении детей с церебральным параличом (ЦП). 

В исследование были отобраны 9 детей в возрасте от 2 до 8 лет с тяжелыми формами ЦП. Эндолюмбальное введение М2-подобных макрофагов  сопровождалось развитием цитокиновых реакций у 10 (62,5%) детей. Локальных или системных аллергических реакций немедленного типа, а также гематом или инфекционных осложнений, связанных  с введением клеток, не отмечалось. Через три месяца после лечения уровень спастичности в нижних конечностях (балл по шкале Эшворта) снизился с 3,9 ± 0,2 до 3,1 ± 0,2 (p<0,01). Уровень двигательной активности по шкале GMFM (Gross Motor Function Measure) возрос с 12,1 ± 9,0 до 60 ± 19 баллов (p<0,01). У трех из шести детей было отмечено полное прекращение судорожного синдрома, у четырех детей отмечено улучшение ментальных функций (способность понимать обращенную речь и говорить). Трансплантация М2-подобных макрофагов путем люмбальной пункции не сопровождалась возрастанием  уровня интерлейкина-17 и интерферона-γ в сыворотке крови, однако приводила к достоверному увеличению  нейроторофического фактора головного мозга (с 695 ± 60 до 1183 ± 153 пг/мл; pU=0,015) и выраженной тенденции к возрастанию концентрации фактора роста эндотелия сосудов (с 190 ± 41 до 240 ± 40 pg/ml; pU=0,07).

Полученные нами данные свидетельствуют о том, что эндолюмбальное ведение М2-подобных макрофагов является безопасным и улучшает неврологический статус у детей с ЦП. Однако для более полной оценки терапевтического потенциала этих клеток у детей с ЦП необходимы дальнейшие рандомизированные контролируемые проспективные исследования с оценкой отдаленных эффектов.

Ключевые слова

М2-макрофаги, церебральный паралич, цитокины, нейротрофические фактор

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Повреждение центральной нервной системы (ЦНС) сопровождается развитием иммуноопосредованных воспалительных реакций, которые оказывают существенное влияние на выживаемость и регенерацию нервных клеток. Роль воспаления, индуцированного  главным образом макрофагами, противоречива,  поскольку макрофаги могут проявлять как нейротоксическую активность в отношении нейронов и клеток глии, так и способствовать репарации нервной ткани. Оппозитные эффекты макрофагов могут быть обусловлены их функциональной гетерогенностью. Так классические провоспалительные макрофаги (М1) являются тканедеструктивными, а противовоспалительные макрофаги (М2) участвуют в репарации тканей. Кроме того, М2 макрофаги индуцируют преимущественно Th2 ответ, который  в наибольшей степени способствует восстановлению ЦНС. Используя культуральные условия  с дефицитом ростовых факторов, мы разработали метод получения М2-подобных макрофагов и исследовали безопасность и клиническую эффективность эндолюмбального введения  этих клеток в лечении детей с церебральным параличом (ЦП). 

В исследование были отобраны 9 детей в возрасте от 2 до 8 лет с тяжелыми формами ЦП. Эндолюмбальное введение М2-подобных макрофагов  сопровождалось развитием цитокиновых реакций у 10 (62,5%) детей. Локальных или системных аллергических реакций немедленного типа, а также гематом или инфекционных осложнений, связанных  с введением клеток, не отмечалось. Через три месяца после лечения уровень спастичности в нижних конечностях (балл по шкале Эшворта) снизился с 3,9 ± 0,2 до 3,1 ± 0,2 (p<0,01). Уровень двигательной активности по шкале GMFM (Gross Motor Function Measure) возрос с 12,1 ± 9,0 до 60 ± 19 баллов (p<0,01). У трех из шести детей было отмечено полное прекращение судорожного синдрома, у четырех детей отмечено улучшение ментальных функций (способность понимать обращенную речь и говорить). Трансплантация М2-подобных макрофагов путем люмбальной пункции не сопровождалась возрастанием  уровня интерлейкина-17 и интерферона-γ в сыворотке крови, однако приводила к достоверному увеличению  нейроторофического фактора головного мозга (с 695 ± 60 до 1183 ± 153 пг/мл; pU=0,015) и выраженной тенденции к возрастанию концентрации фактора роста эндотелия сосудов (с 190 ± 41 до 240 ± 40 pg/ml; pU=0,07).

Полученные нами данные свидетельствуют о том, что эндолюмбальное ведение М2-подобных макрофагов является безопасным и улучшает неврологический статус у детей с ЦП. Однако для более полной оценки терапевтического потенциала этих клеток у детей с ЦП необходимы дальнейшие рандомизированные контролируемые проспективные исследования с оценкой отдаленных эффектов.

Ключевые слова

М2-макрофаги, церебральный паралич, цитокины, нейротрофические фактор

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Introduction 

Despite advances in oral and maxillofacial surgery, traumatology and orthopedics, full repair of cartilaginous and bone tissues in mammals is still a challenging problem, because large bone defects cannot regenerate in a natural way. The usage of stem cells for such purposes is therefore referred to as “regenerative biology” and “regenerative medicine”. This is a rapidly developing area of research, with high hopes for more effective treatment of bone injuries. New therapeutic approaches with stem cells may be helpful or even replace standard surgical methods when the latter are ineffective [3, 4].

The application of mesenchymal stem cells (MSC) leads to faster regeneration of injured bones and an increase in bone density, when compared to natural restorative processes [6, 7, 20]. 

The products of fibrin degradation lead to more rapid restoration of surgical bone defects in experiments and in clinical practice.  It is noteworthy that fibrin not only stimulates the migration of fibroblasts but also accelerates the synthesis of connective tissue [8-11].

Hence, for acceleration of repair we performed an experimental study of jawbone regeneration in rats treated by introduction of the following substances into the injured areas: (1) autologous platelet-enriched fibrin clot (PEFC); (2) a suspension of autologous mesenchymal stem cells from a bone marrow origin (AMSC) in a culture medium; and (3) PEFC with absorbed AMSC.

The effects of these different methods upon bone and marrow repair were revealed with light microscopy and X-ray densitometry. 

Materials and methods

Male six-month old Wag rats (180–200 g) were used in this study. All manipulations with the animals were carried out under general ether inhalation anesthesia, in a clean operating room, in compliance with international “Regulations for Working with Experimental Animals”. At least 8 rats were studied at each time-point of the observation period.

Damaged bone tissue model in the experiment 

We used an original experimental model of bone damage and repair, as described elsewhere [11]. In brief, the surgery was performed under general ether inhalation anesthesia, under aseptic conditions, after skin preparation with ethyl alcohol. A 1.5–2 cm longitudinal incision was made along the inferior edge of the lower jaw. By means of a blunt technique and a raspatory, the mastication muscle was exfoliated and the lower jawbone surface was exposed at the jaw angle. A round hole (2mm in diameter) was made at the outside jaw angle bone with a dental drill. The defect passed through all layers of the bone but was not connected with the oral cavity.

Animals were divided into the following four groups according to the method used to regenerate the damaged lower jawbones:

1.    In the first group (58 rats), the natural events of bone repair were followed. The hole in the bone was covered with the mastication muscle, and the soft tissues were sutured in layers with vicryl.

2.    The second group (56 rats) represented the regeneration after inserting PEFC into the hole. After densely filling the hole with PEFC, it was covered with the mastication muscle and the skin was sutured with vicryl.

3.    In the third group (58 rats) the course of repair was observed after the introduction of an AMSC suspension in an α-МЕМ medium (100 mcl, 106 cells per 1 ml) into the hole in the lower jaw.

4.    In the fourth group (60 rats) we used PEFC with AMSC. Prepared PEFC was immediately dipped into the AMSC suspension in culture medium (106 cells per 1 ml) for 2 hours, as living cells are attached to any solid substrate.

PEFC preparation 

Several rats of the same breed were decapitated, and 2–7 ml of blood was collected in sterile glass tubes. The blood was centrifuged at 2800 rpm for 12 minutes [8-11]. Then the upper layer (platelet-enriched fibrin clot or fibrin clot with platelets) was placed in sterile Petri dishes and was stored for a few hours at 37°C until use. Immediately before use, PEFC fragments were cut with sterile scissors to the necessary size. 

AMSC preparation

AMSC were separated by flushing out bone marrow from the epiphysis of Wag-male rat femoral bones. Individual cell suspensions were placed into plastic vials (“Nunc”, Denmark). After 48 hours the unattached cells were poured off. Adherent cells were cultivated in an α-МЕМ medium with 10% embryonic calf serum (“Biolot”, Russia) at 37°C in a СО2 incubator with 5% СО2 and 100% humidity. The medium was changed every three days. During sub-cultures, the monolayer cultures were dispersed at a density of 1000–5000 cells/cm2 (depending on the growth effects of the embryonic serum). Standard solutions of EDTA and trypsin were used for MSC yielding. 

Using the common approaches of light and fluorescent microscopy and standard methods of cytological staining and immunochemistry, we revealed the general characteristics of the cultured marrow cells to be as follows:

• CD90+, CD105+, CD34-, CD45-,
• Plastic-adherent cell populations in vitro,
• Fibroblast-like morphology of cells through the entire period of culture,
• The cells were capable of several passages in culture,
• Form colonies of fibroblast-like cells after sub-culture of low cell density, 
• Ability to differentiate into bone cells in the presence of lineage-specific factors.

However, these physical, morphological, and phenotypic signs are not specific criteria for precise identification of AMSC. The ability of AMSC to differentiate in vitro into bone, fat, and cartilage is the only criteria to determine a prospective population of stem cells. 

Induction of osteogenic differentiation of mesenchymal stem cells in vitro: AMSC possess the ability to differentiate into the cells of bone tissue under reproducible conditions [3-6, 13, 14, 20]. Therefore, the osteogenic differentiation of mesenchymal stems cells is commonly tested in vitro. Osteogenic differentiation is a typical method of developing most AMSC in a culture. To induce osteogenic differentiation, 0.1 µM deoxymetazone, 50 µM ascorbic acid and 10 mM β-glycerophosphate (“Sigma”, US) were applied.

The osteogenic differentiation was defined by two histochemical markers: active alkaline phosphatase and mineralization of the intercellular matrix by calcium ions. Cytochemical detection of the alkaline phosphatase was made with Nitrotetrazolium Blue in the presence of 5-bromo-4–chloro-3-indolyl, a substrate for alkaline phosphatase. Calcium deposits in the intercellular matrix were registered by Alizarin Red staining.

The animals were removed from the experiment at the first, second, third, fourth, and fifth week after the operation. Fragments of the lower jaws with the experimental injuries were fixed in a 4% solution of paraformaldehyde in phosphate buffer (рН 7.4) for at least 24 hours.

The bone fragments of the rats’ lower jaws devoid of skin, muscles, and connective tissue were examined using X-ray densitometry. The software “Tomodent” (Anvisystem, Russia) installed on a radiovisiographic computer device “Heliodont+” (Herona, Germany, 2010) allowed evaluation of bone tissue density in conventional units, as a ratio of retrieved data of the bone density in the damaged area to the measurements for contralateral undamaged bone fragments.

The big lower jaw fragments were then decalcified in “Biodek R” solution (Bio Optica, Milano, Italy) for 24 hours, dehydrated in a gradient of increasing concentrations of ethanol, clarified in xylene and embedded into histoplast perpendicularly aperture in a bone so that the sections passed in parallel to the outer bone surface. Sections 5–7 microns thick were stained with hematoxylin and eosin and studied with an Axioimager M1 light microscope (Carl Zeiss, Germany), at an optical magnification of up to 1200x.

To research the area of structures of red bone marrow on a section of the bottom jawbone, we applied the square test system combined on the computer screen with the image received from a digital camera on a microscope. Using a lens with an increase of 5 times, the final test square area was equal to 16,900 microns (square party was equal to 130 microns).

Statistical analysis of results was performed with MS Excel’s applied statistical program (Microsoft, USA). Both arithmetic means and standard deviations were determined. The differences between the mean values were considered to be significant at p≤0.05, using Student’s coefficient.

Results

Natural course of bone regeneration:

One week after the injury, the hole was partially filled with blood, some fragments of friable connective tissue, and structures of granulation tissue. These events represented the initial stages of tissue repair in the bone defect area, as evidenced by de novo formation of separate bone and cartilage islands among the granulation tissues (Figure 1a, b).

CTT-3-10-2012-Maiborodin-et-al-Figure1.png

Figure 1. Microscopic analysis of the damaged fragment of rat's lower jaw after different methods of influence on restorative processes, hematoxylin and eosin staining

a: Damaged fragment of rat's lower jaw during natural healing at one postoperative week. The defect is filled with blood clot and detritus.
b: Figure 1a fragment, with the beginning of formation of single little bone island in the blood clot.
c: Healing of the damaged area of rat's lower jaw after PRFC use at one week after surgery. Bone defect is filled with fused islands of the new bone tissue.
d: Figure 1c fragment. The border of the damaged area, islands of the new bone tissue with a large number of vessels.
e: Damaged fragment of rat's lower jaw at two weeks post-surgery with AMSC application. The defect is filled with fused islands of the new bone tissue and formed structures of red bone marrow among them.
f: Figure 1e fragment with a bone cavity containing wide vessels and the bone marrow cells similar to lymphocytes.
g: Lower jaw defect at a week after the operation and PRFC+AMSC application. The lower jaw defect is almost filled with newly formed bone tissue.
h: Figure 1g fragment. Connective tissue and granulations in the periphery of bone callus in hole.

Two weeks after injury the bone defect was completely closed with conjugated islands of new bone tissue. Some cartilage tissue was also present among the newly formed bone structures, especially in the middle of the former hole.

Three weeks after injury the hole was entirely filled by the newly formed bone tissue. Multiple, randomly arranged trabeculae (callus structures) were the only evidence of the surgical intervention. In some cases (3 out of 12), bone marrow cavities were already formed by that time. In most cases, at 4 to 5 weeks, a post-injury callus remained as the only sign that the operation had been performed.

Statistical analysis of densitometric data of bone regeneration in lower jawbones of rats by natural healing has revealed that bone density in the damaged fragment was 12.1%, 11%, 10.5% and 9.3% lower than in the corresponding healthy fragment on the contralateral side, when measured respectively, at week 1, 2, 3, 4, and 5 after surgery (Table 1) (Figure 2a).

CTT-3-10-2012-Maiborodin-et-al-Figure2.png

Figure 2. A radiovisiographic X-ray evaluation of the experimentally injured area of rat lower jaw five weeks after the use of different methods of treatment (an oval artificial defect is indicated by the arrow)

a: Natural regeneration, the tissue density is nearly similar to surrounding intact areas.

b: 
After PRFC use, the density of tissues in the defect is higher than when healing naturally. 

c:
 The administration of AMSC, the tissue density is lower, and the defect seems wider, when compared to the healing observed during the non-modified restoration.

d:
 When PRFC and AMSCBMO are applied together, the tissue defect is practically absent.

Defects Filled with PEFC: 

One week after the injury, the hole was completely filled with conjugated islands of the newly formed bone (Figure 1c, d).

In most cases, in two weeks after the bone injury, the hole was absolutely closed with newly formed bone tissue. 

In three weeks after the bone injury, the hole was absolutely closed with newly formed bone tissue with chaotically arranged trabeculae of the formed callus and cavities with bone marrow. 

In 4 and 5 weeks after the injury, the hole was absolutely closed with newly formed bone tissue, as it was with the natural healing.

After PEFC use the bone density in the defect was 9.5% lower than the undamaged contralateral side in the first week, and 4.9% lower in the second week (Figure 2b) (Table 1).

Table 1. Bone density in defect of the rat's lower jaw in comparison with intact tissues of contralateral undamaged bone fragments (S±σ)

Postoperative periods

Regeneration Process


 

Natural healing course

After PRFC application

After AMSC application

After PRFC+AMSC application

1

2

3

4

5

1 Week 

0.892±0.053*

0.913±0.017*

0.928±0.044

0.917±0.037*

2 Weeks 

0.901±0.035*

0.953±0.021*

0.903±0.046*

0.905±0.057

3 Weeks 

0.905±0.02*

0.949±0.036

0.96±0.086

0.927±0.04

4 Weeks 

0.912±0.059

0.942±0.048

0.932±0.052

0.922±0.032*

5 Weeks 

0.915±0.016*5

0.924±0.063

0.856±0.028*

0.978±0.022

Notes: * –  data, significantly different from the intact bone (р ≤ 0.05), 2, 3, 4, 5 – data, significantly different from each other in this columns (р < 0.05)

Cell Ther Transplant. 2012;3:e.000101.01. doi:10.3205/ctt-2012-en-000101.01-table1


Healing of defects filled with AMSC suspension:

One week after the injury the bone defects were completely filled with blood; typical granulations were found between the blood clot and margins of the defect. Notably, some signs of bone formation were also detectable, presenting as separate islands of new bone and cartilage in the defect area. The tissues within the damaged area were similar to those in controls (normal regeneration) at the same time point. However, it is noteworthy that there were many more blood vessels penetrating the bone hole, as well as in the granulation structures.

After two weeks, the defects in lower jawbone were completely replaced by new bone and cartilage tissue, with a great number of conjugated bone cell islands and a plethora of thin-walled blood vessels. It's notable that formation of red bone marrow (with hematopoietic cells) structures took place by this period (Figure 1e, f). By this time a significant acceleration of repair processes had been observed, thus resulting in rapid development and regeneration of hematopoietic tissue such as bone marrow in the bone callus. 

Within the subsequent period, the bone tissue islands fused together, forming osseous callus structures, along with progressive restoration of red bone marrow.

Statistical differences between bone densities after AMSC treatment and those at the intact contralateral side were found only during the second and fifth weeks: 10.7% and 16.8% less respectively. However, five weeks after surgical injury, X-ray density of the bone defect after AMSC treatment alone was even less than in the natural regenerative process (Figure 2c) (Table 1). 

The terms of occurrence and development of cavities containing red bone marrow in the compared groups are presented in Table 2. The area of such structures after application of AMSC at week 3 did not differ to a statistically significant amount from the intact control. During the healing course with other influences the size of cavities with marrow began to correspond to control only at the 4-week point.

Table 2. The occurrence and development of red bone marrow in the rat's lower jaw

Post-
operative periods

Regeneration process

Natural healing course


 

 

Number of animals in group

 (n)

 

Number of animals with restoration of bone marrow

 (n(%))

 

The size of cavities with marrow in a casual section of the bone

 (mm2, S±σ)

 

Number of animals in group

 (n)

 

Number of animals with restoration of bone marrow

 (n(%))

 

The size of cavities with marrow in a casual section of the bone

 (mm2, S±σ)

1

2

3

4

5

6

7

1 Week 

12

-

-*

12

-

-*

2 Weeks 

12

-

-*9

12

-

-*9

3Weeks 

12

3(25)

0.225±0.035*

12

4(33.3)

0.232±0.021*

4 Weeks 

12

11(91.7)

0.269±0.024

12

8(66.7)

0.268±0.029

5 Weeks 

10

10(100)

0.326±0.041

8

8(100)

0.336±0.023

After AMSC application


 

 

Number of animals in group

 (n)

 

Number of animals with restoration of bone marrow

 (n(%))

 

The size of cavities with marrow in a casual section of bone

 (mm2,S±σ)

 

Number of animals in group

 (n)

 

Number of animals with restoration of bone marrow

 (n(%))

 

The size of cavities with marrow in a casual section of the bone

 (mm2, S±σ)

1

8

9

10

11

12

13

1 Week 

12

-

-*

12

-

-*

2 Weeks 

12

8(66.7)

0.203±0.013*47, 13

12

-

-*9

3Weeks 

12

12(100)

0.287±0.032

12

5(41.7)

0.226±0.035*

4 Weeks 

12

11(91.7)

0.34±0.032

12

10(83.3)

0.316±0.025

5 Weeks 

10

10(100)

0.355±0.041

12

12(100)

0.344±0.03

Notes: * –  data, significantly different from the intact bone (0.339±0.04 mm2; р≤0.05), 4, 7, 10, 13 – data, significantly different from each other in this columns (р < 0.05)

Cell Ther Transplant. 2012;3:e.000101.01. doi:10.3205/ctt-2012-en-000101.01-table2


Defects Filled with PEFC and AMSC:

In a week after the surgery and PEFC and AMSC taken together, in most cases, more than 2/3 of the defect of the lower jawbone was filled with newly formed bone tissue. However, the tissue was separated from the “old bone” (the defect edge) by connective tissue with granulations. It is likely that in these cases the bone formation starts and progresses rapidly in the defect center and gradually comes up to the defect edges where granulations still exist. In the areas of the defect that had still not been filled with bone tissue, there were granulations with a large number of blood vessels (Figure 1g, h).

Two weeks after the surgery, in most cases, the defect was completely closed with new bone and cartilage tissues. 

In 3–5 weeks after PEFC with AMSC use, the defect of the lower jawbone was fully closed with the bone tissue. The presence of callus structures was the only difference from the undamaged contralateral jawbone.

After PEFC with AMSC use, statistically significant differences of the bone tissue density from the contralateral fragment of the lower jawbone were found only during the first and fourth weeks – 9.1% and 8.5% lower respectively. Moreover, in this group of animals five weeks after the operation, there was a significant difference in the density of bone tissue – 6.9% higher compared to the natural regenerative process at the same time (Figure 2d) (Table 1).

Discussion

According to published scientific literature, fibrin in tissues reduces the intensity of the inflammatory process and limits the spread of infection [8-11]. That is, the introduction of PEFC in the wound cavity can protect the surrounding tissues from the dissemination of microorganisms, and from excessive exposure to the lysosomal enzymes of phagocytes. By limiting this destruction, the regenerative processes in tissues begin earlier, and there are lower amounts of antigens and detritus, so the wound is cleansed rapidly. 

Plasma and fibrin clot contain many cytokines and high concentrations of growth factors: platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-b), platelet-derived epidermal growth factor, platelet-derived angiogenesis factor, insulin-like growth factor 1 (IGF-1), and platelet-derived factor 4. These releases cause migration and division of all mesenchymal cells (including chondrocytes and mesenchymal stem cells) and epithelial cells, stimulate collagen synthesis and the formation of connective tissues matrix [1, 2, 16].

In addition, the fibrin clot acts as a matrix on which the migration of leukocytes (neutrophils), endotheliocytes, and fibroblasts occurs. Migrating on fibrin, neutrophils more rapidly reach all parts of the wound, even if the wound is covered with layers of pus and detritus. Thus, antigenic substances (microorganisms and detritus) are cleansed from tissues more rapidly. Moreover, when neutrophils migrate on fibrin clot they partially dissolve the fibrin clot with their own enzymes, so as a result even a dense fibrin clot starts to resemble a net. Fibroblasts, located on the fibrin net [1, 2, 16], begin to synthesize collagen, not only from the bottom of the wound, but also from its cavity. Thus the scar tissue forms more rapidly.

Therefore, using PEFC contributes to more rapid regeneration of the damaged fragment of the lower jawbone.

In the course of the natural regenerative process of the damaged lower jawbone, the tissue regeneration starts from the edges of the holes. Pre-existing osteoblasts and stem cells migrate from residual bone tissue [12, 17] and periosteum [5] in the blood clot. As a result, separate isolated foci of osteogenesis may be detected in the blood clot filling the bone defect as early as 1 week after the surgical injury.

After the introduction of the AMSC suspension, in our opinion, a large number of stem cells immediately appear in all parts of the artificial bone hole. In this case, there is no lag period for stem cells to migrate to the damaged fragment and to penetrate directly into the damaged tissues. 

Since the mesenchymal stem cells in our experiments were of bone marrow origin, it is likely that some hematopoietic cells were present among the stem cells. Apparently, the activity of these cell precursors enables rapid and early regeneration of hematopoietic structures, i.e., red bone marrow. It's necessary to note an opportunity of AMSC differentiation into hematopoietic stem cells [15].

According to the literature, we expected an acceleration of the damaged bone repair and, respectively, its higher density in comparison with results of jaw densitometry obtained in the cases of non-modified repair [6, 7, 20]. 

Most likely, the lower tissue density registered at the 2nd and 5th week after surgery may be ascribed to the development of red bone marrow, in accordance with densitometry data. During the first week after injury, active bone regeneration (mineralization) took place, and there was a noticeable increase in the bone tissue density. Thereafter, red bone marrow was formed in the cavities, and, therefore, bone density could be decreased. After AMSC application, the formation of bone marrow seemed then to be more rapid and pronounced. Therefore, bone density could decrease in the damaged fragment and became even lower than the healing without using stem cells. It is necessary to take into consideration the possible lowering of the strength properties of the regenerated bone due to the presence of large cavities filled with bone marrow.  

One week after using PEFC with AMSC, the lower jawbone defect was mostly filled with newly formed bone tissue. It's likely that in these cases the bone formation began in the center of the defect, and not along the edges. After two weeks, the lower jawbone defect was completely filled with new bone tissue. In the following period the artificial hole had disappeared – the only trace of it was the callus structures. 

According to scientific literature data, good results were obtained when the combination of MSC and platelet-enriched plasma were used for acceleration of bone tissue regeneration and the implant osteointegration. Such plasma can maintain the bone tissue growth and act as a matrix for bone growth from MSC [13, 14, 19]. It is based on the fact that cytokines of megakaryocytes influence MSC differentiation. Moreover, the interaction of thrombopoietic structures and MSC stimulates endochondral ossification [18]. MSC with plasma and platelets can be delivered to the areas of regenerating bone and cartilaginous tissues by means of injection [19]. The modification of platelet-enriched plasma is a fibrin gel, glue, and sponge, which can be used very effectively together with AMSC. 

Most likely when PEFC is used together with AMSC, the synthesis of the two optimizes bone defect regeneration. The stem cells in fibrin clot fill the entire defect more or less evenly. These cells do not migrate from the place of introduction (actively or passively, as happens when AMSC is used alone). Cytokines, platelet factors, and especially megakaryocytes in PEFC stimulate the proliferation of AMSC as well as its differentiation in the direction of osteogenesis. As a result, the most rapid and successful regeneration of damaged bone tissue is achieved.

Conclusion

According to the experimental data, the best results in bone regeneration were achieved by applying PEFC with AMSC to the bone defect. After one week, the hole in the lower jawbone was mostly filled with formed bone tissue. It is more likely, in this case, that the combined characteristics of fibrin and stem cells optimize bone defect regeneration. The bones regenerated significantly faster than when PEFC and AMSC were used separately. Evidently, the bone formation starts in the center of the defect rather than from the edges. Stem cells in fibrin clot spread throughout the defect and fill it more or less evenly and completely. As a result, the most rapid and successful regeneration of the bone tissue defect is achieved. The development of red bone marrow in the bone callus occurs much earlier after the use of AMSC during surgery than in the other courses of influence on tissue repair. Formation of cavities with functional bone marrow may cause a decrease in tissue density within the 4th and 5th weeks after injury with AMSC application at the site of damage. 

Acknowledgements

This work was financially supported by the Fundamental Research Program of the Presidium of RAS “Fundamental Science - Medicine” (project № 21.31 “Development of technologies for process control of bone-tissue regeneration with biodegradable polymers application”).

References

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2. Anitua E, Sanchez M, Nurden AT, et al. Autologous fibrin matrices: a potential source of biological mediators that modulate tendon cell activities. Journal of Biomedical Materials Research. Part A. 2006:77(2):285-293. doi:10.1002/jbm.a.30585.

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4. Clines GA. Prospects for osteoprogenitor stem cells in fracture repair and osteoporosis. Current Opinion in Organ Transplantation. 2010:15(1):73-78. pmid:19935065.

5. Hayashi O, Katsube Y, Hirose M, et al. Comparison of osteogenic ability of rat mesenchymal stem cells from bone marrow, periosteum, and adipose tissue. Calcified Tissue International. 2008:82(3):238-247. doi:10.1007/s00223-008-9112-y.

6. Kallai I, Lenthe van GH, Ruffoni D, et al. Quantitative, structural, and image-based mechanical analysis of nonunion fracture repaired by genetically engineered mesenchymal stem cells. Journal of Biomechanics. 2010:43(12):2315-2320.

7. Kumar S, Wan C, Ramaswamy G, et al. Mesenchymal stem cells expressing osteogenic and angiogenic factors synergistically enhance bone formation in a mouse model of segmental bone defect. Molecular Therapy: the Journal of the American Society of Gene Therapy. 2010:18(5):1026-1034. doi:10.1038/mt.2009.315.

8. Maiborodin IV, Kolesnikov IS, Sheplev BV and Ragimova TM. Application of fibrin and its preparations in stomatology. Stomatologiia (Mosk). 2008:87(6):75-77.

9. Maiborodin IV, Kolesnikov IS, Sheplev BV, et al. Granulomatous inflammation after fibrin preparation use. Morphological letters. 2007:(3-4):116-118.

10. Maiborodin IV, Kolesnikov IS, Sheplev BV, et al. Adjusting gingival tissues morphology after dental implantation with fibrin use. Stomatologiia (Mosk). 2009:88(1):9-13.

11. Maiborodin I, Shevela A, Perrin T, et al. Experimental results of the fibrin clot use to accelerate the regeneration of damaged bone in the rat lower jaw. Surgical Science. 2010:1(1):1-6. doi:10.4236/ss.2010.11001.

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14. Pieri F, Lucarelli E, Corinaldesi G, et al. Effect of mesenchymal stem cells and platelet-rich plasma on the healing of standardized bone defects in the alveolar ridge: a comparative histomorphometric study in minipigs. Journal of Oral and Maxillofacial Surgery: Official Journal of the American Association of Oral and Maxillofacial Surgeons. 2009:67(2):265-272.

15. Ratajczak MZ, Kucia M, Reca R, et al. Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells 'hide out' in the bone marrow. Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004:18(1):29-40. doi:10.1038/sj.leu.2403184.

16. Schwartz-Arad D, Levin L and Aba M. The use of platelet rich plasma (PRP) and platelet rich fibrin (PRP) extracts in dental implantology and oral surgery. Refu’at Ha-peh Veha-shinayim. 2007:24(1):51-55,84.

17. Steenhuis P, Carr KM, Pettway GJ and Ignelzi MA Jr. Osteogenic and adipogenic cell fractions isolated from postnatal mouse calvaria. Cells, Tissues, Organs. 2009:190(3):150-157. doi:10.1159/000187633.

18. Sumiyoshi K, Kubota S, Furuta RA, et al. Thrombopoietic-mesenchymal interaction that may facilitate both endochondral ossification and platelet maturation via CCN2. Journal of Cell Communication and Signaling. 2010:4(1):5-14. doi:10.1007/s12079-009-0067-1.

19. Yoshimi R, Yamada Y, Ito K, et al. Self-assembling peptide nanofiber scaffolds, platelet-rich plasma, and mesenchymal stem cells for injectable bone regeneration with tissue engineering. The Journal of Craniofacial Surgery. 2009:20(5):1523-1530. doi:10.1097/SCS.0b013e3181b09b7e.

20. Zhang ZY, Teoh SH, Chong MS, et al. Neo-vascularization and bone formation mediated by fetal mesenchymal stem cell tissue-engineered bone grafts in critical-size femoral defects. Biomaterials. 2010:31(4):608-620.

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Introduction 

Despite advances in oral and maxillofacial surgery, traumatology and orthopedics, full repair of cartilaginous and bone tissues in mammals is still a challenging problem, because large bone defects cannot regenerate in a natural way. The usage of stem cells for such purposes is therefore referred to as “regenerative biology” and “regenerative medicine”. This is a rapidly developing area of research, with high hopes for more effective treatment of bone injuries. New therapeutic approaches with stem cells may be helpful or even replace standard surgical methods when the latter are ineffective [3, 4].

The application of mesenchymal stem cells (MSC) leads to faster regeneration of injured bones and an increase in bone density, when compared to natural restorative processes [6, 7, 20]. 

The products of fibrin degradation lead to more rapid restoration of surgical bone defects in experiments and in clinical practice.  It is noteworthy that fibrin not only stimulates the migration of fibroblasts but also accelerates the synthesis of connective tissue [8-11].

Hence, for acceleration of repair we performed an experimental study of jawbone regeneration in rats treated by introduction of the following substances into the injured areas: (1) autologous platelet-enriched fibrin clot (PEFC); (2) a suspension of autologous mesenchymal stem cells from a bone marrow origin (AMSC) in a culture medium; and (3) PEFC with absorbed AMSC.

The effects of these different methods upon bone and marrow repair were revealed with light microscopy and X-ray densitometry. 

Materials and methods

Male six-month old Wag rats (180–200 g) were used in this study. All manipulations with the animals were carried out under general ether inhalation anesthesia, in a clean operating room, in compliance with international “Regulations for Working with Experimental Animals”. At least 8 rats were studied at each time-point of the observation period.

Damaged bone tissue model in the experiment 

We used an original experimental model of bone damage and repair, as described elsewhere [11]. In brief, the surgery was performed under general ether inhalation anesthesia, under aseptic conditions, after skin preparation with ethyl alcohol. A 1.5–2 cm longitudinal incision was made along the inferior edge of the lower jaw. By means of a blunt technique and a raspatory, the mastication muscle was exfoliated and the lower jawbone surface was exposed at the jaw angle. A round hole (2mm in diameter) was made at the outside jaw angle bone with a dental drill. The defect passed through all layers of the bone but was not connected with the oral cavity.

Animals were divided into the following four groups according to the method used to regenerate the damaged lower jawbones:

1.    In the first group (58 rats), the natural events of bone repair were followed. The hole in the bone was covered with the mastication muscle, and the soft tissues were sutured in layers with vicryl.

2.    The second group (56 rats) represented the regeneration after inserting PEFC into the hole. After densely filling the hole with PEFC, it was covered with the mastication muscle and the skin was sutured with vicryl.

3.    In the third group (58 rats) the course of repair was observed after the introduction of an AMSC suspension in an α-МЕМ medium (100 mcl, 106 cells per 1 ml) into the hole in the lower jaw.

4.    In the fourth group (60 rats) we used PEFC with AMSC. Prepared PEFC was immediately dipped into the AMSC suspension in culture medium (106 cells per 1 ml) for 2 hours, as living cells are attached to any solid substrate.

PEFC preparation 

Several rats of the same breed were decapitated, and 2–7 ml of blood was collected in sterile glass tubes. The blood was centrifuged at 2800 rpm for 12 minutes [8-11]. Then the upper layer (platelet-enriched fibrin clot or fibrin clot with platelets) was placed in sterile Petri dishes and was stored for a few hours at 37°C until use. Immediately before use, PEFC fragments were cut with sterile scissors to the necessary size. 

AMSC preparation

AMSC were separated by flushing out bone marrow from the epiphysis of Wag-male rat femoral bones. Individual cell suspensions were placed into plastic vials (“Nunc”, Denmark). After 48 hours the unattached cells were poured off. Adherent cells were cultivated in an α-МЕМ medium with 10% embryonic calf serum (“Biolot”, Russia) at 37°C in a СО2 incubator with 5% СО2 and 100% humidity. The medium was changed every three days. During sub-cultures, the monolayer cultures were dispersed at a density of 1000–5000 cells/cm2 (depending on the growth effects of the embryonic serum). Standard solutions of EDTA and trypsin were used for MSC yielding. 

Using the common approaches of light and fluorescent microscopy and standard methods of cytological staining and immunochemistry, we revealed the general characteristics of the cultured marrow cells to be as follows:

• CD90+, CD105+, CD34-, CD45-,
• Plastic-adherent cell populations in vitro,
• Fibroblast-like morphology of cells through the entire period of culture,
• The cells were capable of several passages in culture,
• Form colonies of fibroblast-like cells after sub-culture of low cell density, 
• Ability to differentiate into bone cells in the presence of lineage-specific factors.

However, these physical, morphological, and phenotypic signs are not specific criteria for precise identification of AMSC. The ability of AMSC to differentiate in vitro into bone, fat, and cartilage is the only criteria to determine a prospective population of stem cells. 

Induction of osteogenic differentiation of mesenchymal stem cells in vitro: AMSC possess the ability to differentiate into the cells of bone tissue under reproducible conditions [3-6, 13, 14, 20]. Therefore, the osteogenic differentiation of mesenchymal stems cells is commonly tested in vitro. Osteogenic differentiation is a typical method of developing most AMSC in a culture. To induce osteogenic differentiation, 0.1 µM deoxymetazone, 50 µM ascorbic acid and 10 mM β-glycerophosphate (“Sigma”, US) were applied.

The osteogenic differentiation was defined by two histochemical markers: active alkaline phosphatase and mineralization of the intercellular matrix by calcium ions. Cytochemical detection of the alkaline phosphatase was made with Nitrotetrazolium Blue in the presence of 5-bromo-4–chloro-3-indolyl, a substrate for alkaline phosphatase. Calcium deposits in the intercellular matrix were registered by Alizarin Red staining.

The animals were removed from the experiment at the first, second, third, fourth, and fifth week after the operation. Fragments of the lower jaws with the experimental injuries were fixed in a 4% solution of paraformaldehyde in phosphate buffer (рН 7.4) for at least 24 hours.

The bone fragments of the rats’ lower jaws devoid of skin, muscles, and connective tissue were examined using X-ray densitometry. The software “Tomodent” (Anvisystem, Russia) installed on a radiovisiographic computer device “Heliodont+” (Herona, Germany, 2010) allowed evaluation of bone tissue density in conventional units, as a ratio of retrieved data of the bone density in the damaged area to the measurements for contralateral undamaged bone fragments.

The big lower jaw fragments were then decalcified in “Biodek R” solution (Bio Optica, Milano, Italy) for 24 hours, dehydrated in a gradient of increasing concentrations of ethanol, clarified in xylene and embedded into histoplast perpendicularly aperture in a bone so that the sections passed in parallel to the outer bone surface. Sections 5–7 microns thick were stained with hematoxylin and eosin and studied with an Axioimager M1 light microscope (Carl Zeiss, Germany), at an optical magnification of up to 1200x.

To research the area of structures of red bone marrow on a section of the bottom jawbone, we applied the square test system combined on the computer screen with the image received from a digital camera on a microscope. Using a lens with an increase of 5 times, the final test square area was equal to 16,900 microns (square party was equal to 130 microns).

Statistical analysis of results was performed with MS Excel’s applied statistical program (Microsoft, USA). Both arithmetic means and standard deviations were determined. The differences between the mean values were considered to be significant at p≤0.05, using Student’s coefficient.

Results

Natural course of bone regeneration:

One week after the injury, the hole was partially filled with blood, some fragments of friable connective tissue, and structures of granulation tissue. These events represented the initial stages of tissue repair in the bone defect area, as evidenced by de novo formation of separate bone and cartilage islands among the granulation tissues (Figure 1a, b).

CTT-3-10-2012-Maiborodin-et-al-Figure1.png

Figure 1. Microscopic analysis of the damaged fragment of rat's lower jaw after different methods of influence on restorative processes, hematoxylin and eosin staining

a: Damaged fragment of rat's lower jaw during natural healing at one postoperative week. The defect is filled with blood clot and detritus.
b: Figure 1a fragment, with the beginning of formation of single little bone island in the blood clot.
c: Healing of the damaged area of rat's lower jaw after PRFC use at one week after surgery. Bone defect is filled with fused islands of the new bone tissue.
d: Figure 1c fragment. The border of the damaged area, islands of the new bone tissue with a large number of vessels.
e: Damaged fragment of rat's lower jaw at two weeks post-surgery with AMSC application. The defect is filled with fused islands of the new bone tissue and formed structures of red bone marrow among them.
f: Figure 1e fragment with a bone cavity containing wide vessels and the bone marrow cells similar to lymphocytes.
g: Lower jaw defect at a week after the operation and PRFC+AMSC application. The lower jaw defect is almost filled with newly formed bone tissue.
h: Figure 1g fragment. Connective tissue and granulations in the periphery of bone callus in hole.

Two weeks after injury the bone defect was completely closed with conjugated islands of new bone tissue. Some cartilage tissue was also present among the newly formed bone structures, especially in the middle of the former hole.

Three weeks after injury the hole was entirely filled by the newly formed bone tissue. Multiple, randomly arranged trabeculae (callus structures) were the only evidence of the surgical intervention. In some cases (3 out of 12), bone marrow cavities were already formed by that time. In most cases, at 4 to 5 weeks, a post-injury callus remained as the only sign that the operation had been performed.

Statistical analysis of densitometric data of bone regeneration in lower jawbones of rats by natural healing has revealed that bone density in the damaged fragment was 12.1%, 11%, 10.5% and 9.3% lower than in the corresponding healthy fragment on the contralateral side, when measured respectively, at week 1, 2, 3, 4, and 5 after surgery (Table 1) (Figure 2a).

CTT-3-10-2012-Maiborodin-et-al-Figure2.png

Figure 2. A radiovisiographic X-ray evaluation of the experimentally injured area of rat lower jaw five weeks after the use of different methods of treatment (an oval artificial defect is indicated by the arrow)

a: Natural regeneration, the tissue density is nearly similar to surrounding intact areas.

b: 
After PRFC use, the density of tissues in the defect is higher than when healing naturally. 

c:
 The administration of AMSC, the tissue density is lower, and the defect seems wider, when compared to the healing observed during the non-modified restoration.

d:
 When PRFC and AMSCBMO are applied together, the tissue defect is practically absent.

Defects Filled with PEFC: 

One week after the injury, the hole was completely filled with conjugated islands of the newly formed bone (Figure 1c, d).

In most cases, in two weeks after the bone injury, the hole was absolutely closed with newly formed bone tissue. 

In three weeks after the bone injury, the hole was absolutely closed with newly formed bone tissue with chaotically arranged trabeculae of the formed callus and cavities with bone marrow. 

In 4 and 5 weeks after the injury, the hole was absolutely closed with newly formed bone tissue, as it was with the natural healing.

After PEFC use the bone density in the defect was 9.5% lower than the undamaged contralateral side in the first week, and 4.9% lower in the second week (Figure 2b) (Table 1).

Table 1. Bone density in defect of the rat's lower jaw in comparison with intact tissues of contralateral undamaged bone fragments (S±σ)

Postoperative periods

Regeneration Process


 

Natural healing course

After PRFC application

After AMSC application

After PRFC+AMSC application

1

2

3

4

5

1 Week 

0.892±0.053*

0.913±0.017*

0.928±0.044

0.917±0.037*

2 Weeks 

0.901±0.035*

0.953±0.021*

0.903±0.046*

0.905±0.057

3 Weeks 

0.905±0.02*

0.949±0.036

0.96±0.086

0.927±0.04

4 Weeks 

0.912±0.059

0.942±0.048

0.932±0.052

0.922±0.032*

5 Weeks 

0.915±0.016*5

0.924±0.063

0.856±0.028*

0.978±0.022

Notes: * –  data, significantly different from the intact bone (р ≤ 0.05), 2, 3, 4, 5 – data, significantly different from each other in this columns (р < 0.05)

Cell Ther Transplant. 2012;3:e.000101.01. doi:10.3205/ctt-2012-en-000101.01-table1


Healing of defects filled with AMSC suspension:

One week after the injury the bone defects were completely filled with blood; typical granulations were found between the blood clot and margins of the defect. Notably, some signs of bone formation were also detectable, presenting as separate islands of new bone and cartilage in the defect area. The tissues within the damaged area were similar to those in controls (normal regeneration) at the same time point. However, it is noteworthy that there were many more blood vessels penetrating the bone hole, as well as in the granulation structures.

After two weeks, the defects in lower jawbone were completely replaced by new bone and cartilage tissue, with a great number of conjugated bone cell islands and a plethora of thin-walled blood vessels. It's notable that formation of red bone marrow (with hematopoietic cells) structures took place by this period (Figure 1e, f). By this time a significant acceleration of repair processes had been observed, thus resulting in rapid development and regeneration of hematopoietic tissue such as bone marrow in the bone callus. 

Within the subsequent period, the bone tissue islands fused together, forming osseous callus structures, along with progressive restoration of red bone marrow.

Statistical differences between bone densities after AMSC treatment and those at the intact contralateral side were found only during the second and fifth weeks: 10.7% and 16.8% less respectively. However, five weeks after surgical injury, X-ray density of the bone defect after AMSC treatment alone was even less than in the natural regenerative process (Figure 2c) (Table 1). 

The terms of occurrence and development of cavities containing red bone marrow in the compared groups are presented in Table 2. The area of such structures after application of AMSC at week 3 did not differ to a statistically significant amount from the intact control. During the healing course with other influences the size of cavities with marrow began to correspond to control only at the 4-week point.

Table 2. The occurrence and development of red bone marrow in the rat's lower jaw

Post-
operative periods

Regeneration process

Natural healing course


 

 

Number of animals in group

 (n)

 

Number of animals with restoration of bone marrow

 (n(%))

 

The size of cavities with marrow in a casual section of the bone

 (mm2, S±σ)

 

Number of animals in group

 (n)

 

Number of animals with restoration of bone marrow

 (n(%))

 

The size of cavities with marrow in a casual section of the bone

 (mm2, S±σ)

1

2

3

4

5

6

7

1 Week 

12

-

-*

12

-

-*

2 Weeks 

12

-

-*9

12

-

-*9

3Weeks 

12

3(25)

0.225±0.035*

12

4(33.3)

0.232±0.021*

4 Weeks 

12

11(91.7)

0.269±0.024

12

8(66.7)

0.268±0.029

5 Weeks 

10

10(100)

0.326±0.041

8

8(100)

0.336±0.023

After AMSC application


 

 

Number of animals in group

 (n)

 

Number of animals with restoration of bone marrow

 (n(%))

 

The size of cavities with marrow in a casual section of bone

 (mm2,S±σ)

 

Number of animals in group

 (n)

 

Number of animals with restoration of bone marrow

 (n(%))

 

The size of cavities with marrow in a casual section of the bone

 (mm2, S±σ)

1

8

9

10

11

12

13

1 Week 

12

-

-*

12

-

-*

2 Weeks 

12

8(66.7)

0.203±0.013*47, 13

12

-

-*9

3Weeks 

12

12(100)

0.287±0.032

12

5(41.7)

0.226±0.035*

4 Weeks 

12

11(91.7)

0.34±0.032

12

10(83.3)

0.316±0.025

5 Weeks 

10

10(100)

0.355±0.041

12

12(100)

0.344±0.03

Notes: * –  data, significantly different from the intact bone (0.339±0.04 mm2; р≤0.05), 4, 7, 10, 13 – data, significantly different from each other in this columns (р < 0.05)

Cell Ther Transplant. 2012;3:e.000101.01. doi:10.3205/ctt-2012-en-000101.01-table2


Defects Filled with PEFC and AMSC:

In a week after the surgery and PEFC and AMSC taken together, in most cases, more than 2/3 of the defect of the lower jawbone was filled with newly formed bone tissue. However, the tissue was separated from the “old bone” (the defect edge) by connective tissue with granulations. It is likely that in these cases the bone formation starts and progresses rapidly in the defect center and gradually comes up to the defect edges where granulations still exist. In the areas of the defect that had still not been filled with bone tissue, there were granulations with a large number of blood vessels (Figure 1g, h).

Two weeks after the surgery, in most cases, the defect was completely closed with new bone and cartilage tissues. 

In 3–5 weeks after PEFC with AMSC use, the defect of the lower jawbone was fully closed with the bone tissue. The presence of callus structures was the only difference from the undamaged contralateral jawbone.

After PEFC with AMSC use, statistically significant differences of the bone tissue density from the contralateral fragment of the lower jawbone were found only during the first and fourth weeks – 9.1% and 8.5% lower respectively. Moreover, in this group of animals five weeks after the operation, there was a significant difference in the density of bone tissue – 6.9% higher compared to the natural regenerative process at the same time (Figure 2d) (Table 1).

Discussion

According to published scientific literature, fibrin in tissues reduces the intensity of the inflammatory process and limits the spread of infection [8-11]. That is, the introduction of PEFC in the wound cavity can protect the surrounding tissues from the dissemination of microorganisms, and from excessive exposure to the lysosomal enzymes of phagocytes. By limiting this destruction, the regenerative processes in tissues begin earlier, and there are lower amounts of antigens and detritus, so the wound is cleansed rapidly. 

Plasma and fibrin clot contain many cytokines and high concentrations of growth factors: platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-b), platelet-derived epidermal growth factor, platelet-derived angiogenesis factor, insulin-like growth factor 1 (IGF-1), and platelet-derived factor 4. These releases cause migration and division of all mesenchymal cells (including chondrocytes and mesenchymal stem cells) and epithelial cells, stimulate collagen synthesis and the formation of connective tissues matrix [1, 2, 16].

In addition, the fibrin clot acts as a matrix on which the migration of leukocytes (neutrophils), endotheliocytes, and fibroblasts occurs. Migrating on fibrin, neutrophils more rapidly reach all parts of the wound, even if the wound is covered with layers of pus and detritus. Thus, antigenic substances (microorganisms and detritus) are cleansed from tissues more rapidly. Moreover, when neutrophils migrate on fibrin clot they partially dissolve the fibrin clot with their own enzymes, so as a result even a dense fibrin clot starts to resemble a net. Fibroblasts, located on the fibrin net [1, 2, 16], begin to synthesize collagen, not only from the bottom of the wound, but also from its cavity. Thus the scar tissue forms more rapidly.

Therefore, using PEFC contributes to more rapid regeneration of the damaged fragment of the lower jawbone.

In the course of the natural regenerative process of the damaged lower jawbone, the tissue regeneration starts from the edges of the holes. Pre-existing osteoblasts and stem cells migrate from residual bone tissue [12, 17] and periosteum [5] in the blood clot. As a result, separate isolated foci of osteogenesis may be detected in the blood clot filling the bone defect as early as 1 week after the surgical injury.

After the introduction of the AMSC suspension, in our opinion, a large number of stem cells immediately appear in all parts of the artificial bone hole. In this case, there is no lag period for stem cells to migrate to the damaged fragment and to penetrate directly into the damaged tissues. 

Since the mesenchymal stem cells in our experiments were of bone marrow origin, it is likely that some hematopoietic cells were present among the stem cells. Apparently, the activity of these cell precursors enables rapid and early regeneration of hematopoietic structures, i.e., red bone marrow. It's necessary to note an opportunity of AMSC differentiation into hematopoietic stem cells [15].

According to the literature, we expected an acceleration of the damaged bone repair and, respectively, its higher density in comparison with results of jaw densitometry obtained in the cases of non-modified repair [6, 7, 20]. 

Most likely, the lower tissue density registered at the 2nd and 5th week after surgery may be ascribed to the development of red bone marrow, in accordance with densitometry data. During the first week after injury, active bone regeneration (mineralization) took place, and there was a noticeable increase in the bone tissue density. Thereafter, red bone marrow was formed in the cavities, and, therefore, bone density could be decreased. After AMSC application, the formation of bone marrow seemed then to be more rapid and pronounced. Therefore, bone density could decrease in the damaged fragment and became even lower than the healing without using stem cells. It is necessary to take into consideration the possible lowering of the strength properties of the regenerated bone due to the presence of large cavities filled with bone marrow.  

One week after using PEFC with AMSC, the lower jawbone defect was mostly filled with newly formed bone tissue. It's likely that in these cases the bone formation began in the center of the defect, and not along the edges. After two weeks, the lower jawbone defect was completely filled with new bone tissue. In the following period the artificial hole had disappeared – the only trace of it was the callus structures. 

According to scientific literature data, good results were obtained when the combination of MSC and platelet-enriched plasma were used for acceleration of bone tissue regeneration and the implant osteointegration. Such plasma can maintain the bone tissue growth and act as a matrix for bone growth from MSC [13, 14, 19]. It is based on the fact that cytokines of megakaryocytes influence MSC differentiation. Moreover, the interaction of thrombopoietic structures and MSC stimulates endochondral ossification [18]. MSC with plasma and platelets can be delivered to the areas of regenerating bone and cartilaginous tissues by means of injection [19]. The modification of platelet-enriched plasma is a fibrin gel, glue, and sponge, which can be used very effectively together with AMSC. 

Most likely when PEFC is used together with AMSC, the synthesis of the two optimizes bone defect regeneration. The stem cells in fibrin clot fill the entire defect more or less evenly. These cells do not migrate from the place of introduction (actively or passively, as happens when AMSC is used alone). Cytokines, platelet factors, and especially megakaryocytes in PEFC stimulate the proliferation of AMSC as well as its differentiation in the direction of osteogenesis. As a result, the most rapid and successful regeneration of damaged bone tissue is achieved.

Conclusion

According to the experimental data, the best results in bone regeneration were achieved by applying PEFC with AMSC to the bone defect. After one week, the hole in the lower jawbone was mostly filled with formed bone tissue. It is more likely, in this case, that the combined characteristics of fibrin and stem cells optimize bone defect regeneration. The bones regenerated significantly faster than when PEFC and AMSC were used separately. Evidently, the bone formation starts in the center of the defect rather than from the edges. Stem cells in fibrin clot spread throughout the defect and fill it more or less evenly and completely. As a result, the most rapid and successful regeneration of the bone tissue defect is achieved. The development of red bone marrow in the bone callus occurs much earlier after the use of AMSC during surgery than in the other courses of influence on tissue repair. Formation of cavities with functional bone marrow may cause a decrease in tissue density within the 4th and 5th weeks after injury with AMSC application at the site of damage. 

Acknowledgements

This work was financially supported by the Fundamental Research Program of the Presidium of RAS “Fundamental Science - Medicine” (project № 21.31 “Development of technologies for process control of bone-tissue regeneration with biodegradable polymers application”).

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Maiborodin, Andrew I. Shevela, Vera A. Matveeva, Ivan S. Kolesnikov, Michail N. Drovosekov, Michail S. Toder, Tatyana V. Perrin</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(142) "

Igor V. Maiborodin, Andrew I. Shevela, Vera A. Matveeva, Ivan S. Kolesnikov, Michail N. Drovosekov, Michail S. Toder, Tatyana V. Perrin

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Center of New Medical Technologies (Director - Prof. A.I. Shevela), Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS, 630090, Novosibirsk, Russia


Correspondence
Center of New Medical Technologies (Director - Prof. A.I. Shevela), Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS, 630090, Novosibirsk, Russia
E-mail: imai@spam is badmail.ru 

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According to scientific literature data, the application of mesenchymal stem cells leads to faster regeneration of injured bones and an increase in bone density. The regeneration processes at the site of a rat’s damaged bottom jawbone after the administration of the following substances: (1) autologous platelet-enriched fibrin clot (PEFC); (2) a suspension of autologous marrow-derived mesenchymal stem cells (AMSC) in a culture medium; and (3) PEFC with absorbed AMSC were studied with light microscopy and x-ray densitometry. Morphological examination showed that the development of red bone marrow in the bone callus occurs much earlier after AMSC application than during natural bone restoration. The formation of marrow-containing bone cavities after AMSC introduction is associated with decreased local tissue density at the 4th and 5th weeks of observation. The revealed changes are detectable in all observations, thus confirming the acceleration of the regenerative events in damaged bone tissue. The combination of PEFC with AMSC achieved the best results. After one week the hole in the lower jawbone was mostly filled with the regenerated bone tissue. It is very likely that in this case the synthesis of fibrin and stem cell characteristics optimized bone regeneration. Apparently, the bone formation started in the center of the defect, it did not start from the edges. Stem cells in the fibrin clot spread in the space of defect and filled it evenly. As a result, the most rapid and successful regeneration of the bone tissue defect was achieved.

Keywords

bone damage, rat jaw, bone repair, mesenchymal stem cells, autologous bone marrow, regeneration

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Maiborodin, Andrew I. Shevela, Vera A. Matveeva, Ivan S. Kolesnikov, Michail N. Drovosekov, Michail S. Toder, Tatyana V. Perrin</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(142) "

Igor V. Maiborodin, Andrew I. Shevela, Vera A. Matveeva, Ivan S. Kolesnikov, Michail N. Drovosekov, Michail S. Toder, Tatyana V. Perrin

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Igor V. Maiborodin, Andrew I. Shevela, Vera A. Matveeva, Ivan S. Kolesnikov, Michail N. Drovosekov, Michail S. Toder, Tatyana V. Perrin

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19502" ["VALUE"]=> array(2) { ["TEXT"]=> string(1760) "<p class="bodytext">According to scientific literature data, the application of mesenchymal stem cells leads to faster regeneration of injured bones and an increase in bone density. The regeneration processes at the site of a rat’s damaged bottom jawbone after the administration of the following substances: (1) autologous platelet-enriched fibrin clot (PEFC); (2) a suspension of autologous marrow-derived mesenchymal stem cells (AMSC) in a culture medium; and (3) PEFC with absorbed AMSC were studied with light microscopy and x-ray densitometry. Morphological examination showed that the development of red bone marrow in the bone callus occurs much earlier after AMSC application than during natural bone restoration. The formation of marrow-containing bone cavities after AMSC introduction is associated with decreased local tissue density at the 4th and 5th weeks of observation. The revealed changes are detectable in all observations, thus confirming the acceleration of the regenerative events in damaged bone tissue. The combination of PEFC with AMSC achieved the best results. After one week the hole in the lower jawbone was mostly filled with the regenerated bone tissue. It is very likely that in this case the synthesis of fibrin and stem cell characteristics optimized bone regeneration. Apparently, the bone formation started in the center of the defect, it did not start from the edges. Stem cells in the fibrin clot spread in the space of defect and filled it evenly. As a result, the most rapid and successful regeneration of the bone tissue defect was achieved. </p> <h3>Keywords</h3><p>bone damage, rat jaw, bone repair, mesenchymal stem cells, autologous bone marrow, regeneration </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1714) "

According to scientific literature data, the application of mesenchymal stem cells leads to faster regeneration of injured bones and an increase in bone density. The regeneration processes at the site of a rat’s damaged bottom jawbone after the administration of the following substances: (1) autologous platelet-enriched fibrin clot (PEFC); (2) a suspension of autologous marrow-derived mesenchymal stem cells (AMSC) in a culture medium; and (3) PEFC with absorbed AMSC were studied with light microscopy and x-ray densitometry. Morphological examination showed that the development of red bone marrow in the bone callus occurs much earlier after AMSC application than during natural bone restoration. The formation of marrow-containing bone cavities after AMSC introduction is associated with decreased local tissue density at the 4th and 5th weeks of observation. The revealed changes are detectable in all observations, thus confirming the acceleration of the regenerative events in damaged bone tissue. The combination of PEFC with AMSC achieved the best results. After one week the hole in the lower jawbone was mostly filled with the regenerated bone tissue. It is very likely that in this case the synthesis of fibrin and stem cell characteristics optimized bone regeneration. Apparently, the bone formation started in the center of the defect, it did not start from the edges. Stem cells in the fibrin clot spread in the space of defect and filled it evenly. As a result, the most rapid and successful regeneration of the bone tissue defect was achieved.

Keywords

bone damage, rat jaw, bone repair, mesenchymal stem cells, autologous bone marrow, regeneration

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According to scientific literature data, the application of mesenchymal stem cells leads to faster regeneration of injured bones and an increase in bone density. The regeneration processes at the site of a rat’s damaged bottom jawbone after the administration of the following substances: (1) autologous platelet-enriched fibrin clot (PEFC); (2) a suspension of autologous marrow-derived mesenchymal stem cells (AMSC) in a culture medium; and (3) PEFC with absorbed AMSC were studied with light microscopy and x-ray densitometry. Morphological examination showed that the development of red bone marrow in the bone callus occurs much earlier after AMSC application than during natural bone restoration. The formation of marrow-containing bone cavities after AMSC introduction is associated with decreased local tissue density at the 4th and 5th weeks of observation. The revealed changes are detectable in all observations, thus confirming the acceleration of the regenerative events in damaged bone tissue. The combination of PEFC with AMSC achieved the best results. After one week the hole in the lower jawbone was mostly filled with the regenerated bone tissue. It is very likely that in this case the synthesis of fibrin and stem cell characteristics optimized bone regeneration. Apparently, the bone formation started in the center of the defect, it did not start from the edges. Stem cells in the fibrin clot spread in the space of defect and filled it evenly. As a result, the most rapid and successful regeneration of the bone tissue defect was achieved.

Keywords

bone damage, rat jaw, bone repair, mesenchymal stem cells, autologous bone marrow, regeneration

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Center of New Medical Technologies (Director - Prof. A.I. Shevela), Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS, 630090, Novosibirsk, Russia


Correspondence
Center of New Medical Technologies (Director - Prof. A.I. Shevela), Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS, 630090, Novosibirsk, Russia
E-mail: imai@spam is badmail.ru 

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Center of New Medical Technologies (Director - Prof. A.I. Shevela), Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS, 630090, Novosibirsk, Russia


Correspondence
Center of New Medical Technologies (Director - Prof. A.I. Shevela), Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS, 630090, Novosibirsk, Russia
E-mail: imai@spam is badmail.ru 

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Case Report

The treatment of Monoclonal Immunoglobulin Deposition Disease (MIDD) has not been standardized because of the small number of patients reported in the literature [3, 8, 7]. However, as MIDD is associated with plasma cell dyscrasia, patients have typically been treated with regimens used for multiple myeloma, most commonly melphalan and prednisolone. In the largest series of patients, seven patients with MIDD were treated with high dose melphalan and autologous stem Cell Transplant (ASCT), some prior to renal allograft, with beneficial results3.

To add to this preliminary experience, we report on a 36-year-old female, originally referred to the renal unit in April 2006 with hypertension and nephrotic range proteinuria (24 hr urine protein 4.69g, serum albumin 40g/l) and an elevated serum creatinine (380umol/L). She had several small palpable lymph nodes but no splenomegaly. Urine protein immune electrophoresis showed kappa monoclonal free light chain 0.04g/l. A renal ultrasound scan was normal and a CT thorax, abdomen, and pelvis showed no evidence of lymphoma. A renal biopsy confirmed nodular glomerulosclerosis and monotypic staining for kappa on immunofluorescence. Electron microscopy showed nodular glomerulosclerosis, numerous medium to large heterogeneous electron dense deposits in paramesangial areas, linear densities on the endothelial side of the glomerular basement membrane with similar electron dense material seen at the periphery of the arterioles, and membranes suggestive of MIDD at the periphery of the tubular basement. In association, criteria for myeloma were fulfilled based on Kappa Bence Jones proteinuria (0.04g/l), kappa serum free light chains (1000 mg/l) and 13% atypical plasma cells on bone marrow examination. Immunoglobulin immunofixation showed no serum monoclonal immunoglobulin, but immune paresis was confirmed. A SAP scan showed no evidence of light chain deposition or amyloidosis in other organs. The patient progressed to end stage renal disease and was initiated on peritoneal dialysis and subsequently transferred to hemodialysis via an arteriovenous fistula in February 2007. The plasma cell dyscrasia was treated with attenuated cyclophosphamide, thalidomide, and dexamethasone (CTD regimen) without significant complications and a good partial response was achieved after six cycles (January – June 2008).

Given her age and otherwise good performance status, the long-term strategy of a renal allograft was considered reasonable. It was logical to consider that maximal suppression of the plasma cell dyscrasia for the longest period would offer the best protection of a potential renal allograft from MIDD. High-dose melphalan and autologous stem cell transplant (ASCT) is a standard of care in myeloma patients which offers a prolonged treatment-free period and high chance of a complete remission that is associated with immunofixation negativity. Although feasible in patients with renal failure, the treatment-related mortality is significantly higher [7]. Clinical review confirmed her fitness to proceed with high-dose melphalan and ASCT, and after weighing up the risks and benefits, the patient consented to the procedure.
 
Peripheral blood stem cells were successfully harvested with G-CSF 10mcg/kg subcutaneously and apheresis. In September 2008, the patient was admitted for high dose melphalan and ASCT. Hemodialysis was performed on the day prior to inpatient admission (day –3), admitted and received high dose melphalan 140mg/m2 (day –2), hemodialysed on day –1, and underwent autologous stem cell infusion (2.86x10*6/kg CD34+ cells) and hemodialysis on day 0. No major complications occurred following stem cell infusion apart from the routine toxicities (vomiting, diarrhea, vaginal thrush, cytopenia, and upper GI mucositis). Neutropenic sepsis was successfully treated with broad-spectrum antibiotics (meropenem and vancomycin). The response to HDM and ASCT was assessed at around day +100 (Jan 6, 2009) following the procedure. A bone marrow aspirate and trephine biopsy examination on day 100 post stem cell infusion showed no excess of plasma cells (1%). Serological responses to induction treatment and autologous transplant are summarized in Fig. 1, confirming an excellent prolonged response after SCT.

Figure 1. Serum Free kappa light chain assay

Bansal_fig01.jpg

In March 2009, the patient underwent a live related renal transplant from her sister (112 mismatch, CMV negative-negative). A low level HLA donor specific antibody (DSA) was detected in the recipient serum by Luminex single antigen beads (DR 17) both before and after the high dose melphalan. Flow cytometric crossmatching with T and B cells was negative. Thymoglobulin induction was considered too hazardous in the context of recent high dose melphalan and immune paresis. A standard immunosuppression regime of prednisolone, tacrolimus, and mycophenolate mofetil (MMF) with Basiliximab induction was used. There were no immediate complications and she was discharged one week later. Tacrolimus doses were adjusted according to whole blood levels; target level 8–12ug/l. A renal allograft biopsy in April 2009 showed no evidence of rejection or recurrent disease, but electron microscopy was not performed. She had a period of chronic diarrhea but no evidence of CMV colitis on sigmiodoscopy and rectal biopsy. MMF was switched to mycophenolate sodium and the diarrhea resolved. She developed BK viruria (peak level >1,000,000 viral copies/ml) and low level viremia (50 viral copies/ml) associated with graft dysfunction nearly one year after her renal transplant. A biopsy was not performed but her immunosuppression was reduced to aim for a tacrolimus level between 3–4 µg/l. There has been no recurrence of proteinuria; recent serum creatinine was 110 umol/l. The only late effect of the chemotherapy and transplant procedures has been a premature menopause requiring hormone replacement therapy (osteoporosis on bone mineral density scan), although this required cessation due to fluid retention and was replaced with weekly alendronic acid. ECG and echocardiography have shown no long-term cardiac dysfunction (cardiac investigations were done to monitor cardiotoxicity from treatment). As of December 2010, the patient continues under regular joint follow up with hematologists and nephrologists, and has successfully returned to work with normal performance status.

Discussion

Renal involvement is considered universal in patients with MIDD [7, 9, 10]. It classically present as nodular mesangial sclerosis, thickening of glomerular basement membrane, and mesangial expansion, with endocapillary proliferation being other common findings, though diagnosis is usually confirmed with electron microscopy, which can demonstrate granular electron-dense deposits located with in the tubular basement membrane, glomerular basement membrane, vessel wall and also mesangium [10]. Renal transplant is generally not considered in these patients due to an almost universal recurrence of the disease and poor survival of renal allograft [4]. For patients with MIDD who do not have multiple myeloma, the median allograft survival rate is only 37.5 months. This increases to 47.9 months if deaths with a functioning graft are excluded, but it is far from the 12.5 to 19.9 years projected for median allograft survival rate in patients without MIDD [6]. Renal allograft survival could be prolonged by achieving good hematological remission. Recently this has been achieved by using high dose chemotherapy followed by ASCT, though no evidence is available in control settings [5, 1, 2]. It is therefore logical to aim for maximal suppression of light chain production and delay in recurrence of disease in renal allograft. An additional interest of this case is the fact that the high dose melphalan did not abrogate the allosensitization. However, despite the presence of a DSA and standard immunosuppression the recipient did not experience rejection.

This case adds to the limited literature regarding the management of MIDD with intensive anti-myeloma treatment, including the feasibility of consolidation with high dose melphalan and ASCT as a means of achieving as deep a remission as possible prior to renal allograft. The goal of successful therapy may hinge on the complete suppression of light chain production and, in view of this; an excellent clonal response has been sustained for over two years following the high dose melphalan and ASCT. Clearly, long- term follow up of all such cases is necessary to evaluate the efficacy of high dose melphalan and ASCT and other anti-myeloma treatments in the protection of the renal allograft from the re-emergent MIDD, and also in relation to how close monitoring may extend this protection by guiding the early re-introduction of second line therapies, including novel agents such as bortezomib and lenalidomide, or even further SCT procedures. Given the rarity of MIDD, further reports of such cases would be valuable. Multi-centre registry based studies may help address these questions.

Acknowledgements

The authors have declared that no competing interests exist.

References

1. Bird JM, Fuge R, Sirohi B, Apperley JF, Hunter A, Snowden J, Mahendra P, Milligan D, Byrne J, Littlewood T, Fegan C, McQuaker G, Pagliuca A, Johnson P, Rahemtulla A, Morris C, Marks DI; British Society of Blood and Marrow Transplantation. The clinical outcome and toxicity of high-dose chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and severe renal impairment: a British Society of Blood and Marrow Transplantation study. British Journal of Haematology 2006; 134:385-90, doi:10.1111/j.1365-2141.2006.06191.x.

2. Bird JM, Owen R, D’Sa S, Snowden J, Pratt G, Ashcroft J, Yong K, Cook G, Feyler S, Davies F, Morgan G, Cavenagh J, Low E, Behrens J. Guidelines for the diagnosis and management of multiple myeloma 2010. British Journal of Haematology, in press.

3. Dhodapkar MV, Merlini G, Solomon A. Biology and therapy of immunoglobulin deposition diseases. Hematol Oncol Clin North Am. 1997;11:89-110.

4. European Best Practice Guidelines for Renal Transplantation. Produced by the EBPG Expert Group on Renal Transplantation. Foreword, Preface, Part 1: Evaluation, selection and preparation of the potential transplant recipient. (26 items of which 12 are open access) Nephrol Dial Transplant 2000; 15 [Suppl 7]:3-38.

5. Firkin F, Hill PA, Dwyer K, Gock H. Reversal of dialysis dependent renal failure in light-chain deposition disease by autologous peripheral blood stem cell transplantation. Am J Kidney Dis. 2004;44:551-555.

6. Hariharan S, Johnson CP, Bresnahan BA, et al. Improved graft survival after renal transplantation in the United states,1988to1996. N Engl J Med. 2000;342:605-612. doi:10.1056/NEJM200003023420901.

7. Hassoun H, Flombaum C, VD D’Agati3, BT Rafferty, Cohen A, Klimek V, Boruchov A, Kewalramani T, Reich L, Nimer SD, Comenzo RL. High-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease. Bone Marrow Transplantation. 2008;42:405-412. doi:10.1038/bmt.2008.179.

8. Heilman RL, Velosa JA, Holley KE, Offord KP, Kyle RA. Long-term follow-up and response to chemotherapy in patients with light-chain deposition disease. Am J Kidney Dis. 1992;20:34-41.

9. Lin J, Markowitz GS, Valeri AM, Kambham N, Sherman WH, Appel GB et al. Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J Am Soc Nephrol. 2001;12:1482-1492.

10. Leung N, Lager DJ, Gertz MA, Wilson K, Kanakiriya S, Fervenza FC. Long-Term Outcome of RenalTransplantation in Light-Chain Deposition Disease. Am J Kidney Dis. 2004;43:147-153.

" ["~DETAIL_TEXT"]=> string(13343) "

Case Report

The treatment of Monoclonal Immunoglobulin Deposition Disease (MIDD) has not been standardized because of the small number of patients reported in the literature [3, 8, 7]. However, as MIDD is associated with plasma cell dyscrasia, patients have typically been treated with regimens used for multiple myeloma, most commonly melphalan and prednisolone. In the largest series of patients, seven patients with MIDD were treated with high dose melphalan and autologous stem Cell Transplant (ASCT), some prior to renal allograft, with beneficial results3.

To add to this preliminary experience, we report on a 36-year-old female, originally referred to the renal unit in April 2006 with hypertension and nephrotic range proteinuria (24 hr urine protein 4.69g, serum albumin 40g/l) and an elevated serum creatinine (380umol/L). She had several small palpable lymph nodes but no splenomegaly. Urine protein immune electrophoresis showed kappa monoclonal free light chain 0.04g/l. A renal ultrasound scan was normal and a CT thorax, abdomen, and pelvis showed no evidence of lymphoma. A renal biopsy confirmed nodular glomerulosclerosis and monotypic staining for kappa on immunofluorescence. Electron microscopy showed nodular glomerulosclerosis, numerous medium to large heterogeneous electron dense deposits in paramesangial areas, linear densities on the endothelial side of the glomerular basement membrane with similar electron dense material seen at the periphery of the arterioles, and membranes suggestive of MIDD at the periphery of the tubular basement. In association, criteria for myeloma were fulfilled based on Kappa Bence Jones proteinuria (0.04g/l), kappa serum free light chains (1000 mg/l) and 13% atypical plasma cells on bone marrow examination. Immunoglobulin immunofixation showed no serum monoclonal immunoglobulin, but immune paresis was confirmed. A SAP scan showed no evidence of light chain deposition or amyloidosis in other organs. The patient progressed to end stage renal disease and was initiated on peritoneal dialysis and subsequently transferred to hemodialysis via an arteriovenous fistula in February 2007. The plasma cell dyscrasia was treated with attenuated cyclophosphamide, thalidomide, and dexamethasone (CTD regimen) without significant complications and a good partial response was achieved after six cycles (January – June 2008).

Given her age and otherwise good performance status, the long-term strategy of a renal allograft was considered reasonable. It was logical to consider that maximal suppression of the plasma cell dyscrasia for the longest period would offer the best protection of a potential renal allograft from MIDD. High-dose melphalan and autologous stem cell transplant (ASCT) is a standard of care in myeloma patients which offers a prolonged treatment-free period and high chance of a complete remission that is associated with immunofixation negativity. Although feasible in patients with renal failure, the treatment-related mortality is significantly higher [7]. Clinical review confirmed her fitness to proceed with high-dose melphalan and ASCT, and after weighing up the risks and benefits, the patient consented to the procedure.
 
Peripheral blood stem cells were successfully harvested with G-CSF 10mcg/kg subcutaneously and apheresis. In September 2008, the patient was admitted for high dose melphalan and ASCT. Hemodialysis was performed on the day prior to inpatient admission (day –3), admitted and received high dose melphalan 140mg/m2 (day –2), hemodialysed on day –1, and underwent autologous stem cell infusion (2.86x10*6/kg CD34+ cells) and hemodialysis on day 0. No major complications occurred following stem cell infusion apart from the routine toxicities (vomiting, diarrhea, vaginal thrush, cytopenia, and upper GI mucositis). Neutropenic sepsis was successfully treated with broad-spectrum antibiotics (meropenem and vancomycin). The response to HDM and ASCT was assessed at around day +100 (Jan 6, 2009) following the procedure. A bone marrow aspirate and trephine biopsy examination on day 100 post stem cell infusion showed no excess of plasma cells (1%). Serological responses to induction treatment and autologous transplant are summarized in Fig. 1, confirming an excellent prolonged response after SCT.

Figure 1. Serum Free kappa light chain assay

Bansal_fig01.jpg

In March 2009, the patient underwent a live related renal transplant from her sister (112 mismatch, CMV negative-negative). A low level HLA donor specific antibody (DSA) was detected in the recipient serum by Luminex single antigen beads (DR 17) both before and after the high dose melphalan. Flow cytometric crossmatching with T and B cells was negative. Thymoglobulin induction was considered too hazardous in the context of recent high dose melphalan and immune paresis. A standard immunosuppression regime of prednisolone, tacrolimus, and mycophenolate mofetil (MMF) with Basiliximab induction was used. There were no immediate complications and she was discharged one week later. Tacrolimus doses were adjusted according to whole blood levels; target level 8–12ug/l. A renal allograft biopsy in April 2009 showed no evidence of rejection or recurrent disease, but electron microscopy was not performed. She had a period of chronic diarrhea but no evidence of CMV colitis on sigmiodoscopy and rectal biopsy. MMF was switched to mycophenolate sodium and the diarrhea resolved. She developed BK viruria (peak level >1,000,000 viral copies/ml) and low level viremia (50 viral copies/ml) associated with graft dysfunction nearly one year after her renal transplant. A biopsy was not performed but her immunosuppression was reduced to aim for a tacrolimus level between 3–4 µg/l. There has been no recurrence of proteinuria; recent serum creatinine was 110 umol/l. The only late effect of the chemotherapy and transplant procedures has been a premature menopause requiring hormone replacement therapy (osteoporosis on bone mineral density scan), although this required cessation due to fluid retention and was replaced with weekly alendronic acid. ECG and echocardiography have shown no long-term cardiac dysfunction (cardiac investigations were done to monitor cardiotoxicity from treatment). As of December 2010, the patient continues under regular joint follow up with hematologists and nephrologists, and has successfully returned to work with normal performance status.

Discussion

Renal involvement is considered universal in patients with MIDD [7, 9, 10]. It classically present as nodular mesangial sclerosis, thickening of glomerular basement membrane, and mesangial expansion, with endocapillary proliferation being other common findings, though diagnosis is usually confirmed with electron microscopy, which can demonstrate granular electron-dense deposits located with in the tubular basement membrane, glomerular basement membrane, vessel wall and also mesangium [10]. Renal transplant is generally not considered in these patients due to an almost universal recurrence of the disease and poor survival of renal allograft [4]. For patients with MIDD who do not have multiple myeloma, the median allograft survival rate is only 37.5 months. This increases to 47.9 months if deaths with a functioning graft are excluded, but it is far from the 12.5 to 19.9 years projected for median allograft survival rate in patients without MIDD [6]. Renal allograft survival could be prolonged by achieving good hematological remission. Recently this has been achieved by using high dose chemotherapy followed by ASCT, though no evidence is available in control settings [5, 1, 2]. It is therefore logical to aim for maximal suppression of light chain production and delay in recurrence of disease in renal allograft. An additional interest of this case is the fact that the high dose melphalan did not abrogate the allosensitization. However, despite the presence of a DSA and standard immunosuppression the recipient did not experience rejection.

This case adds to the limited literature regarding the management of MIDD with intensive anti-myeloma treatment, including the feasibility of consolidation with high dose melphalan and ASCT as a means of achieving as deep a remission as possible prior to renal allograft. The goal of successful therapy may hinge on the complete suppression of light chain production and, in view of this; an excellent clonal response has been sustained for over two years following the high dose melphalan and ASCT. Clearly, long- term follow up of all such cases is necessary to evaluate the efficacy of high dose melphalan and ASCT and other anti-myeloma treatments in the protection of the renal allograft from the re-emergent MIDD, and also in relation to how close monitoring may extend this protection by guiding the early re-introduction of second line therapies, including novel agents such as bortezomib and lenalidomide, or even further SCT procedures. Given the rarity of MIDD, further reports of such cases would be valuable. Multi-centre registry based studies may help address these questions.

Acknowledgements

The authors have declared that no competing interests exist.

References

1. Bird JM, Fuge R, Sirohi B, Apperley JF, Hunter A, Snowden J, Mahendra P, Milligan D, Byrne J, Littlewood T, Fegan C, McQuaker G, Pagliuca A, Johnson P, Rahemtulla A, Morris C, Marks DI; British Society of Blood and Marrow Transplantation. The clinical outcome and toxicity of high-dose chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and severe renal impairment: a British Society of Blood and Marrow Transplantation study. British Journal of Haematology 2006; 134:385-90, doi:10.1111/j.1365-2141.2006.06191.x.

2. Bird JM, Owen R, D’Sa S, Snowden J, Pratt G, Ashcroft J, Yong K, Cook G, Feyler S, Davies F, Morgan G, Cavenagh J, Low E, Behrens J. Guidelines for the diagnosis and management of multiple myeloma 2010. British Journal of Haematology, in press.

3. Dhodapkar MV, Merlini G, Solomon A. Biology and therapy of immunoglobulin deposition diseases. Hematol Oncol Clin North Am. 1997;11:89-110.

4. European Best Practice Guidelines for Renal Transplantation. Produced by the EBPG Expert Group on Renal Transplantation. Foreword, Preface, Part 1: Evaluation, selection and preparation of the potential transplant recipient. (26 items of which 12 are open access) Nephrol Dial Transplant 2000; 15 [Suppl 7]:3-38.

5. Firkin F, Hill PA, Dwyer K, Gock H. Reversal of dialysis dependent renal failure in light-chain deposition disease by autologous peripheral blood stem cell transplantation. Am J Kidney Dis. 2004;44:551-555.

6. Hariharan S, Johnson CP, Bresnahan BA, et al. Improved graft survival after renal transplantation in the United states,1988to1996. N Engl J Med. 2000;342:605-612. doi:10.1056/NEJM200003023420901.

7. Hassoun H, Flombaum C, VD D’Agati3, BT Rafferty, Cohen A, Klimek V, Boruchov A, Kewalramani T, Reich L, Nimer SD, Comenzo RL. High-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease. Bone Marrow Transplantation. 2008;42:405-412. doi:10.1038/bmt.2008.179.

8. Heilman RL, Velosa JA, Holley KE, Offord KP, Kyle RA. Long-term follow-up and response to chemotherapy in patients with light-chain deposition disease. Am J Kidney Dis. 1992;20:34-41.

9. Lin J, Markowitz GS, Valeri AM, Kambham N, Sherman WH, Appel GB et al. Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J Am Soc Nephrol. 2001;12:1482-1492.

10. Leung N, Lager DJ, Gertz MA, Wilson K, Kanakiriya S, Fervenza FC. Long-Term Outcome of RenalTransplantation in Light-Chain Deposition Disease. Am J Kidney Dis. 2004;43:147-153.

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Сноуден</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(113) "

Тарун Банзал, Рашид Хоссейн, Уильям МкКейн, Джон А. Сноуден

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Болезнь депозитов моноклональных иммуноглобулинов (БДМИ) практически всегда поражает почки и нередко приводит к полной почечной недостаточности (ПН). Трансплантация почки как метод лечения при этом обычно не рассматривается, так как болезнь практически всегда рецидивирует, в силу чего вероятность приживления аллотрансплантата очень низкая. Мы приводим результат лечения 36-летней больной, которой после курса индукционной химиотерапии ввели высокую дозу мелфалана и аутологичные стволовые клетки, а затем ей пересадили почку сестры. В течение последующего более чем 2-летнего наблюдения не было отмечено ни признаков отторжения аллотрансплантата и каких-либо связанных с трансплантацией типичных осложнений, ни рецидива БДМИ. Данное клиническое  наблюдение даёт основание рассматривать приведенный метод лечения приемлемым для больных БДМИ, осложнённой конечной стадией ПН, однако, больные для этого должны быть тщательно отобраны.

Ключевые слова

трансплантация аутологичных стволовых клеток, конечная стадия почечной недостаточности, болезнь депозитов моноклональных иммуноглобулинов, БДМИ, аллотрансплантат почки, свободные цепи иммуноглобулинов в сыворотке крови, мелфалан

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Tarun Bansal2, Rashed Hossain1, William McKane2, John A Snowden1

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1Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK;
2Department of Renal Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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Monoclonal immunoglobulin deposition disease (MIDD) nearly always has renal involvement and frequently leads to end stage renal failure (ESRF). Renal transplantation is not usually considered due to an almost universal recurrence of the disease and poor survival of the renal allograft. We report the case of a 36-year-old female who was treated with induction chemotherapy followed by high dose melphalan and autologous stem cell transplantation and subsequently received a live related renal transplant from her sister. She had no rejection or major post transplant complications, and showed no signs of recurrence of disease after over 2 years of follow up. Our case suggests this mode of therapy could be considered in carefully selected patients with ESRF due to MIDD.

Keywords

Autologous stem cell transplantation (ASCT), End stage renal failure, Monoclonal Immunoglobulin Deposition Disease (MIDD), Renal allograft, Serum free light chains, Melphalan

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Tarun Bansal2, Rashed Hossain1, William McKane2, John A Snowden1

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Tarun Bansal2, Rashed Hossain1, William McKane2, John A Snowden1

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Monoclonal immunoglobulin deposition disease (MIDD) nearly always has renal involvement and frequently leads to end stage renal failure (ESRF). Renal transplantation is not usually considered due to an almost universal recurrence of the disease and poor survival of the renal allograft. We report the case of a 36-year-old female who was treated with induction chemotherapy followed by high dose melphalan and autologous stem cell transplantation and subsequently received a live related renal transplant from her sister. She had no rejection or major post transplant complications, and showed no signs of recurrence of disease after over 2 years of follow up. Our case suggests this mode of therapy could be considered in carefully selected patients with ESRF due to MIDD.

Keywords

Autologous stem cell transplantation (ASCT), End stage renal failure, Monoclonal Immunoglobulin Deposition Disease (MIDD), Renal allograft, Serum free light chains, Melphalan

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Monoclonal immunoglobulin deposition disease (MIDD) nearly always has renal involvement and frequently leads to end stage renal failure (ESRF). Renal transplantation is not usually considered due to an almost universal recurrence of the disease and poor survival of the renal allograft. We report the case of a 36-year-old female who was treated with induction chemotherapy followed by high dose melphalan and autologous stem cell transplantation and subsequently received a live related renal transplant from her sister. She had no rejection or major post transplant complications, and showed no signs of recurrence of disease after over 2 years of follow up. Our case suggests this mode of therapy could be considered in carefully selected patients with ESRF due to MIDD.

Keywords

Autologous stem cell transplantation (ASCT), End stage renal failure, Monoclonal Immunoglobulin Deposition Disease (MIDD), Renal allograft, Serum free light chains, Melphalan

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1Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK;
2Department of Renal Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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1Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK;
2Department of Renal Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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Тарун Банзал, Рашид Хоссейн, Уильям МкКейн, Джон А. Сноуден

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Тарун Банзал, Рашид Хоссейн, Уильям МкКейн, Джон А. Сноуден

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Болезнь депозитов моноклональных иммуноглобулинов (БДМИ) практически всегда поражает почки и нередко приводит к полной почечной недостаточности (ПН). Трансплантация почки как метод лечения при этом обычно не рассматривается, так как болезнь практически всегда рецидивирует, в силу чего вероятность приживления аллотрансплантата очень низкая. Мы приводим результат лечения 36-летней больной, которой после курса индукционной химиотерапии ввели высокую дозу мелфалана и аутологичные стволовые клетки, а затем ей пересадили почку сестры. В течение последующего более чем 2-летнего наблюдения не было отмечено ни признаков отторжения аллотрансплантата и каких-либо связанных с трансплантацией типичных осложнений, ни рецидива БДМИ. Данное клиническое  наблюдение даёт основание рассматривать приведенный метод лечения приемлемым для больных БДМИ, осложнённой конечной стадией ПН, однако, больные для этого должны быть тщательно отобраны.

Ключевые слова

трансплантация аутологичных стволовых клеток, конечная стадия почечной недостаточности, болезнь депозитов моноклональных иммуноглобулинов, БДМИ, аллотрансплантат почки, свободные цепи иммуноглобулинов в сыворотке крови, мелфалан

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Болезнь депозитов моноклональных иммуноглобулинов (БДМИ) практически всегда поражает почки и нередко приводит к полной почечной недостаточности (ПН). Трансплантация почки как метод лечения при этом обычно не рассматривается, так как болезнь практически всегда рецидивирует, в силу чего вероятность приживления аллотрансплантата очень низкая. Мы приводим результат лечения 36-летней больной, которой после курса индукционной химиотерапии ввели высокую дозу мелфалана и аутологичные стволовые клетки, а затем ей пересадили почку сестры. В течение последующего более чем 2-летнего наблюдения не было отмечено ни признаков отторжения аллотрансплантата и каких-либо связанных с трансплантацией типичных осложнений, ни рецидива БДМИ. Данное клиническое  наблюдение даёт основание рассматривать приведенный метод лечения приемлемым для больных БДМИ, осложнённой конечной стадией ПН, однако, больные для этого должны быть тщательно отобраны.

Ключевые слова

трансплантация аутологичных стволовых клеток, конечная стадия почечной недостаточности, болезнь депозитов моноклональных иммуноглобулинов, БДМИ, аллотрансплантат почки, свободные цепи иммуноглобулинов в сыворотке крови, мелфалан

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Introduction

One of ten women in the Western world will develop breast cancer during their lifetime. About 25% are premenopausal. Ten to fifteen percent of these women present initially with stage III and fewer with stage IV disease. The majority of stage III breast cancer cases relapse over time. Ten percent of patients developing metastatic disease survive at ten years with  standard treatment. It was for this reason that dose intensification was practiced in the past century and herein we discuss the results observed, the current practice and answer the question whether there is hope for the future.

Dose-dense chemotherapy

In the past century dose intensification by dose-dense induction in stage III and IV breast cancer showed an increase in response rates that were reflected in the significant improvement of disease-free survival in one study in stage III disease [1]; the other studies confirmed higher response rates but showed no impact on disease-free and overall survival [2-4]. Dose density sets the stage for further therapy.

High-dose chemotherapy, stage II and III disease

Peters et al. compared adjuvant AMF chemotherapy (adriamycin, methotrexate, 5-fluoro-uracil) plus intermediate dose chemotherapy and granulocyte colony stimulating factor with upfront and delayed high-dose conditioning (cyclophosphamide, cisplatin, carmustine) plus autologous transplants in 785 women with ten or more positive lymph nodes [5]. Seventy-five percent were younger than fifty years of age. The estrogen receptor (ER) or progesterone receptor (PR) was positive in 70% of patients. A 7% treatment related mortality rate was reported following high-dose conditioning autologous transplants and 0% following the intermediate dose preparative regimen. No difference in disease-free survival was found. It is noteworthy that at 11 years follow-up almost all recipients of intermediate dose chemotherapy had relapsed whereas only 75% of recipients of high-dose conditioning autologous transplants had. Women younger than  fifty years tolerated high-dose chemotherapy better, and intermediate dose chemotherapy was better for older women.

In earlier years Peters et al. reported extensively about high-dose chemotherapy and autologous transplants for breast cancer in an outpatient setting, and the cost-efficiency of such a setting compared to the conventional in-patient setting [6].

Rodenhuis et al. reported the results of a study comparing dose-intensive adjuvant versus high-dose chemotherapy (cyclophosphamide, thiotepa, carboplatin) and autologous transplants after three cycles of intensified chemotherapy (5-fluorouracil, epirubicin, cyclophosphamide) in 885 women with four or more positive lymph nodes, aged 55 years or younger [7]; in the standard arm five cycles of FEC were given. The majority of women had receptor positive breast cancer. Patients with receptor positive breast cancer received five years of tamoxifen. At three years follow-up significant disease free survival was reported in the high-dose cohort (0.037). There was no significant overall survival advantage although 4% more patients survived at 3 years follow-up in the high-dose cohort.

Zander et al. reported on 307 patients with 10+ lymph nodes randomized to four cycles of induction chemotherapy (epirubicin and cyclophosphamide) whereafter either three additional chemotherapy cycles (cyclophosphamide, methotrexate or 5-fluorouracil) or high-dose chemotherapy (cyclophosphamide, thiotepa and mitoxantrone) and autologous transplant were administered [8]. At a median follow-up of 6.1 years 166 events had been reported. Five years disease-free survival was 49% in the high-dose chemotherapy cohort and 42% in the standard dose cohort. The difference was non-significant. Overall survival was respectively 64% and 62%.

Nitz et al. reported on 403 patients with at least nine positive lymph nodes, randomly assigned to either two cycles of dose-dense standard treatment (cyclophosphamide and epirubicin) followed by two courses of high-dose conditioning (epirubicin, cyclophosphamide and thiotepa) and autologous stem cell transplant or four identical cycles of dose-dense standard treatment followed by three cycles of accelerated cyclophosphamide, methotrexate, and fluorouracil [9]. Four-year event-free survival was 60% in high-dose chemotherapy and 44% in the control group (p=.00069). Overall survival was 75% versus 70% (p=.02) respectively. There were no treatment-related deaths.

High-dose chemotherapy, stage IV disease

Vredenburgh et al. published twice in 2006. He compared standard chemotherapy (AFM) with standard chemotherapy plus high-dose chemotherapy and autologous transplants up-front versus delayed in patients with bone metastatic disease [<10, 11]. Radiotherapy was part of the therapeutic plan. One study included 425 chemotherapy-naïve women with metastatic (387) or inflammatory (39) breast cancer [10]. Patients were receptor negative or had experienced treatment failure of at least one round of hormonal therapy if the tumor was ER or PR receptor positive. The other study included 85 chemotherapy naïve breast cancer patients who were confirmed metastatic with only bony metastases [11]. Patient with receptor positive breast cancer had failed at least one hormonal treatment. He showed that upfront transplants induced better disease free survival than observation and  transplantation in the second instance. The significance at ten-year follow-up reached 10% despite a 9.7% treatment related mortality. Radiotherapy might have contributed to the high treatment related mortality. Patients transplanted in complete remission did better than patients with less than complete response to first-line chemotherapy.

Kroger et al. reported on 187 women who were randomly assigned to one or two cycles of high-dose chemotherapy (stamp V, cyclophosphamide, thiotepa, carboplatin) and autologous stem cell rescue after no more than six cycles of first line therapy [12]. Fourty-nine percent and 43% respectively were ER positive and 50% and 40% were PR positive. A 3% treatment-related mortality was observed with first and second high-dose transplants, but the second high-dose cycle could not be administered in the majority of patients. Patients who had achieved complete response after first line therapy did remarkably better than patients who had obtained a partial response. There was no disease-free or overall survival advantage observed following high-dose chemotherapy and autologous transplants in either cohort.

Farquhar et al. reported a meta-analysis representing 483 women from six studies of high-dose chemotherapy and autologous transplants. In all studies conventional chemotherapy had been compared with first line chemotherapy and high-dose conditioning autologous transplants.  The authors found statistically significant improvements of disease free survival at one and five years in the high-dose arm but this was not reflected in a significant improvement in the overall survival at either one, three, or five-year follow-ups [13]. One of these reports was that by Stadtmauer et al. (b). The authors randomized patients who had metastatic breast cancer and who achieved complete (58) or partial response (252) after four to six cycles of standard chemotherapy to either high-dose chemotherapy and autologous stem cell rescue (110) or up to 24 cycles of standard dose cyclophosphamide, methotrexate, and fluorouracil (89) [14]. Prior treatment had consisted of adjuvant chemotherapy or hormonal therapy or hormonal therapy for metastatic disease. ER was positive in about 50% of patients. Time to progression was 9.6 and 9.0 months respectively. Overall survival at three years was not significantly different with a rate of 32% and 38% respectively.

Schulman et al. performed an economic analysis of 180 women enrolled in a study of conventional chemotherapy (up to 24 cycles CMF) versus high-dose chemotherapy (cyclophosphamide, carboplatin, thiotepa) plus autologous stem cell transplant for metastatic breast cancer, who responded to first line treatment (CMF or CAF) [15]. Mean follow-up was 758 days in the conventional group and 690 days in the transplant group. Patients in the transplant group were hospitalized for more days (p=.0041) and incurred higher costs than patients receiving conventional treatment with a mean difference of $ 55,886. Clinical results showed no improvement in survival. Thus high-dose chemotherapy plus stem cell transplant resulted in substantial additional morbidity and costs; the authors concluded that there was no place for such treatment outside clinical trial setting.

Ablative allogeneic transplants and cell therapy for stage IV disease

In 1996 Eibl et al. reported on a pregnant women with grade III, ER-, PR- inflammatory breast cancer [16]. Her pregnancy was terminated. After three neoadjuvant and two adjuvant cycles (cyclophosphamide and epidoxorubicin) her liver and bone metastases became progressive. The option of a high-dose autologous or ablative allogeneic transplant was considered and ablative allogeneic transplant was selected; high dose conditioning was done with thiotepa, carboplatin and cyclophosphamide. At day 28 post-transplant, graft versus host disease (GVHD) became manifest and her metastatic disease had disappeared; this was attributed to a graft versus tumor effect. At day 72 post-transplant she had a liver relapse and at day 110 she died due to progressive liver metastases. At autopsy no bone disease was found.

In the same year Ben Josef et al.  reported on a 36 year old woman referred for a left breast mass [17]. She had 17+ lymph nodes. She received seven cycles of CAF neoadjuvant chemotherapy and a left quadrantectomy and radiotherapy on the axilla and breast. Twenty-three months after treatment she relapsed on the left chest wall and acute myeloid leukemia M2 was detected. The leukemia was treated with chemotherapy and an ablative allogeneic bone marrow transplant with donor lymphocyte infusion. Twelve months post- transplant she remained in complete remission of leukemia and the chest wall abnormality had disappeared.
 
In 1998 Or et al. of the same group reported on six cases who received high-dose autologous transplants and IL2-activated allogeneic cell therapy [18]. It was well tolerated with little toxicity. Disease-free survival was observed in one of the six patients at the time of the report, 34 months after her treatment. Five of the six had progressive disease after seven to thirteen months and died as result of their disease.

Ueno et al. reported a case series of ten patients with liver and bone metastases [19] in 1998. Their median age was 42 years and there were six relapsed and four primary cases. They received FAC induction and then cyclosphosphamide, thiotepa and BCNU and allogeneic cell transplants. All patients engrafted. Graft versus host disease was seen in three of ten patients. There was a 50% response rate with one complete response and no treatment-related mortality. At a median follow-up of 510 days one patient was progression free and she initially had stable disease, and the overall survival rate was 70%. In two patients a graft versus tumor effect was seen concurrently with graft versus host disease and this was observed at withdrawal of cyclosporin; thus the response observed was mainly a post transplant immune modulation effect.

In 2008 Ueno et al. reported about 66 breast cancer patients from the international center for bone marrow transplant registry who received either ablative (n=39) or non-myeloablative (n=27) allogeneic transplants (RIC) for stage IV breast cancer [20]. More patients in the RIC group had a poor pre-transplant performance status (63% vs. 26%, p=.002). In ablative transplants more acute and chronic graft versus host disease at one year (p=.003) was seen and treatment-related mortality at 100 days was 29% versus 7% in non-myeloablative transplants (p=.03). Progression- free survival at one year was 23% with myeloablative conditioning and 8% with RIC (p=.09). Acute graft versus host disease was associated with longer progression-free survival and associated with a graft versus tumor effect.

Non-myeloablative reduced intensity conditioning allogeneic transplants, stage IV

Transplant Creations was founded in 2000 to work on the improvement of clinical research and disease outcome. High-dose autologous transplants for breast cancer had just received negative press and an allogeneic immune response in breast cancer had been observed. Non-myeloablative reduced intensity conditioning allogeneic transplants, a venture of the turn of the century, offered opportunities for cure. The goal was to establish a collaboration between disciplines to better use existent treatment modalities and thereto a study plan was designed consisting of dose dense induction, an autologous transplant strategy and a non-myeloablative reduced intensity conditioning allogeneic transplant [21-23]. Subsequently a handful of case studies were reported.

Pedrazzoli et al. reported in 2001 on two stage IV breast cancer patients who received a non-myeloablative reduced intensity conditioning allogeneic transplant using fludarabine and cyclophosphamide [24]. Cyclosporin and short term methotrexate was used as graft versus host prophylaxis. Both engrafted and there was no treatment-related mortality, both cases obtained partial remission, and both died within one year of the transplant due to progressive disease.

In 2002 Bregni et al. reported six breast cancer patients who received non-myeloablative conditioning with thiotepa, fludarabine, and cyclophosphamide [25]. Graft versus host disease prophylaxis consisted of cyclosporin and methotrexate. All engrafted and two received a donor lymphocyte infusion (DLI). Two achieved partial response, one after cyclosporin withdrawal and one after the DLI. Responses were accompanied by the occurrence of acute graft versus host disease and extensive chronic graft versus host disease. The patient who received a DLI died as result of the procedure; other patients died due to progressive disease. The median survival was 450 days.

Ueno et al. reported in 2003 on eight breast cancer patients who received reduced intensity conditioning with fludarabine and melphalan [26]. Graft versus host prophylaxis consisted of tacrolimus and methotrexate. All engrafted and two received DLI. They observed acute graft versus host disease in two cases and chronic graft versus host disease in six cases. There was no treatment-related mortality and two patients obtained partial remission and two patients a minor response. At a median of 10,3 months and 23 months follow-up four patients were alive.

Bishop et al. reported in 2004 on 16 recipients of a T-deplete, T-replete procedure [27]. Patients who had progressed after treatment with anthracyclines, taxanes, hormonal agents and trastuzumab received reduced intensity conditioning allogeneic transplants. The conditioning regimen consisted of cyclophosphamide and fludarabine. Graft versus host prophylaxis consisted of cyclosporin. Stem cell grafts were depleted of T-lymphocyte cells and  donor lymphocyte infusions at 1, 5, and 10 x 10e6 CD3+ cells/kg were administered on days +42, +70, and +98 post-transplant. Primary engraftment occurred in 15 patients, and 12 received DLI. Complete donor chimerism was observed in all 15 patients by six months post-transplant after the scheduled DLI. Acute GVHD occurred in 10 patients, and 9 had complete resolution of GVHD after treatment with steroids. Four of 13 assessable patients developed chronic GVHD, which was extensive in two cases. Two patients had partial response, three had minor response, six had stable disease and six had progressive disease. At a follow-up of 23.4 months, median survival was 10.3 months. One patient died early post-transplant from multiple organ failure and one six months post-transplant from hemorrhage during thoracentesis to drain a malignant pleural effusion. 

In 2004 Carella reported on 17 heavily pretreated patients who received tandem transplants with high dose chemotherapy and autologous transplants and non-myeloablative reduced intensity conditioning allogeneic transplants and DLI [28]. Thirteen allogeneic transplant recipients primarily engrafted and 4 had primary engraftment failure and secondarily engrafted with DLI. In total 11 patients received DLI. Acute and chronic graft versus host disease occurred in 25% and 39% of patients. Five patients had extensive chronic graft versus host disease. No 100 days treatment-related mortality occurred and overall response was 24%. At a median follow-up of 1320 days, 29% were alive.

Blaise et al. reported in 2004 and 2006 on 18 cases [29]. Whether they gave a DLI is not reported neither is there any notice whether graft versus host disease had been observed. Treatment related mortality did not occur, the response was 18% and at 2 years overall survival was 22%.

De Souza et al. reported on 18 patients who received a reduced intensity conditioning allogeneic transplant [30]. Twelve had stable disease and six were in partial response after standard dose chemotherapy. The preparative regimen consisted of melphalan and fludarabine. Tacrolimus and methotrexate were given as graft versus host prophylaxis. All patients engrafted. Acute GVHD occurred in 50% and chronic GVHD in 78%. Treatment-related mortality was observed in 11%. Median progression free survival was at 202 days and median survival 643 days. The authors observed prolonged disease control in 17% of patients: two were in complete remission 1555 and 2525 days after stem cell transplantation, and one with progressive bone metastatic disease was 1118 days after stem cell transplantation.

The future

The question arises whether there is a future for transplantation for breast cancer. In the late nineties transplantation for breast cancer received negative press as the procedure was used at random and at a too advanced stage. The benefits of autologous transplants were observed when transplants were conducted in stage II and III premenopausal women [5-9] and good risk stage IV disease who achieved complete remission prior to transplant [10-12]. Beyond these stages there is no place for autologous nor for allogeneic transplantation [30]. Transplantation is a costly procedure and should only be used if significance can be obtained and cure is the goal of the treatment.

In stage I to III breast cancer bone marrow assessment by immunohistochemistry has been shown to be strongly predictive for risk of relapse, independent of the lymph node status [31]. The quantitative polymerase chain reaction has been reported to be even more sensitive [32]. Thus application of methods to define the disease status at microscopic level in the bone marrow are warranted.

This century almost no autologous transplants for breast cancer have been conducted and if at all, they were in combination with reduced intensity conditioning allogeneic transplants [21-23, 28].

There is though just a handful of reports on the application of non-myeloablative reduced intensity conditioning allogeneic transplants for advanced breast cancer, and the treatment modality has not yet been practiced in earlier stage disease [24-30]. These reports show that risks are limited if the treatment is administered in experienced hands.
 
There is a future for transplantation for stage II-III breast cancer, and may be good risk stage IV disease but only when the disease status is assessed by evaluation of micrometastatic disease in stage II and III and clinical complete remission has been obtained prior to autologous transplantation in stage IV. It will be critical to follow the procedure that has in the past shown to induce cure in leukemia, namely to induce response by standard or dose dense therapy, to double consolidate response with semi-high-dose conditioning autologous transplants and to eradicate minimal residual disease by reduced intensity conditioning allogeneic transplantation [23]. The results by Peters et al. also suggest that double consolidation is mandatory for optimization of disease outcome, as risk of relapse remained after single intermediate dose chemotherapy [5]. Institutions are invited to license the method, participate in studies and contribute to the program [23].

References

1. Citron ML, Berry DA, Cirrincioe C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B trial 9741. J Clin Oncol 2003;21:1431-1439.

2. Van Hoef MEHM, I Baumann, C Lange, M Ranson, T Luft, EA de Wynter, et al. Dose-escalating induction chemotherapy supported by lenograstim preceding high-dose consolidation chemotherapy for advanced breast cancer: Selection of the optimal regimen to induce maximal tumor response and investigation of the optimal time to collect peripheral blood progenitor cells for bone marrow rescue. Ann Oncol 1994;5:217- 224.

3. Venturini M, Del Mastro L, Aitini E, Baldini E, Caroti C, Contu A, et al. Dose dense adjuvant chemotherapy in early breast cancer patients: results form a randomized trial. J Natl Cancer Institute 2005;97:1724-1733. doi: 10.1093/jnci/dji398.

4. Baldini E, Gardin G, Giannessi PG, Evangelista G, Roncella M, Prochillo T, et al. Accelerated versus standard cyclophosphamide, epirubicin and 5-fluorouracil or cyclophosphamide, methotrexate and 5-fluorouracil: a randomized phase III trial in locally advanced breast cancer. Ann Oncol 2003;14:227-232. doi: 10.1093/annonc/mdg069.

5. Peters WP, Rosner GL, Vredenburgh JJ, Shpall EJ, Crump M, Richardson PG, et al. Prospective randomized comparison of high-dose chemotherapy with stem cell support versus intermediate dose chemotherapy after surgery and adjuvant chemotherapy in women with high-risk primary breast cancer: a report of CALGB 9082, SWOG 9114, NCIC MA-13. J Clin Oncol 2005;23:2191-2200.doi: 10.1200/JCO.2005.10.202.

6. Peters WP, Ross M, Vredenburgh JJ, Hussein A, Rubin P, Dukelow K, et al. The use of intensive clinic support to permit out patient autologous bone marrow transplant for breast cancer. Semin Oncol. 1994;21(4 suppl 7):25-31.

7. Rodenhuis S, Bontenbal M, Beex LVAM, Wagstaff J, Richel DJ, Nooij MA, et al. High dose chemotherapy with hematopoietic stem cell rescue for high-risk breast cancer. N Eng J med 2003;349:7-16.

8. Zander AR, Schmoor C, Kroger N, Kruger N, Moba V, Frickenhofen N, et al. Randomized trial of high-dose adjuvant chemotherapy with autologous hematopoietc stem-cell support versus standard dose chemotherapy in breast cancer patients with ten or more positive lymph nodes: overall survival after 6 years follow-up. Ann Oncol 2008;19(8):1082-9. doi: 10.1093/annonc/mdn023.

9. Nitz UA, Mohrmann S, Fischer J, Lindemann W, Berdel WE, Jackisch C, et al. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral blood stem cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a mulicentre phase III trial. Lancet. 2005;366(9501):1935-1944.

10. Vredenburgh JJ, Coniglio D, Broadwater G, Jones RB, Ross M, Shpall EJ, et al. Consolidation with high-dose combination alkylating agents with bone marrow transplantation significantly improves disease-free survival in home-intensive metastatic breast cancer in complete remission compared with intensive standard dose chemotherapy alone. Biology of Blood and Marrow Transplant. 2006;12:195-203. doi: 10.1016/j.bbmt.2005.10.009.

11. Vredenburgh JJ, Madon B, Coniglio D, Rod M, Broadwater G, Niedzwecker D, et al. A randomized phase III comparative trial of immediate consolidation with high-dose chemotherapy and autologous peripheral blood progenitor cell support compared to observation with delayed consolidation in women with metastatic breast cancer and only bone metastases following intensive induction chemotherapy. Bone Marrow Transplant. 2006; 37(11):1009-15.

12. Kroger N, Frick M, Gluz O, Mohrman S, Metzner B, Jackisch C, et al. Randomized trial of single compared with tandem high-dose chemotherapy followed by autologous stem cell transplantation in patients with chemotherapy sensitive metastatic breast cancer. J Clin Oncol. 2006;24:3919-3926. doi: 10.1200/JCO.2005.04.0352.

13. Farquhar C, Majoribanks J, Basser R, Hetrick S, Lethaby A. High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer. The Cochrane database of systematic reviews 2005, issue 3, Art. No: CD003142.pub2.

14. Stadtmauer EA, O’Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN et al. Conventional dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med 2000;342(15): 1069-1076.

15. Schulman KA, Stadtmauer EA, Reed SD, Glick HA, Goldstein LJ, Pines JM, et al. Economic analysis of conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Bone Marrow Transplant. 2003;31:205-210.

16. Eibl B, Schwaighofer H. Nachbaur D, Marth C, Gachter A, Knupp R, et al.Evidence for graft versus tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer. Blood. 1996;88:11501-1508.

17. Ben-Yosef R, Or R, Nagler A, Slavin S. Graft versus tumor and graft versus leukemia effect in patient with concurrent breast cancer and acute myelocytic leukemia. Lancet. 1996;348(9036):1242-1243.

18. Or R, Ackerstein A, Nagler A, Kapelushnik J, Narpastek E, Samuel S, et al. Allogeneic cell-mediated immune therapy for breast cancer after autologous stem cell transplantation: a clinical pilot study. Cytokines Cell Mol Ther. 1998;4:1-6.

19. Ueno NT, Rondon G, Mirza NQ, Geisler DK, Anderline P, Giralt SA, et al. Allogeneic peripheral blood progenitor cell transplantation for poor risk patients with metastatic breast cancer. J Clin Oncol. 1998;16:986-993.

20. Ueno NT, Rizzo JD, Demirer T, Cheng YC, Hegenbart U, Zang MJ, et al. Allogeneic hematopoietic cell transplantation for metastatic breast cancer. Bone Marrow Transplant. 2008; 41(6):537-45.

21. Van Hoef MEHM. Development of non-myeloablative transplant strategy (NMTx) for breast cancer. Blood. 2001;98(suppl 1):415b(abst 5451).

22. Van Hoef MEHM. Non-myeloablative transplant development program inviting participation by laying the basis for collaborative clinical research between oncologists, hematologists and transplanters. Blood. 2001;98(suppl 1):415b(abst5452).

23. Van Hoef MEHM. Clinical development of non-myeloablative transplants: application as integrated treatment strategy. Hematol Journal. 2002;3(suppl 1):161 (abst 534).

24. Pedrazzoli P, Da Prada GA, Giorgiani G, Schiavo R, Zambelli A, Giraldi E, et al. Allogeneic blood stem cell transplantation after a reduced intensity, preparative regimen: a pilot study in patients with refractory malignancies. Cancer. 2002;94(9):2409‑2415.

25. Bregni M, Dodero A, Peccatori J, Bernardi M, Sassi I, Vena C, et al. Non-myeloablative conditioning followed by hematopoietic cell allografting and donor lymphocyte infusions for patients with metastatic renal and breast cancer. Blood. 2002;99(1): 4234-4236.

26. Ueno NT, Chung Cheng Y, Rondon G, Tannir NM, Gajewsli JL, Courike DR, et al. Rapid induction of complete donor chimerism by the use of reduced intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors. Blood. 2003;102:3829-3837.

27. Bishop MR. Allogeneic lymphocytes induce tumor regression of advanced metastatic breast cancer. J Clin Oncol. 2004;22(19):3886-3892. doi: 10.1200/JCO.2004.01.127.

28. Carella AM, Beltrami G, Corsetti MT, Nati S, Musto P, Scalzulli P, et al. Reduced intensity conditioning for allograft after cytoreductive autograft in metastatic breast cancer. Lancet. 2005;366:318-320.

29. Blaise D, Furst S, Facer C, Bay JO, Goncalves A, Viet F, Mohty M, et al. Allogeneic hematopoietic stem cell transplantation for metastatic breast cancer. Bone Marrow Transplant. 2006;37(suppl 1): S14 abst 148.

30. De Souza JA, Davis ML, Rondon JA, Cheng YC, Jones RB, Champlin RE, et al. Prolonged disease control by non-myeloablative allogeneic transplantation for metastatic breast cancer. Bone Marrow Transplant. 2009;44(2):81-7.

31. Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich LR, et al. Cytokeratin positive cells in the bone marrow and survival of patients with stage I, II or III breast cancer. N Engl J med 2000;342;525-533.

32. Slade MJ, Smith BM, Sinnett HD, Cross NC, Coombes RC. Quantitative polymerase chain reaction for the detection of micrometastases in patients with breast cancer. J Clin Oncol. 1999;17(3):870-9.

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Introduction

One of ten women in the Western world will develop breast cancer during their lifetime. About 25% are premenopausal. Ten to fifteen percent of these women present initially with stage III and fewer with stage IV disease. The majority of stage III breast cancer cases relapse over time. Ten percent of patients developing metastatic disease survive at ten years with  standard treatment. It was for this reason that dose intensification was practiced in the past century and herein we discuss the results observed, the current practice and answer the question whether there is hope for the future.

Dose-dense chemotherapy

In the past century dose intensification by dose-dense induction in stage III and IV breast cancer showed an increase in response rates that were reflected in the significant improvement of disease-free survival in one study in stage III disease [1]; the other studies confirmed higher response rates but showed no impact on disease-free and overall survival [2-4]. Dose density sets the stage for further therapy.

High-dose chemotherapy, stage II and III disease

Peters et al. compared adjuvant AMF chemotherapy (adriamycin, methotrexate, 5-fluoro-uracil) plus intermediate dose chemotherapy and granulocyte colony stimulating factor with upfront and delayed high-dose conditioning (cyclophosphamide, cisplatin, carmustine) plus autologous transplants in 785 women with ten or more positive lymph nodes [5]. Seventy-five percent were younger than fifty years of age. The estrogen receptor (ER) or progesterone receptor (PR) was positive in 70% of patients. A 7% treatment related mortality rate was reported following high-dose conditioning autologous transplants and 0% following the intermediate dose preparative regimen. No difference in disease-free survival was found. It is noteworthy that at 11 years follow-up almost all recipients of intermediate dose chemotherapy had relapsed whereas only 75% of recipients of high-dose conditioning autologous transplants had. Women younger than  fifty years tolerated high-dose chemotherapy better, and intermediate dose chemotherapy was better for older women.

In earlier years Peters et al. reported extensively about high-dose chemotherapy and autologous transplants for breast cancer in an outpatient setting, and the cost-efficiency of such a setting compared to the conventional in-patient setting [6].

Rodenhuis et al. reported the results of a study comparing dose-intensive adjuvant versus high-dose chemotherapy (cyclophosphamide, thiotepa, carboplatin) and autologous transplants after three cycles of intensified chemotherapy (5-fluorouracil, epirubicin, cyclophosphamide) in 885 women with four or more positive lymph nodes, aged 55 years or younger [7]; in the standard arm five cycles of FEC were given. The majority of women had receptor positive breast cancer. Patients with receptor positive breast cancer received five years of tamoxifen. At three years follow-up significant disease free survival was reported in the high-dose cohort (0.037). There was no significant overall survival advantage although 4% more patients survived at 3 years follow-up in the high-dose cohort.

Zander et al. reported on 307 patients with 10+ lymph nodes randomized to four cycles of induction chemotherapy (epirubicin and cyclophosphamide) whereafter either three additional chemotherapy cycles (cyclophosphamide, methotrexate or 5-fluorouracil) or high-dose chemotherapy (cyclophosphamide, thiotepa and mitoxantrone) and autologous transplant were administered [8]. At a median follow-up of 6.1 years 166 events had been reported. Five years disease-free survival was 49% in the high-dose chemotherapy cohort and 42% in the standard dose cohort. The difference was non-significant. Overall survival was respectively 64% and 62%.

Nitz et al. reported on 403 patients with at least nine positive lymph nodes, randomly assigned to either two cycles of dose-dense standard treatment (cyclophosphamide and epirubicin) followed by two courses of high-dose conditioning (epirubicin, cyclophosphamide and thiotepa) and autologous stem cell transplant or four identical cycles of dose-dense standard treatment followed by three cycles of accelerated cyclophosphamide, methotrexate, and fluorouracil [9]. Four-year event-free survival was 60% in high-dose chemotherapy and 44% in the control group (p=.00069). Overall survival was 75% versus 70% (p=.02) respectively. There were no treatment-related deaths.

High-dose chemotherapy, stage IV disease

Vredenburgh et al. published twice in 2006. He compared standard chemotherapy (AFM) with standard chemotherapy plus high-dose chemotherapy and autologous transplants up-front versus delayed in patients with bone metastatic disease [<10, 11]. Radiotherapy was part of the therapeutic plan. One study included 425 chemotherapy-naïve women with metastatic (387) or inflammatory (39) breast cancer [10]. Patients were receptor negative or had experienced treatment failure of at least one round of hormonal therapy if the tumor was ER or PR receptor positive. The other study included 85 chemotherapy naïve breast cancer patients who were confirmed metastatic with only bony metastases [11]. Patient with receptor positive breast cancer had failed at least one hormonal treatment. He showed that upfront transplants induced better disease free survival than observation and  transplantation in the second instance. The significance at ten-year follow-up reached 10% despite a 9.7% treatment related mortality. Radiotherapy might have contributed to the high treatment related mortality. Patients transplanted in complete remission did better than patients with less than complete response to first-line chemotherapy.

Kroger et al. reported on 187 women who were randomly assigned to one or two cycles of high-dose chemotherapy (stamp V, cyclophosphamide, thiotepa, carboplatin) and autologous stem cell rescue after no more than six cycles of first line therapy [12]. Fourty-nine percent and 43% respectively were ER positive and 50% and 40% were PR positive. A 3% treatment-related mortality was observed with first and second high-dose transplants, but the second high-dose cycle could not be administered in the majority of patients. Patients who had achieved complete response after first line therapy did remarkably better than patients who had obtained a partial response. There was no disease-free or overall survival advantage observed following high-dose chemotherapy and autologous transplants in either cohort.

Farquhar et al. reported a meta-analysis representing 483 women from six studies of high-dose chemotherapy and autologous transplants. In all studies conventional chemotherapy had been compared with first line chemotherapy and high-dose conditioning autologous transplants.  The authors found statistically significant improvements of disease free survival at one and five years in the high-dose arm but this was not reflected in a significant improvement in the overall survival at either one, three, or five-year follow-ups [13]. One of these reports was that by Stadtmauer et al. (b). The authors randomized patients who had metastatic breast cancer and who achieved complete (58) or partial response (252) after four to six cycles of standard chemotherapy to either high-dose chemotherapy and autologous stem cell rescue (110) or up to 24 cycles of standard dose cyclophosphamide, methotrexate, and fluorouracil (89) [14]. Prior treatment had consisted of adjuvant chemotherapy or hormonal therapy or hormonal therapy for metastatic disease. ER was positive in about 50% of patients. Time to progression was 9.6 and 9.0 months respectively. Overall survival at three years was not significantly different with a rate of 32% and 38% respectively.

Schulman et al. performed an economic analysis of 180 women enrolled in a study of conventional chemotherapy (up to 24 cycles CMF) versus high-dose chemotherapy (cyclophosphamide, carboplatin, thiotepa) plus autologous stem cell transplant for metastatic breast cancer, who responded to first line treatment (CMF or CAF) [15]. Mean follow-up was 758 days in the conventional group and 690 days in the transplant group. Patients in the transplant group were hospitalized for more days (p=.0041) and incurred higher costs than patients receiving conventional treatment with a mean difference of $ 55,886. Clinical results showed no improvement in survival. Thus high-dose chemotherapy plus stem cell transplant resulted in substantial additional morbidity and costs; the authors concluded that there was no place for such treatment outside clinical trial setting.

Ablative allogeneic transplants and cell therapy for stage IV disease

In 1996 Eibl et al. reported on a pregnant women with grade III, ER-, PR- inflammatory breast cancer [16]. Her pregnancy was terminated. After three neoadjuvant and two adjuvant cycles (cyclophosphamide and epidoxorubicin) her liver and bone metastases became progressive. The option of a high-dose autologous or ablative allogeneic transplant was considered and ablative allogeneic transplant was selected; high dose conditioning was done with thiotepa, carboplatin and cyclophosphamide. At day 28 post-transplant, graft versus host disease (GVHD) became manifest and her metastatic disease had disappeared; this was attributed to a graft versus tumor effect. At day 72 post-transplant she had a liver relapse and at day 110 she died due to progressive liver metastases. At autopsy no bone disease was found.

In the same year Ben Josef et al.  reported on a 36 year old woman referred for a left breast mass [17]. She had 17+ lymph nodes. She received seven cycles of CAF neoadjuvant chemotherapy and a left quadrantectomy and radiotherapy on the axilla and breast. Twenty-three months after treatment she relapsed on the left chest wall and acute myeloid leukemia M2 was detected. The leukemia was treated with chemotherapy and an ablative allogeneic bone marrow transplant with donor lymphocyte infusion. Twelve months post- transplant she remained in complete remission of leukemia and the chest wall abnormality had disappeared.
 
In 1998 Or et al. of the same group reported on six cases who received high-dose autologous transplants and IL2-activated allogeneic cell therapy [18]. It was well tolerated with little toxicity. Disease-free survival was observed in one of the six patients at the time of the report, 34 months after her treatment. Five of the six had progressive disease after seven to thirteen months and died as result of their disease.

Ueno et al. reported a case series of ten patients with liver and bone metastases [19] in 1998. Their median age was 42 years and there were six relapsed and four primary cases. They received FAC induction and then cyclosphosphamide, thiotepa and BCNU and allogeneic cell transplants. All patients engrafted. Graft versus host disease was seen in three of ten patients. There was a 50% response rate with one complete response and no treatment-related mortality. At a median follow-up of 510 days one patient was progression free and she initially had stable disease, and the overall survival rate was 70%. In two patients a graft versus tumor effect was seen concurrently with graft versus host disease and this was observed at withdrawal of cyclosporin; thus the response observed was mainly a post transplant immune modulation effect.

In 2008 Ueno et al. reported about 66 breast cancer patients from the international center for bone marrow transplant registry who received either ablative (n=39) or non-myeloablative (n=27) allogeneic transplants (RIC) for stage IV breast cancer [20]. More patients in the RIC group had a poor pre-transplant performance status (63% vs. 26%, p=.002). In ablative transplants more acute and chronic graft versus host disease at one year (p=.003) was seen and treatment-related mortality at 100 days was 29% versus 7% in non-myeloablative transplants (p=.03). Progression- free survival at one year was 23% with myeloablative conditioning and 8% with RIC (p=.09). Acute graft versus host disease was associated with longer progression-free survival and associated with a graft versus tumor effect.

Non-myeloablative reduced intensity conditioning allogeneic transplants, stage IV

Transplant Creations was founded in 2000 to work on the improvement of clinical research and disease outcome. High-dose autologous transplants for breast cancer had just received negative press and an allogeneic immune response in breast cancer had been observed. Non-myeloablative reduced intensity conditioning allogeneic transplants, a venture of the turn of the century, offered opportunities for cure. The goal was to establish a collaboration between disciplines to better use existent treatment modalities and thereto a study plan was designed consisting of dose dense induction, an autologous transplant strategy and a non-myeloablative reduced intensity conditioning allogeneic transplant [21-23]. Subsequently a handful of case studies were reported.

Pedrazzoli et al. reported in 2001 on two stage IV breast cancer patients who received a non-myeloablative reduced intensity conditioning allogeneic transplant using fludarabine and cyclophosphamide [24]. Cyclosporin and short term methotrexate was used as graft versus host prophylaxis. Both engrafted and there was no treatment-related mortality, both cases obtained partial remission, and both died within one year of the transplant due to progressive disease.

In 2002 Bregni et al. reported six breast cancer patients who received non-myeloablative conditioning with thiotepa, fludarabine, and cyclophosphamide [25]. Graft versus host disease prophylaxis consisted of cyclosporin and methotrexate. All engrafted and two received a donor lymphocyte infusion (DLI). Two achieved partial response, one after cyclosporin withdrawal and one after the DLI. Responses were accompanied by the occurrence of acute graft versus host disease and extensive chronic graft versus host disease. The patient who received a DLI died as result of the procedure; other patients died due to progressive disease. The median survival was 450 days.

Ueno et al. reported in 2003 on eight breast cancer patients who received reduced intensity conditioning with fludarabine and melphalan [26]. Graft versus host prophylaxis consisted of tacrolimus and methotrexate. All engrafted and two received DLI. They observed acute graft versus host disease in two cases and chronic graft versus host disease in six cases. There was no treatment-related mortality and two patients obtained partial remission and two patients a minor response. At a median of 10,3 months and 23 months follow-up four patients were alive.

Bishop et al. reported in 2004 on 16 recipients of a T-deplete, T-replete procedure [27]. Patients who had progressed after treatment with anthracyclines, taxanes, hormonal agents and trastuzumab received reduced intensity conditioning allogeneic transplants. The conditioning regimen consisted of cyclophosphamide and fludarabine. Graft versus host prophylaxis consisted of cyclosporin. Stem cell grafts were depleted of T-lymphocyte cells and  donor lymphocyte infusions at 1, 5, and 10 x 10e6 CD3+ cells/kg were administered on days +42, +70, and +98 post-transplant. Primary engraftment occurred in 15 patients, and 12 received DLI. Complete donor chimerism was observed in all 15 patients by six months post-transplant after the scheduled DLI. Acute GVHD occurred in 10 patients, and 9 had complete resolution of GVHD after treatment with steroids. Four of 13 assessable patients developed chronic GVHD, which was extensive in two cases. Two patients had partial response, three had minor response, six had stable disease and six had progressive disease. At a follow-up of 23.4 months, median survival was 10.3 months. One patient died early post-transplant from multiple organ failure and one six months post-transplant from hemorrhage during thoracentesis to drain a malignant pleural effusion. 

In 2004 Carella reported on 17 heavily pretreated patients who received tandem transplants with high dose chemotherapy and autologous transplants and non-myeloablative reduced intensity conditioning allogeneic transplants and DLI [28]. Thirteen allogeneic transplant recipients primarily engrafted and 4 had primary engraftment failure and secondarily engrafted with DLI. In total 11 patients received DLI. Acute and chronic graft versus host disease occurred in 25% and 39% of patients. Five patients had extensive chronic graft versus host disease. No 100 days treatment-related mortality occurred and overall response was 24%. At a median follow-up of 1320 days, 29% were alive.

Blaise et al. reported in 2004 and 2006 on 18 cases [29]. Whether they gave a DLI is not reported neither is there any notice whether graft versus host disease had been observed. Treatment related mortality did not occur, the response was 18% and at 2 years overall survival was 22%.

De Souza et al. reported on 18 patients who received a reduced intensity conditioning allogeneic transplant [30]. Twelve had stable disease and six were in partial response after standard dose chemotherapy. The preparative regimen consisted of melphalan and fludarabine. Tacrolimus and methotrexate were given as graft versus host prophylaxis. All patients engrafted. Acute GVHD occurred in 50% and chronic GVHD in 78%. Treatment-related mortality was observed in 11%. Median progression free survival was at 202 days and median survival 643 days. The authors observed prolonged disease control in 17% of patients: two were in complete remission 1555 and 2525 days after stem cell transplantation, and one with progressive bone metastatic disease was 1118 days after stem cell transplantation.

The future

The question arises whether there is a future for transplantation for breast cancer. In the late nineties transplantation for breast cancer received negative press as the procedure was used at random and at a too advanced stage. The benefits of autologous transplants were observed when transplants were conducted in stage II and III premenopausal women [5-9] and good risk stage IV disease who achieved complete remission prior to transplant [10-12]. Beyond these stages there is no place for autologous nor for allogeneic transplantation [30]. Transplantation is a costly procedure and should only be used if significance can be obtained and cure is the goal of the treatment.

In stage I to III breast cancer bone marrow assessment by immunohistochemistry has been shown to be strongly predictive for risk of relapse, independent of the lymph node status [31]. The quantitative polymerase chain reaction has been reported to be even more sensitive [32]. Thus application of methods to define the disease status at microscopic level in the bone marrow are warranted.

This century almost no autologous transplants for breast cancer have been conducted and if at all, they were in combination with reduced intensity conditioning allogeneic transplants [21-23, 28].

There is though just a handful of reports on the application of non-myeloablative reduced intensity conditioning allogeneic transplants for advanced breast cancer, and the treatment modality has not yet been practiced in earlier stage disease [24-30]. These reports show that risks are limited if the treatment is administered in experienced hands.
 
There is a future for transplantation for stage II-III breast cancer, and may be good risk stage IV disease but only when the disease status is assessed by evaluation of micrometastatic disease in stage II and III and clinical complete remission has been obtained prior to autologous transplantation in stage IV. It will be critical to follow the procedure that has in the past shown to induce cure in leukemia, namely to induce response by standard or dose dense therapy, to double consolidate response with semi-high-dose conditioning autologous transplants and to eradicate minimal residual disease by reduced intensity conditioning allogeneic transplantation [23]. The results by Peters et al. also suggest that double consolidation is mandatory for optimization of disease outcome, as risk of relapse remained after single intermediate dose chemotherapy [5]. Institutions are invited to license the method, participate in studies and contribute to the program [23].

References

1. Citron ML, Berry DA, Cirrincioe C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B trial 9741. J Clin Oncol 2003;21:1431-1439.

2. Van Hoef MEHM, I Baumann, C Lange, M Ranson, T Luft, EA de Wynter, et al. Dose-escalating induction chemotherapy supported by lenograstim preceding high-dose consolidation chemotherapy for advanced breast cancer: Selection of the optimal regimen to induce maximal tumor response and investigation of the optimal time to collect peripheral blood progenitor cells for bone marrow rescue. Ann Oncol 1994;5:217- 224.

3. Venturini M, Del Mastro L, Aitini E, Baldini E, Caroti C, Contu A, et al. Dose dense adjuvant chemotherapy in early breast cancer patients: results form a randomized trial. J Natl Cancer Institute 2005;97:1724-1733. doi: 10.1093/jnci/dji398.

4. Baldini E, Gardin G, Giannessi PG, Evangelista G, Roncella M, Prochillo T, et al. Accelerated versus standard cyclophosphamide, epirubicin and 5-fluorouracil or cyclophosphamide, methotrexate and 5-fluorouracil: a randomized phase III trial in locally advanced breast cancer. Ann Oncol 2003;14:227-232. doi: 10.1093/annonc/mdg069.

5. Peters WP, Rosner GL, Vredenburgh JJ, Shpall EJ, Crump M, Richardson PG, et al. Prospective randomized comparison of high-dose chemotherapy with stem cell support versus intermediate dose chemotherapy after surgery and adjuvant chemotherapy in women with high-risk primary breast cancer: a report of CALGB 9082, SWOG 9114, NCIC MA-13. J Clin Oncol 2005;23:2191-2200.doi: 10.1200/JCO.2005.10.202.

6. Peters WP, Ross M, Vredenburgh JJ, Hussein A, Rubin P, Dukelow K, et al. The use of intensive clinic support to permit out patient autologous bone marrow transplant for breast cancer. Semin Oncol. 1994;21(4 suppl 7):25-31.

7. Rodenhuis S, Bontenbal M, Beex LVAM, Wagstaff J, Richel DJ, Nooij MA, et al. High dose chemotherapy with hematopoietic stem cell rescue for high-risk breast cancer. N Eng J med 2003;349:7-16.

8. Zander AR, Schmoor C, Kroger N, Kruger N, Moba V, Frickenhofen N, et al. Randomized trial of high-dose adjuvant chemotherapy with autologous hematopoietc stem-cell support versus standard dose chemotherapy in breast cancer patients with ten or more positive lymph nodes: overall survival after 6 years follow-up. Ann Oncol 2008;19(8):1082-9. doi: 10.1093/annonc/mdn023.

9. Nitz UA, Mohrmann S, Fischer J, Lindemann W, Berdel WE, Jackisch C, et al. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral blood stem cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a mulicentre phase III trial. Lancet. 2005;366(9501):1935-1944.

10. Vredenburgh JJ, Coniglio D, Broadwater G, Jones RB, Ross M, Shpall EJ, et al. Consolidation with high-dose combination alkylating agents with bone marrow transplantation significantly improves disease-free survival in home-intensive metastatic breast cancer in complete remission compared with intensive standard dose chemotherapy alone. Biology of Blood and Marrow Transplant. 2006;12:195-203. doi: 10.1016/j.bbmt.2005.10.009.

11. Vredenburgh JJ, Madon B, Coniglio D, Rod M, Broadwater G, Niedzwecker D, et al. A randomized phase III comparative trial of immediate consolidation with high-dose chemotherapy and autologous peripheral blood progenitor cell support compared to observation with delayed consolidation in women with metastatic breast cancer and only bone metastases following intensive induction chemotherapy. Bone Marrow Transplant. 2006; 37(11):1009-15.

12. Kroger N, Frick M, Gluz O, Mohrman S, Metzner B, Jackisch C, et al. Randomized trial of single compared with tandem high-dose chemotherapy followed by autologous stem cell transplantation in patients with chemotherapy sensitive metastatic breast cancer. J Clin Oncol. 2006;24:3919-3926. doi: 10.1200/JCO.2005.04.0352.

13. Farquhar C, Majoribanks J, Basser R, Hetrick S, Lethaby A. High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer. The Cochrane database of systematic reviews 2005, issue 3, Art. No: CD003142.pub2.

14. Stadtmauer EA, O’Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN et al. Conventional dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med 2000;342(15): 1069-1076.

15. Schulman KA, Stadtmauer EA, Reed SD, Glick HA, Goldstein LJ, Pines JM, et al. Economic analysis of conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Bone Marrow Transplant. 2003;31:205-210.

16. Eibl B, Schwaighofer H. Nachbaur D, Marth C, Gachter A, Knupp R, et al.Evidence for graft versus tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer. Blood. 1996;88:11501-1508.

17. Ben-Yosef R, Or R, Nagler A, Slavin S. Graft versus tumor and graft versus leukemia effect in patient with concurrent breast cancer and acute myelocytic leukemia. Lancet. 1996;348(9036):1242-1243.

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Ван Гуф</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(43) "

Марлис Е.Г.М. Ван Гуф

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19372" ["VALUE"]=> array(2) { ["TEXT"]=> string(2174) "<p class="bodytext">В конце прошлого века для лечения рака молочной железы были широко внедрены в практику программы интенсивной химиотерапии. Ряд авторов сообщили о схемах лечения с применением более плотного по частоте введения или более высоких доз химиопрепаратов. Кроме того, были начаты клинические исследования по сочетанию высокодозной химиотерапии и трансплантации аутологичных стволовых клеток больным раком молочной железы II-IV стадий. Первые результаты аллогенной трансплантации гемопоэтических клеток при раке молочной железы в последнем десятилетии 1900-х годов свидетельствовали о положительном иммунном эффекте такого подхода и способствовали началу подобных клинических исследований на небольших группах больных. <br /><br />В данной работе обсуждаются результаты нескольких исследований эффективности высокодозной химиотерапии и трансплантации аутологичных стволовых клеток, а также аллогенной трансплантации при раке молочной железы. </p> <h3>Ключевые слова</h3> <p>рак молочной железы, средневысокие дозы, аутологичный, сниженная интенсивность, кондиционирование, аллогенный, уплотнение режима введения препаратов, химиотерапия  </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2116) "

В конце прошлого века для лечения рака молочной железы были широко внедрены в практику программы интенсивной химиотерапии. Ряд авторов сообщили о схемах лечения с применением более плотного по частоте введения или более высоких доз химиопрепаратов. Кроме того, были начаты клинические исследования по сочетанию высокодозной химиотерапии и трансплантации аутологичных стволовых клеток больным раком молочной железы II-IV стадий. Первые результаты аллогенной трансплантации гемопоэтических клеток при раке молочной железы в последнем десятилетии 1900-х годов свидетельствовали о положительном иммунном эффекте такого подхода и способствовали началу подобных клинических исследований на небольших группах больных. 

В данной работе обсуждаются результаты нескольких исследований эффективности высокодозной химиотерапии и трансплантации аутологичных стволовых клеток, а также аллогенной трансплантации при раке молочной железы.

Ключевые слова

рак молочной железы, средневысокие дозы, аутологичный, сниженная интенсивность, кондиционирование, аллогенный, уплотнение режима введения препаратов, химиотерапия 

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Marlies E.H.M. van Hoef, MD, PhD

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Transplant Creations, www.transplantcreations.com, Amsterdam, The Netherlands


Correspondence
Marlies E.H.M. Van Hoef, MD, PhD, Transplant Creations, P.O. Box 51342, 1007 EH Amsterdam, The Netherlands
Phone: +31-6-12433616
E-mail: mvanhoef@spam is badtransplantcreations.com

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At the end of the past century chemotherapy for breast cancer was characterized by dose intensification. Several authors reported on dose-dense (more frequent) and dose-intense (high-dose) treatment. In addition, studies of high-dose chemotherapy and autologous stem transplantation for stage II to IV breast cancer were started. The first results of allogeneic hematopoietic cell transplantation for breast cancer revealed a positive immune effect and encouraged a handful of small case studies in the last decade of the last century.
This article summarizes the results of several studies using high-dose chemotherapy and autologous stem cell transplantation, as well as the results of studies using allogeneic transplantation for breast cancer.

Keywords

breast cancer, semi-high-dose, autologous, reduced intensity, conditioning, allogeneic, dose-dense treatment, chemotherapy

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Marlies E.H.M. van Hoef, MD, PhD

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Marlies E.H.M. van Hoef, MD, PhD

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19377" ["VALUE"]=> array(2) { ["TEXT"]=> string(981) "<p class="bodytext">At the end of the past century chemotherapy for breast cancer was characterized by dose intensification. Several authors reported on dose-dense (more frequent) and dose-intense (high-dose) treatment. In addition, studies of high-dose chemotherapy and autologous stem transplantation for stage II to IV breast cancer were started. The first results of allogeneic hematopoietic cell transplantation for breast cancer revealed a positive immune effect and encouraged a handful of small case studies in the last decade of the last century.<br />This article summarizes the results of several studies using high-dose chemotherapy and autologous stem cell transplantation, as well as the results of studies using allogeneic transplantation for breast cancer. </p> <h3>Keywords</h3><p> breast cancer, semi-high-dose, autologous, reduced intensity, conditioning, allogeneic, dose-dense treatment, chemotherapy </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(929) "

At the end of the past century chemotherapy for breast cancer was characterized by dose intensification. Several authors reported on dose-dense (more frequent) and dose-intense (high-dose) treatment. In addition, studies of high-dose chemotherapy and autologous stem transplantation for stage II to IV breast cancer were started. The first results of allogeneic hematopoietic cell transplantation for breast cancer revealed a positive immune effect and encouraged a handful of small case studies in the last decade of the last century.
This article summarizes the results of several studies using high-dose chemotherapy and autologous stem cell transplantation, as well as the results of studies using allogeneic transplantation for breast cancer.

Keywords

breast cancer, semi-high-dose, autologous, reduced intensity, conditioning, allogeneic, dose-dense treatment, chemotherapy

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At the end of the past century chemotherapy for breast cancer was characterized by dose intensification. Several authors reported on dose-dense (more frequent) and dose-intense (high-dose) treatment. In addition, studies of high-dose chemotherapy and autologous stem transplantation for stage II to IV breast cancer were started. The first results of allogeneic hematopoietic cell transplantation for breast cancer revealed a positive immune effect and encouraged a handful of small case studies in the last decade of the last century.
This article summarizes the results of several studies using high-dose chemotherapy and autologous stem cell transplantation, as well as the results of studies using allogeneic transplantation for breast cancer.

Keywords

breast cancer, semi-high-dose, autologous, reduced intensity, conditioning, allogeneic, dose-dense treatment, chemotherapy

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Transplant Creations, www.transplantcreations.com, Amsterdam, The Netherlands


Correspondence
Marlies E.H.M. Van Hoef, MD, PhD, Transplant Creations, P.O. Box 51342, 1007 EH Amsterdam, The Netherlands
Phone: +31-6-12433616
E-mail: mvanhoef@spam is badtransplantcreations.com

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Transplant Creations, www.transplantcreations.com, Amsterdam, The Netherlands


Correspondence
Marlies E.H.M. Van Hoef, MD, PhD, Transplant Creations, P.O. Box 51342, 1007 EH Amsterdam, The Netherlands
Phone: +31-6-12433616
E-mail: mvanhoef@spam is badtransplantcreations.com

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Марлис Е.Г.М. Ван Гуф

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Марлис Е.Г.М. Ван Гуф

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Ряд авторов сообщили о схемах лечения с применением более плотного по частоте введения или более высоких доз химиопрепаратов. Кроме того, были начаты клинические исследования по сочетанию высокодозной химиотерапии и трансплантации аутологичных стволовых клеток больным раком молочной железы II-IV стадий. Первые результаты аллогенной трансплантации гемопоэтических клеток при раке молочной железы в последнем десятилетии 1900-х годов свидетельствовали о положительном иммунном эффекте такого подхода и способствовали началу подобных клинических исследований на небольших группах больных. <br /><br />В данной работе обсуждаются результаты нескольких исследований эффективности высокодозной химиотерапии и трансплантации аутологичных стволовых клеток, а также аллогенной трансплантации при раке молочной железы. </p> <h3>Ключевые слова</h3> <p>рак молочной железы, средневысокие дозы, аутологичный, сниженная интенсивность, кондиционирование, аллогенный, уплотнение режима введения препаратов, химиотерапия  </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2116) "

В конце прошлого века для лечения рака молочной железы были широко внедрены в практику программы интенсивной химиотерапии. Ряд авторов сообщили о схемах лечения с применением более плотного по частоте введения или более высоких доз химиопрепаратов. Кроме того, были начаты клинические исследования по сочетанию высокодозной химиотерапии и трансплантации аутологичных стволовых клеток больным раком молочной железы II-IV стадий. Первые результаты аллогенной трансплантации гемопоэтических клеток при раке молочной железы в последнем десятилетии 1900-х годов свидетельствовали о положительном иммунном эффекте такого подхода и способствовали началу подобных клинических исследований на небольших группах больных. 

В данной работе обсуждаются результаты нескольких исследований эффективности высокодозной химиотерапии и трансплантации аутологичных стволовых клеток, а также аллогенной трансплантации при раке молочной железы.

Ключевые слова

рак молочной железы, средневысокие дозы, аутологичный, сниженная интенсивность, кондиционирование, аллогенный, уплотнение режима введения препаратов, химиотерапия 

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В конце прошлого века для лечения рака молочной железы были широко внедрены в практику программы интенсивной химиотерапии. Ряд авторов сообщили о схемах лечения с применением более плотного по частоте введения или более высоких доз химиопрепаратов. Кроме того, были начаты клинические исследования по сочетанию высокодозной химиотерапии и трансплантации аутологичных стволовых клеток больным раком молочной железы II-IV стадий. Первые результаты аллогенной трансплантации гемопоэтических клеток при раке молочной железы в последнем десятилетии 1900-х годов свидетельствовали о положительном иммунном эффекте такого подхода и способствовали началу подобных клинических исследований на небольших группах больных. 

В данной работе обсуждаются результаты нескольких исследований эффективности высокодозной химиотерапии и трансплантации аутологичных стволовых клеток, а также аллогенной трансплантации при раке молочной железы.

Ключевые слова

рак молочной железы, средневысокие дозы, аутологичный, сниженная интенсивность, кондиционирование, аллогенный, уплотнение режима введения препаратов, химиотерапия 

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Introduction

In the canine hematopoietic stem cell transplantation (HSCT) model, durable engraftment of allogeneic dog leukocyte antigen (DLA)-identical littermate bone marrow cells can be achieved following nonmyeloablative conditioning with 2 Gy of total body irradiation (TBI) in combination with pre- and post-transplant immunosuppression consisting of cyclosporin A (CSA) and mycophenolate mofetil (MMF) [1]. A reduction of the radiation dose to 1 Gy TBI resulted in only transient engraftment, and led eventually to graft rejection in this model [1]. Therefore, combinations of 1 Gy HSCT with different forms of immunotherapy were investigated. Post-graft vaccination with recipient hematopoietic cell lysates as well as graft augmentation with donor-derived monocyte-derived dendritic cells (DC) did not support durable engraftment after 1 Gy TBI [2]. Pre-transplant immunosuppression using CTLA4Ig or Pentostatin or graft modification with donor peripheral blood mononuclear cells (PBMC) was shown to improve engraftment to some extent, but long-term engraftment was only seen in 22–63% of the HSCT [5]. Recently, Mielcarek et al. studied 9 different immunosuppressive and/or tolerance-inducing regimens using a TBI dose of 0.5 Gy. None of these strategies was sufficient to ensure sustained engraftment after HSCT [6].

The role of DC as key cells of the immune system is well known. Mature DC especially are highly immunogenic and efficiently induce T-cell proliferation [7]. Furthermore it has been shown that recipient antigen-presenting cells are required to trigger efficiently alloreactive donor T-cells early after total body irradiation [8]. Currently, monocyte-derived DC are the most widely used, since generation of bone-marrow-derived DC is much more invasive. However, when using bone marrow higher numbers of DC were obtained, with a higher capacity to stimulate allogeneic T-cell responses compared to monocyte-derived DC [9].

Therefore, this study investigated whether the addition of monocyte-derived as well as bone marrow-derived mature DC of host origin to the graft and/or administration of DC one week post-transplantation facilitates stable marrow engraftment after 1 Gy conditioning in the canine HSCT model.

Materials and Methods

Experiments were approved by the review board of the state Mecklenburg-Vorpommern (Landesamt für Landwirtschaft, Lebensmittelsicherheit und Fischerei M-V, Germany). 

Animals

Dogs were purchased from commercial kennels licensed by the German Department of Agriculture. All animals were de-wormed and immunized against rabies, parainfluenca, leptospirosis, distemper, hepatitis, and parvovirus. DLA-identical donor/recipient sibling pairs were selected on the basis of matching for highly polymorphic DLA class I and class II microsatellite markers [1].

Hematopoietic stem cell transplantation

HSCT was performed as described previously [1]. Briefly, 7 recipient dogs were conditioned with nonmyeloablative TBI at a single dose of 1 Gy using a high-energy linear accelerator (Siemens Primus; 10 MV X-ray) with a dose rate of 0.25 Gy/min. Bone marrow from DLA-identical siblings was collected under general anesthesia from the humeri, femora, and iliac crest and infused intravenously into the recipients within 24 h after TBI. Immunosuppression consisted of CSA at 15 mg/kg orally 2 times daily on days -1 to +35 in combination with MMF at 20 mg/kg orally 2 times daily on days 0 to +27. In addition to the graft, the dogs were given i.v. infusions of (I) monocyte-derived mature DC of host origin (MoDC) once on day +5 (n=2, group I) and (II) MoDC or CD34+-derived mature DC (CD34+-DC) of host origin twice: once on day 0 together with the graft and once on median day +7 (range +5 to +7) (n=5, group II). The clinical status of recipients was checked twice daily.

Cell isolation and generation of DC

Monocytes were isolated from 300 ml peripheral blood of the recipient at day -2 (group I, one-time DC administration) and at days  7 and -2, respectively (n=2, group II, double DC administration) before transplantation by using an AutoMACS device (Miltenyi Biotec, Bergisch-Gladbach, Germany) [2]. Cells were cultured in 24-well plates for 7 days in RPMI-medium supplemented with 10% dog serum, 1% penicillin/streptomycin, 500 U/ml canine IL-4 and 100 ng/ml human GM-CSF. At day 5 of culture 10 ng/ml TNF-alpha was added to the medium for DC maturation. For generation of CD34+-cell derived DC (n=3; group II, double DC administration) 100 ml of bone marrow were aspirated on days -14 and -7 before transplantation and CD34+ cells were isolated using the AutoMACS device. CD34+ cells were cultured as described previously [10]. For in vitro characterization of cultured DC expression of the DC-specific cell surface marker MHC II and CD11c was analyzed by flow cytometry (Fig. 1).

Figure 1. Analysis of surface marker expression of MHC II (A) and CD11c (B) by flow cytometry. Each histogram represents an overlay of the specific monoclonal antibodies (filled histograms) and isotype-control monoclonal antibodies (solid lines). The histograms show one representative example of bone marrow-derived DC after 14 days of cultivation

Lange_fig01.png

Hematopoietic chimerism analysis

The recipients' peripheral blood was collected weekly. Granulocytes and PBMC were separated by Ficoll-Hypaque density gradient centrifugation (density 1.074 g/ml) and genomic DNA of the cell fractions was isolated (Nucleobond CB 100; Macherey-Nagel, Düren, Germany). Polymorphic tetranucleotide repeats that differed between donors and recipients were amplified and quantified as described previously [11]. Engraftment was defined as detection of >5% of donor-derived DNA. Graft rejection was defined as detection of no donor-derived DNA in the peripheral blood and the bone marrow.

Statistics

The distribution of data was described using medians and ranges. Differences between treatment groups were estimated according to the Mann-Whitney U-Test. Possible association between TNC numbers and their impact on graft rejection was assessed using the Spearman correlation analysis. Probability of p<0.05 was considered significant.

Results

HSCT recipients received DLA-identical marrow grafts containing a median of 4.9 (range 2.6–7.4) x 108 total nucleated cells (TNC)/kg intravenously within 24 h after TBI. The number of DC applied were a median 10.3 (range 6.0–14.5) x 105 DC/kg and 4.7 (range 1.2–7.2) x 105 DC/kg per dose in groups I and II, respectively.

The results of chimerism analyses are depicted in Figure 2. All dogs showed an initial engraftment in the granulocytes and PBMC compartments. The maximum donor chimerisms of the granulocytes accounted for a median 19% (range 14–23) and 33% (range 12–59) in groups I and II, respectively. The maximum PBMC donor chimerisms reached median values of 12% (range 11–12) and 17% (range 14–26) for both groups. Median times to maximum granulocytes chimerisms were 32 days (range 14–49) and 42 days (range 28–56). PBMC chimerisms peaked at days 21 (range 14–28) and 28 (range 28–35) in groups I and II, respectively.

Figure 2. Engraftment kinetics of donor peripheral blood granulocytes (A) and PBMC (B) after 1 Gy HSCT. Dogs received either MoDC vaccination on day +5 (group I, dotted lines) or two-time administration of MoDC and CD34+-DC on day 0 together with the graft and on median day +7 (range +5 to +7) as i.v. vaccination, respectively (group II, solid lines)

Lange_fig02.png

Induction of long-term engraftment could not be achieved in any dog. Rejection of grafts occurred after a median 56 days (range 56–56) and 84 days (range 49–91), respectively. Spearman correlation analysis revealed a significant association between body weight-adjusted numbers of TNC in the graft and time of graft rejection (r=0.871, p=0.01). The maximum chimerism in the granulocyte compartment tended to correlate to the number of TNC/kg as well (r=0.739, p=0.058). 

Of interest, if taking into consideration the influence of TNC counts on graft rejection and chimerism, is the comparison of dog 1 (4.9 TNC/kg, 1x DC) with dog 4 (4.9 TNC/kg, 2x DC) as well as dog 2 (5.4 TNC/kg, 1x DC) with dog 6 (5.5 TNC/kg, 2x DC). These indicate a trend toward lower maximum granulocytes (23% vs 33% and 14% vs 59%) and PBMC donor chimerisms (11% vs 17% and 12% vs 26%) and shortened allograft survival (56 d vs 84 d, both) after a single DC administration.

Discussion

The canine nonmyeloablative HSCT model can be used to investigate novel approaches aiming at improved engraftment as well as long-term graft survival [6]. In the present study we investigated whether the intravenous application of host-derived DC at the time of HSCT and/or one week after HSCT improves engraftment.   

All dogs in our study engrafted. In comparison to our own historical 2 Gy conditioned control animals the engraftment was delayed after 1 Gy conditioning plus DC administration, which lead to significant differences in engraftment kinetics [2]. The maximum levels of donor PBMC and granulocytes attained after 1 Gy TBI in combination with DC application were clearly lower than the maximum chimerisms of 75 and 41% in the granulocytes and PBMC compartments of 2 Gy control animals as well [2]. Times to maximum chimerism were not significantly different compared to the 2 Gy historical control (35 and 29 days, respectively). 

No long-term engraftment could be achieved in any of the dogs in this study. This contrasts to the 2 Gy conditioning, which allows sustained engraftment in the majority of recipients [1, 2]. We hypothesize that the failure of long term engraftment occurred due to the delayed engraftment kinetics and the overall reduced percentage of donor-derived hematopoietic cells. Storb et al. have investigated pharmaceutical approaches combined with 1 Gy conditioning in regards to engraftment in the canine HSCT model. Rejection occurred in their studies 3–12 weeks after HSCT [1]. This corresponds to the time of graft rejection in the present study. 

Our hypothesis that additional host DC administrations can sufficiently support engraftment and prolong graft survival after 1 Gy TBI could not be substantiated by our study. Instead, the number of TNC transplanted seemed to have an impact on graft rejection. This result supports previous data that showed a trend for decreased risk of graft rejection in dogs when transplanted with higher numbers of TNC [12].

A comparison of results regarding host DC application once versus twice after HSCT was performed after adjustment for the TNC/kg infused. Although numbers are low, our data indicate that two applications of host-derived DC i.e., concomitant to and one week after HSCT tend to enhance allo-immune response in the graft-versus-host direction leading to longer graft survival and higher peak chimerisms. An influence of the origin of DC (MoDC versus CD34+-DC) on engraftment could not be suggested from this study; additionally, numbers were small. This does not reflect previous data that shows a higher capacity to stimulate allogeneic T-lymphocyte reactivity for bone-marrow derived DC compared to MoDC [9]. Differences in the applied methods, i.e., the use of unseparated bone marrow mononuclear cells, the human origin of cells, and the in vitro analyses may explain the different immunological response in the previous study.

The role of DC in the graft is not yet completely understood. In contrast to our results, addition of plasmacytoid precursor DC to the graft significantly enhanced HSC engraftment in a mouse model [13]. However, in this study a myeloablative conditioning regimen was applied. In a clinical trial by Reddy et al. high DC numbers during engraftment were associated with better survival and decreased incidence of relapse [14]. However, the authors suggested that only the number of DC reconstituted in the recipient was pivotal. In contrast, another study showed that higher DC counts in donor bone marrow caused an increase in relapse rates following HSCT [15]. Reasons for the variable immunologic responses may be the heterogeneity of the DC population as well as different states of differentiation, maturation, or activation of the DC in these studies [16, 17].

In conclusion, our data indicates that application of host DC concomitant to the HSCT and/or one week after HSCT is not sufficient to support stable engraftment in a canine nonmyeloablative 1 Gy TBI HSCT model. Since the double administration seemed to be superior compared to a single boost further studies might address whether more frequent DC applications support engraftment more efficiently.

Conflict of Interest

The authors of this paper declare no financial or personal conflict of interest.

Acknowledgements

The authors thank all the staff of the animal care facility. We also thank Anett Sekora and Gudrun Knuebel (both from Department of Internal Medicine, Medical Clinic III – Hematoloy, Oncology, Palliative Medicine, University of Rostock, Germany) for technical assistance. This work was supported by the German Research Council (Deutsche Forschungsgemeinschaft) grants JU 417/2-1, 2 2.

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2. Lange S, Altmann S, Brandt B, et al. Investigation of immunological approaches to enhance engraftment in a 1 Gy TBI canine haematopoietic stem cell transplantation model. Exp Hematol. 2009;37:143-50.  doi: 10.1016/j.exphem.2008.09.011.

3. Storb R, Yu C, Zaucha JM, et al. Stable mixed hematopoietic chimerism in dogs given donor antigen, CTLA4Ig, and 100 cGy total body irradiation before and pharmacologic immunosuppression after marrow transplant. Blood. 1999;94:2523-2529.

4. Panse JP, Storb R, Storer B, Santos EB, Wentzel C, Sandmaier BM. Prolonged allogeneic marrow engraftment following nonmyeloablative conditioning using 100 cGy total body irradiation and pentostatin before and pharmacological immunosuppression after transplantation. Transplantation. 2005;80:1518-1521.

5. Zaucha JM, Zellmer E, Georges G, et al. G-CSF-mobilized peripheral blood mononuclear cells added to marrow facilitates engraftment in nonmyeloablated canine recipients: CD3 cells are required. Biol Blood Marrow Transplant. 2001;7:613-619. doi: 10.1053/bbmt.2001.v7.pm11760149.

6. Mielcarek M, Torok-Storb B, Storb R. Pharmacological Immunosuppression Reduces But Does Not Eliminate the Need for Total-Body Irradiation in Nonmyeloablative Conditioning Regimens for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2011 Jan 8. [Epub ahead of print].  doi: 10.1016/j.bbmt.2011.01.003.

7. Zhang CL, Zou XL, Peng JB, Xiang M. Immune tolerance induced by adoptive transfer of dendritic cells in an insulin-dependent diabetes mellitus murine model. Acta Pharmacol Sin. 2007;28:98-104. doi: 10.1111/j.1745-7254.2007.00467.x.

8. Zhang Y, Shlomchik WD, Joe G, et al. APCs in the liver and spleen recruit activated allogeneic CD8+ T-cells to elicit hepatic graft-versus-host disease. J Immunol. 2002;169:7111-7118.

9. Bai L, Feuerer M, Beckhove P, et al. Generation of dendritic cells from human bone marrow mononuclear cells: advantages for clinical application in comparison to peripheral blood monocyte derived cells. Int J Oncol. 2002;20:247-253.

10. Hägglund HG, McSweeney PA, Mathioudakis G, et al. Ex vivo expansion of canine dendritic cells from CD34+ bone marrow progenitor cells. Transplantation. 2000;70:1437-1442.

11. Hilgendorf I, Weirich V, Zeng L, et al. Canine haematopoietic chimerism analyses by semiquantitative fluorescence detection of variable number of tandem repeat polymorphism. Vet Res Commun. 2005;29:103-110. doi: 10.1023/B:VERC.0000047486.01458.c5.

12. Baron F, Sandmaier BM, Zellmer E, Sorror M, Storer B, Storb R. Failure of donor lymphocyte infusion to prevent graft rejection in dogs given DLA-identical marrow after 1 Gy of total body irradiation. Biol Blood Marrow Transplant. 2006;12:813-817. doi: 10.1016/j.bbmt.2006.05.001.

13. Fugier-Vivier IJ, Rezzoug F, Huang Y, et al. Plasmacytoid precursor dendritic cells facilitate allogeneic hematopoietic stem cell engraftment. J Exp Med. 2005;201:373-383. doi: 10.1084/jem.20041399.

14. Reddy V, Iturraspe JA, Tzolas AC, Meier-Kriesche HU, Schold J, Wingard JR. Low dendritic cell count after allogeneic hematopoietic stem cell transplantation predicts relapse, death, and acute graft-versus-host disease. Blood. 2004;103:4330-4335. doi: 10.1182/blood-2003-09-3325.

15. Waller EK, Rosenthal H, Jones TW, et al. Larger numbers of CD4(bright) dendritic cells in donor bone marrow are associated with increased relapse after allogeneic bone marrow transplantation. Blood. 2001;97:2948-2956. doi: 10.1182/blood.V97.10.2948.

16. Jonuleit H, Giesecke-Tuettenberg A, Tüting T, et al. A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection. Int J Cancer. 2001;93:243–251. doi: 10.1002/ijc.1323.

17. Schott M. Immunesurveillance by dendritic cells: potential implication for immunotherapy of endocrine cancers. Endocr Relat Cancer. 2006;13:779-795. doi: 10.1677/erc.1.01133.


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Introduction

In the canine hematopoietic stem cell transplantation (HSCT) model, durable engraftment of allogeneic dog leukocyte antigen (DLA)-identical littermate bone marrow cells can be achieved following nonmyeloablative conditioning with 2 Gy of total body irradiation (TBI) in combination with pre- and post-transplant immunosuppression consisting of cyclosporin A (CSA) and mycophenolate mofetil (MMF) [1]. A reduction of the radiation dose to 1 Gy TBI resulted in only transient engraftment, and led eventually to graft rejection in this model [1]. Therefore, combinations of 1 Gy HSCT with different forms of immunotherapy were investigated. Post-graft vaccination with recipient hematopoietic cell lysates as well as graft augmentation with donor-derived monocyte-derived dendritic cells (DC) did not support durable engraftment after 1 Gy TBI [2]. Pre-transplant immunosuppression using CTLA4Ig or Pentostatin or graft modification with donor peripheral blood mononuclear cells (PBMC) was shown to improve engraftment to some extent, but long-term engraftment was only seen in 22–63% of the HSCT [5]. Recently, Mielcarek et al. studied 9 different immunosuppressive and/or tolerance-inducing regimens using a TBI dose of 0.5 Gy. None of these strategies was sufficient to ensure sustained engraftment after HSCT [6].

The role of DC as key cells of the immune system is well known. Mature DC especially are highly immunogenic and efficiently induce T-cell proliferation [7]. Furthermore it has been shown that recipient antigen-presenting cells are required to trigger efficiently alloreactive donor T-cells early after total body irradiation [8]. Currently, monocyte-derived DC are the most widely used, since generation of bone-marrow-derived DC is much more invasive. However, when using bone marrow higher numbers of DC were obtained, with a higher capacity to stimulate allogeneic T-cell responses compared to monocyte-derived DC [9].

Therefore, this study investigated whether the addition of monocyte-derived as well as bone marrow-derived mature DC of host origin to the graft and/or administration of DC one week post-transplantation facilitates stable marrow engraftment after 1 Gy conditioning in the canine HSCT model.

Materials and Methods

Experiments were approved by the review board of the state Mecklenburg-Vorpommern (Landesamt für Landwirtschaft, Lebensmittelsicherheit und Fischerei M-V, Germany). 

Animals

Dogs were purchased from commercial kennels licensed by the German Department of Agriculture. All animals were de-wormed and immunized against rabies, parainfluenca, leptospirosis, distemper, hepatitis, and parvovirus. DLA-identical donor/recipient sibling pairs were selected on the basis of matching for highly polymorphic DLA class I and class II microsatellite markers [1].

Hematopoietic stem cell transplantation

HSCT was performed as described previously [1]. Briefly, 7 recipient dogs were conditioned with nonmyeloablative TBI at a single dose of 1 Gy using a high-energy linear accelerator (Siemens Primus; 10 MV X-ray) with a dose rate of 0.25 Gy/min. Bone marrow from DLA-identical siblings was collected under general anesthesia from the humeri, femora, and iliac crest and infused intravenously into the recipients within 24 h after TBI. Immunosuppression consisted of CSA at 15 mg/kg orally 2 times daily on days -1 to +35 in combination with MMF at 20 mg/kg orally 2 times daily on days 0 to +27. In addition to the graft, the dogs were given i.v. infusions of (I) monocyte-derived mature DC of host origin (MoDC) once on day +5 (n=2, group I) and (II) MoDC or CD34+-derived mature DC (CD34+-DC) of host origin twice: once on day 0 together with the graft and once on median day +7 (range +5 to +7) (n=5, group II). The clinical status of recipients was checked twice daily.

Cell isolation and generation of DC

Monocytes were isolated from 300 ml peripheral blood of the recipient at day -2 (group I, one-time DC administration) and at days  7 and -2, respectively (n=2, group II, double DC administration) before transplantation by using an AutoMACS device (Miltenyi Biotec, Bergisch-Gladbach, Germany) [2]. Cells were cultured in 24-well plates for 7 days in RPMI-medium supplemented with 10% dog serum, 1% penicillin/streptomycin, 500 U/ml canine IL-4 and 100 ng/ml human GM-CSF. At day 5 of culture 10 ng/ml TNF-alpha was added to the medium for DC maturation. For generation of CD34+-cell derived DC (n=3; group II, double DC administration) 100 ml of bone marrow were aspirated on days -14 and -7 before transplantation and CD34+ cells were isolated using the AutoMACS device. CD34+ cells were cultured as described previously [10]. For in vitro characterization of cultured DC expression of the DC-specific cell surface marker MHC II and CD11c was analyzed by flow cytometry (Fig. 1).

Figure 1. Analysis of surface marker expression of MHC II (A) and CD11c (B) by flow cytometry. Each histogram represents an overlay of the specific monoclonal antibodies (filled histograms) and isotype-control monoclonal antibodies (solid lines). The histograms show one representative example of bone marrow-derived DC after 14 days of cultivation

Lange_fig01.png

Hematopoietic chimerism analysis

The recipients' peripheral blood was collected weekly. Granulocytes and PBMC were separated by Ficoll-Hypaque density gradient centrifugation (density 1.074 g/ml) and genomic DNA of the cell fractions was isolated (Nucleobond CB 100; Macherey-Nagel, Düren, Germany). Polymorphic tetranucleotide repeats that differed between donors and recipients were amplified and quantified as described previously [11]. Engraftment was defined as detection of >5% of donor-derived DNA. Graft rejection was defined as detection of no donor-derived DNA in the peripheral blood and the bone marrow.

Statistics

The distribution of data was described using medians and ranges. Differences between treatment groups were estimated according to the Mann-Whitney U-Test. Possible association between TNC numbers and their impact on graft rejection was assessed using the Spearman correlation analysis. Probability of p<0.05 was considered significant.

Results

HSCT recipients received DLA-identical marrow grafts containing a median of 4.9 (range 2.6–7.4) x 108 total nucleated cells (TNC)/kg intravenously within 24 h after TBI. The number of DC applied were a median 10.3 (range 6.0–14.5) x 105 DC/kg and 4.7 (range 1.2–7.2) x 105 DC/kg per dose in groups I and II, respectively.

The results of chimerism analyses are depicted in Figure 2. All dogs showed an initial engraftment in the granulocytes and PBMC compartments. The maximum donor chimerisms of the granulocytes accounted for a median 19% (range 14–23) and 33% (range 12–59) in groups I and II, respectively. The maximum PBMC donor chimerisms reached median values of 12% (range 11–12) and 17% (range 14–26) for both groups. Median times to maximum granulocytes chimerisms were 32 days (range 14–49) and 42 days (range 28–56). PBMC chimerisms peaked at days 21 (range 14–28) and 28 (range 28–35) in groups I and II, respectively.

Figure 2. Engraftment kinetics of donor peripheral blood granulocytes (A) and PBMC (B) after 1 Gy HSCT. Dogs received either MoDC vaccination on day +5 (group I, dotted lines) or two-time administration of MoDC and CD34+-DC on day 0 together with the graft and on median day +7 (range +5 to +7) as i.v. vaccination, respectively (group II, solid lines)

Lange_fig02.png

Induction of long-term engraftment could not be achieved in any dog. Rejection of grafts occurred after a median 56 days (range 56–56) and 84 days (range 49–91), respectively. Spearman correlation analysis revealed a significant association between body weight-adjusted numbers of TNC in the graft and time of graft rejection (r=0.871, p=0.01). The maximum chimerism in the granulocyte compartment tended to correlate to the number of TNC/kg as well (r=0.739, p=0.058). 

Of interest, if taking into consideration the influence of TNC counts on graft rejection and chimerism, is the comparison of dog 1 (4.9 TNC/kg, 1x DC) with dog 4 (4.9 TNC/kg, 2x DC) as well as dog 2 (5.4 TNC/kg, 1x DC) with dog 6 (5.5 TNC/kg, 2x DC). These indicate a trend toward lower maximum granulocytes (23% vs 33% and 14% vs 59%) and PBMC donor chimerisms (11% vs 17% and 12% vs 26%) and shortened allograft survival (56 d vs 84 d, both) after a single DC administration.

Discussion

The canine nonmyeloablative HSCT model can be used to investigate novel approaches aiming at improved engraftment as well as long-term graft survival [6]. In the present study we investigated whether the intravenous application of host-derived DC at the time of HSCT and/or one week after HSCT improves engraftment.   

All dogs in our study engrafted. In comparison to our own historical 2 Gy conditioned control animals the engraftment was delayed after 1 Gy conditioning plus DC administration, which lead to significant differences in engraftment kinetics [2]. The maximum levels of donor PBMC and granulocytes attained after 1 Gy TBI in combination with DC application were clearly lower than the maximum chimerisms of 75 and 41% in the granulocytes and PBMC compartments of 2 Gy control animals as well [2]. Times to maximum chimerism were not significantly different compared to the 2 Gy historical control (35 and 29 days, respectively). 

No long-term engraftment could be achieved in any of the dogs in this study. This contrasts to the 2 Gy conditioning, which allows sustained engraftment in the majority of recipients [1, 2]. We hypothesize that the failure of long term engraftment occurred due to the delayed engraftment kinetics and the overall reduced percentage of donor-derived hematopoietic cells. Storb et al. have investigated pharmaceutical approaches combined with 1 Gy conditioning in regards to engraftment in the canine HSCT model. Rejection occurred in their studies 3–12 weeks after HSCT [1]. This corresponds to the time of graft rejection in the present study. 

Our hypothesis that additional host DC administrations can sufficiently support engraftment and prolong graft survival after 1 Gy TBI could not be substantiated by our study. Instead, the number of TNC transplanted seemed to have an impact on graft rejection. This result supports previous data that showed a trend for decreased risk of graft rejection in dogs when transplanted with higher numbers of TNC [12].

A comparison of results regarding host DC application once versus twice after HSCT was performed after adjustment for the TNC/kg infused. Although numbers are low, our data indicate that two applications of host-derived DC i.e., concomitant to and one week after HSCT tend to enhance allo-immune response in the graft-versus-host direction leading to longer graft survival and higher peak chimerisms. An influence of the origin of DC (MoDC versus CD34+-DC) on engraftment could not be suggested from this study; additionally, numbers were small. This does not reflect previous data that shows a higher capacity to stimulate allogeneic T-lymphocyte reactivity for bone-marrow derived DC compared to MoDC [9]. Differences in the applied methods, i.e., the use of unseparated bone marrow mononuclear cells, the human origin of cells, and the in vitro analyses may explain the different immunological response in the previous study.

The role of DC in the graft is not yet completely understood. In contrast to our results, addition of plasmacytoid precursor DC to the graft significantly enhanced HSC engraftment in a mouse model [13]. However, in this study a myeloablative conditioning regimen was applied. In a clinical trial by Reddy et al. high DC numbers during engraftment were associated with better survival and decreased incidence of relapse [14]. However, the authors suggested that only the number of DC reconstituted in the recipient was pivotal. In contrast, another study showed that higher DC counts in donor bone marrow caused an increase in relapse rates following HSCT [15]. Reasons for the variable immunologic responses may be the heterogeneity of the DC population as well as different states of differentiation, maturation, or activation of the DC in these studies [16, 17].

In conclusion, our data indicates that application of host DC concomitant to the HSCT and/or one week after HSCT is not sufficient to support stable engraftment in a canine nonmyeloablative 1 Gy TBI HSCT model. Since the double administration seemed to be superior compared to a single boost further studies might address whether more frequent DC applications support engraftment more efficiently.

Conflict of Interest

The authors of this paper declare no financial or personal conflict of interest.

Acknowledgements

The authors thank all the staff of the animal care facility. We also thank Anett Sekora and Gudrun Knuebel (both from Department of Internal Medicine, Medical Clinic III – Hematoloy, Oncology, Palliative Medicine, University of Rostock, Germany) for technical assistance. This work was supported by the German Research Council (Deutsche Forschungsgemeinschaft) grants JU 417/2-1, 2 2.

References

1. Storb R, Yu C, Wagner JL, et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood. 1997;89:3048-3054.

2. Lange S, Altmann S, Brandt B, et al. Investigation of immunological approaches to enhance engraftment in a 1 Gy TBI canine haematopoietic stem cell transplantation model. Exp Hematol. 2009;37:143-50.  doi: 10.1016/j.exphem.2008.09.011.

3. Storb R, Yu C, Zaucha JM, et al. Stable mixed hematopoietic chimerism in dogs given donor antigen, CTLA4Ig, and 100 cGy total body irradiation before and pharmacologic immunosuppression after marrow transplant. Blood. 1999;94:2523-2529.

4. Panse JP, Storb R, Storer B, Santos EB, Wentzel C, Sandmaier BM. Prolonged allogeneic marrow engraftment following nonmyeloablative conditioning using 100 cGy total body irradiation and pentostatin before and pharmacological immunosuppression after transplantation. Transplantation. 2005;80:1518-1521.

5. Zaucha JM, Zellmer E, Georges G, et al. G-CSF-mobilized peripheral blood mononuclear cells added to marrow facilitates engraftment in nonmyeloablated canine recipients: CD3 cells are required. Biol Blood Marrow Transplant. 2001;7:613-619. doi: 10.1053/bbmt.2001.v7.pm11760149.

6. Mielcarek M, Torok-Storb B, Storb R. Pharmacological Immunosuppression Reduces But Does Not Eliminate the Need for Total-Body Irradiation in Nonmyeloablative Conditioning Regimens for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2011 Jan 8. [Epub ahead of print].  doi: 10.1016/j.bbmt.2011.01.003.

7. Zhang CL, Zou XL, Peng JB, Xiang M. Immune tolerance induced by adoptive transfer of dendritic cells in an insulin-dependent diabetes mellitus murine model. Acta Pharmacol Sin. 2007;28:98-104. doi: 10.1111/j.1745-7254.2007.00467.x.

8. Zhang Y, Shlomchik WD, Joe G, et al. APCs in the liver and spleen recruit activated allogeneic CD8+ T-cells to elicit hepatic graft-versus-host disease. J Immunol. 2002;169:7111-7118.

9. Bai L, Feuerer M, Beckhove P, et al. Generation of dendritic cells from human bone marrow mononuclear cells: advantages for clinical application in comparison to peripheral blood monocyte derived cells. Int J Oncol. 2002;20:247-253.

10. Hägglund HG, McSweeney PA, Mathioudakis G, et al. Ex vivo expansion of canine dendritic cells from CD34+ bone marrow progenitor cells. Transplantation. 2000;70:1437-1442.

11. Hilgendorf I, Weirich V, Zeng L, et al. Canine haematopoietic chimerism analyses by semiquantitative fluorescence detection of variable number of tandem repeat polymorphism. Vet Res Commun. 2005;29:103-110. doi: 10.1023/B:VERC.0000047486.01458.c5.

12. Baron F, Sandmaier BM, Zellmer E, Sorror M, Storer B, Storb R. Failure of donor lymphocyte infusion to prevent graft rejection in dogs given DLA-identical marrow after 1 Gy of total body irradiation. Biol Blood Marrow Transplant. 2006;12:813-817. doi: 10.1016/j.bbmt.2006.05.001.

13. Fugier-Vivier IJ, Rezzoug F, Huang Y, et al. Plasmacytoid precursor dendritic cells facilitate allogeneic hematopoietic stem cell engraftment. J Exp Med. 2005;201:373-383. doi: 10.1084/jem.20041399.

14. Reddy V, Iturraspe JA, Tzolas AC, Meier-Kriesche HU, Schold J, Wingard JR. Low dendritic cell count after allogeneic hematopoietic stem cell transplantation predicts relapse, death, and acute graft-versus-host disease. Blood. 2004;103:4330-4335. doi: 10.1182/blood-2003-09-3325.

15. Waller EK, Rosenthal H, Jones TW, et al. Larger numbers of CD4(bright) dendritic cells in donor bone marrow are associated with increased relapse after allogeneic bone marrow transplantation. Blood. 2001;97:2948-2956. doi: 10.1182/blood.V97.10.2948.

16. Jonuleit H, Giesecke-Tuettenberg A, Tüting T, et al. A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection. Int J Cancer. 2001;93:243–251. doi: 10.1002/ijc.1323.

17. Schott M. Immunesurveillance by dendritic cells: potential implication for immunotherapy of endocrine cancers. Endocr Relat Cancer. 2006;13:779-795. doi: 10.1677/erc.1.01133.


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"N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19637" ["VALUE"]=> array(2) { ["TEXT"]=> string(257) "<p>Sandra Lange<sup>1</sup>, Simone Altmann<sup>1</sup>, Heike Vogel<sup>2</sup>, Volker Weirich<sup>3</sup>, Mathias Freund<sup>1</sup>, Christian Junghanss<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(173) "

Sandra Lange1, Simone Altmann1, Heike Vogel2, Volker Weirich3, Mathias Freund1, Christian Junghanss1

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1Department of Internal Medicine, Medical Clinic III – Hematoloy, Oncology, Palliative Medicine; 2Department of Radiation Oncology; 3Institute of Legal Medicine, Medical Faculty, University of Rostock, Rostock, Germany

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The canine nonmyeloablative hematopoietic stem cell transplantation (HSCT) model allows the establishment of mixed hematopoietic chimerism following 2 Gy total body irradiation (TBI) conditioning, but in general fails to do so after 1 Gy TBI. Several studies have used this model to investigate cellular-based therapies as well as pharmaceutical-based approaches in their ability to support engraftment. In the present study we investigated the impact of an intravenous administration of host derived dendritic cells (DC) during (day 0) and/or 1 week post transplantation on long-term engraftment in a canine HSCT model. Dogs were transplanted after conditioning with 1 Gy TBI and received immunosuppression consisting of 15 mg/kg cyclosporin A BID PO (days -1 to +35) in combination with 20 mg/kg mycophenolate mofetil BID PO (days 0 to +27). All dogs transiently engrafted but eventually rejected the graft by a median 56–84 days. Therefore, additional DC administration failed to significantly improve graft survival compared to historical controls. However, administration of DC twice seemed to be superior to a single administration when looking at their ability to support initial engraftment. Future studies might therefore aim at more frequent DC administrations to support successful HSCT in this setting.

Keywords

allogeneic hematopoietic stem cell transplantation, nonmyeloablative, vaccination, dendritic cells, dog, chimerism, engraftment

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Sandra Lange1, Simone Altmann1, Heike Vogel2, Volker Weirich3, Mathias Freund1, Christian Junghanss1

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Sandra Lange1, Simone Altmann1, Heike Vogel2, Volker Weirich3, Mathias Freund1, Christian Junghanss1

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The canine nonmyeloablative hematopoietic stem cell transplantation (HSCT) model allows the establishment of mixed hematopoietic chimerism following 2 Gy total body irradiation (TBI) conditioning, but in general fails to do so after 1 Gy TBI. Several studies have used this model to investigate cellular-based therapies as well as pharmaceutical-based approaches in their ability to support engraftment. In the present study we investigated the impact of an intravenous administration of host derived dendritic cells (DC) during (day 0) and/or 1 week post transplantation on long-term engraftment in a canine HSCT model. Dogs were transplanted after conditioning with 1 Gy TBI and received immunosuppression consisting of 15 mg/kg cyclosporin A BID PO (days -1 to +35) in combination with 20 mg/kg mycophenolate mofetil BID PO (days 0 to +27). All dogs transiently engrafted but eventually rejected the graft by a median 56–84 days. Therefore, additional DC administration failed to significantly improve graft survival compared to historical controls. However, administration of DC twice seemed to be superior to a single administration when looking at their ability to support initial engraftment. Future studies might therefore aim at more frequent DC administrations to support successful HSCT in this setting.

Keywords

allogeneic hematopoietic stem cell transplantation, nonmyeloablative, vaccination, dendritic cells, dog, chimerism, engraftment

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The canine nonmyeloablative hematopoietic stem cell transplantation (HSCT) model allows the establishment of mixed hematopoietic chimerism following 2 Gy total body irradiation (TBI) conditioning, but in general fails to do so after 1 Gy TBI. Several studies have used this model to investigate cellular-based therapies as well as pharmaceutical-based approaches in their ability to support engraftment. In the present study we investigated the impact of an intravenous administration of host derived dendritic cells (DC) during (day 0) and/or 1 week post transplantation on long-term engraftment in a canine HSCT model. Dogs were transplanted after conditioning with 1 Gy TBI and received immunosuppression consisting of 15 mg/kg cyclosporin A BID PO (days -1 to +35) in combination with 20 mg/kg mycophenolate mofetil BID PO (days 0 to +27). All dogs transiently engrafted but eventually rejected the graft by a median 56–84 days. Therefore, additional DC administration failed to significantly improve graft survival compared to historical controls. However, administration of DC twice seemed to be superior to a single administration when looking at their ability to support initial engraftment. Future studies might therefore aim at more frequent DC administrations to support successful HSCT in this setting.

Keywords

allogeneic hematopoietic stem cell transplantation, nonmyeloablative, vaccination, dendritic cells, dog, chimerism, engraftment

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1Department of Internal Medicine, Medical Clinic III – Hematoloy, Oncology, Palliative Medicine; 2Department of Radiation Oncology; 3Institute of Legal Medicine, Medical Faculty, University of Rostock, Rostock, Germany

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1Department of Internal Medicine, Medical Clinic III – Hematoloy, Oncology, Palliative Medicine; 2Department of Radiation Oncology; 3Institute of Legal Medicine, Medical Faculty, University of Rostock, Rostock, Germany

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["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19622" ["VALUE"]=> string(4) "1483" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "1483" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(63) "Christian Junghanss" ["LINK_ELEMENT_VALUE"]=> bool(false) } } } }
Volume 3, Number 1(8)
03/01/2012
Volume 3, Number 1(8)
Editor-in-Chief
Afanasyev B. V. (St. Petersburg, Russia)
Co-Editors-in-Chief
Wagemaker G. (Rotterdam, Netherlands)
Zander A. R. (Hamburg, Germany)
Deputy Editor
Chukhlovin A. B. (St. Petersburg, Russia)
Fehse B. (Hamburg, Germany)
Novik A. А. (Moscow, Russia)
Managing Editor
Claudia Koltzenburg (Hamburg, Germany)
Editorial Board
Aleynikova O. (Minsk, Belarus)
Alyansky A. (St. Petersburg, Russia)
Anagnostou A. (Boston, USA)
Andreeff M. (Houston, USA)
Bacher U. (Hamburg, Germany)
Baуkov V. (St. Petersburg, Russia)
Baranov V. S. (St. Petersburg, Russia)
Barkhatov I. (St. Petersburg, Russia)
Baum C. (Hannover, Germany)
Bilko N. (Kiev, Ukraine)
Borset M. (Trondheim, Norway)
Buechner Th. (Muenster, Germany)
Bykov V. (St. Petersburg, Russia)
Dini G. (Genoa, Italy)
Drize N. (Moscow, Russia)
Egeland T. (Oslo, Norway)
Elstner E. (Berlin, Germany)
Emanuel V. (St. Petersburg, Russia)
Everaus H. (Tartu, Estonia)
Ferrara J. (Ann Arbor, USA)
Fibbe W. (Leiden, Netherlands)
Galibin O. (St. Petersburg, Russia)
Ganser A. (Hannover, Germany)
Granov D. (St. Petersburg, Russia)
Ivanov R. (Moscow, Russia)
Klimko N. (St. Petersburg, Russia)
Kolb H.-J. (Muenchen, Germany)
Konopleva M. (Houston, USA)
Koza V. (Pilsen, Czech Republic)
Kroeger N. (Hamburg, Germany)
Malikov A. (St. Petersburg, Russia)
Mikhailova N. (St. Petersburg, Russia)
Mentkevich G. (Moscow, Russia)
Nagler A. (Tel Hashomer, Israel)
Nemkov A. (St. Petersburg, Russia)
Neth R. (Hamburg, Germany)
Nevorotin A.J. (St. Petersburg, Russia)
Ostertag W. (Hamburg, Germany)
Palutke M. (Detroit, USA)
Roumiantsev A. G. (Moscow, Russia)
Savchenko V. G. (Moscow, Russia)
Smirnov A. V. (St. Petersburg, Russia)
Stamm C. (Berlin, Germany)
Tetz V. (St. Petersburg, Russia)
To B. (Adelaide, Australia)
Totolian A. A. (St. Petersburg, Russia)
Uss A.L. (Minsk, Belarus)
Vilesov A. (St. Petersburg, Russia)
Westenfelder Ch. (Salt Lake City, USA)
Wisloff F. (Oslo, Norway)
Zubarovskaya L. (St. Petersburg, Russia)
Zvartau E. (St. Petersburg, Russia)
In this Issue

Short contributions

In vitro models for stem cell transplantation

Sergey A. Sergeev, Yulia V. Khramova

Articles

Autologous M2-like macrophage applications in children with cerebral palsy

Elena R. Chernykh, Marina Yu. Kafanova, Ekaterina Ya. Shevela, Elena I. Adonina, Lyudmila V. Sakhno, Marina A. Tikhonova, Alexander A. Ostanin

The use of autologous mesenchymal bone marrow stem cells absorbed in fibrin clot for the regeneration of injured lower jawbones in rats

Igor V. Maiborodin, Andrew I. Shevela, Vera A. Matveeva, Ivan S. Kolesnikov, Michail N. Drovosekov, Michail S. Toder, Tatyana V. Perrin

Short contributions

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Юлия А. Нестерук

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В исследование включено 17 пациентов с тяжелой стенокардией, не подлежащих механической реваскуляризации. Этим пациентам в период с 2008 по 2010 гг. выполняли интракоронарную инфузию аутологичных мононуклеарных стволовых клеток костного мозга. Контрольная группа насчитывала 10 пациентов. Всех пациентов обследовали до и после лечения. Перфузию миокарда оценивали с помощью однофотонной эмиссионной компьютерной томографии. Для оценки качества жизни пациентов использовали опросник SF-36. Интракоронарная инфузия аутологичных мононуклеарных стволовых клеток костного мозга способствовала уменьшению функционального класса стенокардии, потребления нитроглицерина, увеличению времени нагрузки, улучшению перфузии миокарда и не оказывала влияния на нарушения ритма. У пациентов, получавших только медикаментозную терапию, возрастал функциональный класс стенокардии и уменьшалась продолжительность физической нагрузки. Спустя год после процедуры в группе интракоронарной инфузии отмечали выраженное улучшение качества жизни. Наибольшее улучшение происходило по индексам физического функционирования, ролевого функционирования и боли. В контрольной группе существенного увеличения данных индексов не наблюдалось, наоборот, для индекса боли отмечена обратная динамика. 

Ключевые слова

стволовые клетки, мононуклеарные клетки, стенокардия, болезнь сердца, аорто-коронарное шунтирование, ангиопластика, лечение стенокардии, продолжительность физической нагрузки, потребление нитроглицерина, опросник SF-36 

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Julia A. Nesteruk

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Cardio surgery department, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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A BMMC group consisted of 17 patients with severe angina pectoris when it is  impossible to use mechanical revascularization. These patients underwent autologous bone marrow mononuclear stem cells intracoronary infusion between 2008 and 2010. A control group consisted of 10 patients. All patients were examined before and after the treatment. Single-photon emission computed tomography was performed to estimate myocardial perfusion. Questionnaire SF-36 was used for an estimation of the patient’s quality of life. Intracoronary infusion of autologous bone marrow mononuclear stem cells has decreased such parameters as the functional class of angina pectoris, and nitroglycerine consumption, and has increased exercise time, and myocardial perfusion, while having no influence on arrhythmia.  On the other hand, the functional class of angina pectoris increased, and the exercise time decreased in patients who received only medical treatment. At the end of one the year a great increase in quality of life in BMMC group can be observed. The best result it is seen in the Physical Functioning scale, and the Role-Physical scale, and the Bodily Pain scale. In the control group it is not seen considerably increasing in all scales and the scale Bodily Pain has changed in opposite direction.

Keywords

stem cells, mononuclear cells, angina pectoris, heart disease, coronary artery bypass surgery, angioplasty, angina treatment, exercise time, nitroglycerine consumption, questionnaire SF-36

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Quality of life in patients with coronary artery disease after intracoronary administration of bone marrow mononuclear cells

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Julia A. Nesteruk

Cardio surgery department, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

A BMMC group consisted of 17 patients with severe angina pectoris when it is  impossible to use mechanical revascularization. These patients underwent autologous bone marrow mononuclear stem cells intracoronary infusion between 2008 and 2010. A control group consisted of 10 patients. All patients were examined before and after the treatment. Single-photon emission computed tomography was performed to estimate myocardial perfusion. Questionnaire SF-36 was used for an estimation of the patient’s quality of life. Intracoronary infusion of autologous bone marrow mononuclear stem cells has decreased such parameters as the functional class of angina pectoris, and nitroglycerine consumption, and has increased exercise time, and myocardial perfusion, while having no influence on arrhythmia.  On the other hand, the functional class of angina pectoris increased, and the exercise time decreased in patients who received only medical treatment. At the end of one the year a great increase in quality of life in BMMC group can be observed. The best result it is seen in the Physical Functioning scale, and the Role-Physical scale, and the Bodily Pain scale. In the control group it is not seen considerably increasing in all scales and the scale Bodily Pain has changed in opposite direction.

Keywords

stem cells, mononuclear cells, angina pectoris, heart disease, coronary artery bypass surgery, angioplasty, angina treatment, exercise time, nitroglycerine consumption, questionnaire SF-36

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Мария В. Загривная

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В настоящее время ведутся активные исследования ключевых механизмов взаимодействия опухолевых клеток с их микроокружением. Выявление таких механизмов и разработка лекарственных средств, которые могли бы на них воздействовать, открывает новые возможности в лечении злокачественных новообразований, в том числе лейкозов. Наибольший интерес на сегодняшний день вызывают механизмы взаимодействия между лейкозными клетками и их микроокружением с участием CXCL12/CXCR4 и Lyn-киназы

Ключевые слова

микроокружение, CXCR4, иматиниб, дазатиниб, хронические миелоидный лейкоз, лекарственная резистентность, bcr-abl, Lyn

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Maria V. Zagrivnaja

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Laboratory of transplantology and molecular hematology, R.M. Gorbacheva Memorial Institute of Pediatric Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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There are ongoing investigations on key mechanisms of interaction between tumor cells and their microenvironment. Identification of these mechanisms and development of therapeutic agents targeting them brings up new opportunities for cancer therapy, including leukemia treatment. Today there are active discussions on mechanisms of interaction between tumor cells and their microenvironment mediated by CXCL12/CXCR4 and Lyn-kinase.

Keywords

microenvironment, CXCR4, imatinib, dasatinib, chronic myeloid leukemia, drug resistance, bcr-abl, Lyn

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The role of CXCR4 and Lyn-kinase in stromal/leukemia interaction

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Maria V. Zagrivnaja

Laboratory of transplantology and molecular hematology, R.M. Gorbacheva Memorial Institute of Pediatric Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

There are ongoing investigations on key mechanisms of interaction between tumor cells and their microenvironment. Identification of these mechanisms and development of therapeutic agents targeting them brings up new opportunities for cancer therapy, including leukemia treatment. Today there are active discussions on mechanisms of interaction between tumor cells and their microenvironment mediated by CXCL12/CXCR4 and Lyn-kinase.

Keywords

microenvironment, CXCR4, imatinib, dasatinib, chronic myeloid leukemia, drug resistance, bcr-abl, Lyn

Short contributions

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Константин Г. Шевченко

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Мышечные дистрофии представляют собой весьма гетерогенную группу наследственных заболеваний, характеризующихся прогрессирующей мышечной слабостью и некрозом мышечной ткани. В настоящее время не имеется специфического лечения для любых форм мышечной дистрофии. В этой области большинство работ по генной и клеточной терапии сконцентрировано на мышечной дистрофии Дюшенна (ДМД) – одном из наиболее частых нервно-мышечных заболеваний со смертельным исходом. В данном кратком обзоре обозначены ключевые темы в этой области, а также основные надежды и препятствия, касающиеся генной терапии ДМД.

Ключевые слова

миодистрофия Дюшенна, генная терапия, искусственные человеческие хромосомы

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Konstantin G. Shevchenko

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Human Stem Cells Institute, Moscow, Russia

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Muscular dystrophies are a highly heterogeneous group of inherited disorders characterized by progressive skeletal muscle weakness and necrosis of the muscle tissue. Currently there is no specific treatment for any of the forms of muscular dystrophy. Most of the gene and cell therapy studies in this field have focused on Duchenne Muscular Dystrophy (DMD), one of the most frequent and fatal neuro-muscular diseases. This short review highlights the key points in these field, as well as main expectations and pitfalls concerning the gene therapy of DMD.

Keywords

Duchenne, DMD, gene therapy, HAC

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Selected issues of the Duchenne Muscular Dystrophy gene and cell therapy

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Konstantin G. Shevchenko

Human Stem Cells Institute, Moscow, Russia

Muscular dystrophies are a highly heterogeneous group of inherited disorders characterized by progressive skeletal muscle weakness and necrosis of the muscle tissue. Currently there is no specific treatment for any of the forms of muscular dystrophy. Most of the gene and cell therapy studies in this field have focused on Duchenne Muscular Dystrophy (DMD), one of the most frequent and fatal neuro-muscular diseases. This short review highlights the key points in these field, as well as main expectations and pitfalls concerning the gene therapy of DMD.

Keywords

Duchenne, DMD, gene therapy, HAC

Short contributions

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Сергей А. Сергеев, Юлия В. Храмова

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Показана быстрая миграция трансплантированных НСПК и ММСК в эксплантатах сетчатки, поврежденных лазерным излучением (достоверно отличающаяся (p<0,05) от скорости миграции в интактных эксплантатах) в течение 24 часов, формирование ими нейритов и взаимосвязей с клетками сетчатки на протяжении 50 дней сокультивирования. Единичные клетки образовывали ассоциаты и экспрессировали GFAP. Через 7 дней после трансплантации на различных дистанциях (600, 1000, 3000мкм) от зоны повреждения детектировали 90%, 56%, 27% EGFP+ клеток соответственно. Для НСПК миграция была активней при инъекции вглубь слоев сетчатки, для ММСК достоверных отличий в миграции от способа инъекции выявлено не было.

Ключевые слова

стволовые клетки, трансплантация in vitro, органотипические культуры сетчатки 

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Sergey A. Sergeev, Yulia V. Khramova

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Lomonosov MSU, Moscow, Russia

Correspondence
Lomonosov MSU, Moscow, Russia, Leninskie gory 1/12, 119234, Moscow, Russia; Phone: +79035187482
E-mail: embryossa@spam is badgmail.com 

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Transplanted NSPC and MMSC quickly migrated in laser damaged retina explants (significantly differs (p<0.05) from the undamaged explants) during the first 24 hours, formed neuritis and connections with the retina cells, and were detected up to 50 days later in damaged recipient tissue. Individual transplanted cells were associated with each other and migrated chaotically with glial differentiation. Seven days after transplantation EGFP+ cells were observed in different distances (600 mkm, 1000 mkm, 3000 mkm) populating damaged zones in 90%, 56%, and 27% respectively. NSPC migration and differentiation in cell layers of neuroretina were higher (p<0.05) than for NSPC transplanted to the explant's surface, and no significant data was obtained for MMSC.

Keywords

Stem cells, in vitro transplantation, retina explant culture

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In vitro models for stem cell transplantation

Download PDF version

Sergey A. Sergeev, Yulia V. Khramova

Lomonosov MSU, Moscow, Russia

Correspondence
Lomonosov MSU, Moscow, Russia, Leninskie gory 1/12, 119234, Moscow, Russia; Phone: +79035187482
E-mail: embryossa@spam is badgmail.com 

Transplanted NSPC and MMSC quickly migrated in laser damaged retina explants (significantly differs (p<0.05) from the undamaged explants) during the first 24 hours, formed neuritis and connections with the retina cells, and were detected up to 50 days later in damaged recipient tissue. Individual transplanted cells were associated with each other and migrated chaotically with glial differentiation. Seven days after transplantation EGFP+ cells were observed in different distances (600 mkm, 1000 mkm, 3000 mkm) populating damaged zones in 90%, 56%, and 27% respectively. NSPC migration and differentiation in cell layers of neuroretina were higher (p<0.05) than for NSPC transplanted to the explant's surface, and no significant data was obtained for MMSC.

Keywords

Stem cells, in vitro transplantation, retina explant culture

Short contributions

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Ilya Ya. Bozo

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Moscow Dental University, OJSC "Human Stem Cells Institute", Moscow, Russia

Correspondence
Ilya Ya. Bozo, Moscow Dental University, OJSC "Human Stem Cells Institute", 3/2 Gubkina str., 119991, Moscow, Russia; Phone: +7965147-12-77, Fax: +7495646-80-76
E-mail: bozo.ilya@spam is badgmail.com 

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The essay presents the problematic aspects of hematopoietic stem cell transplantation, from the position of fundamental notions about cell niches and contemporary data on the bone marrow stroma of recipient and donor, taking into account the results of one’s own research.

Keywords

hematopoietic stem cells (HSCs) transplantation, cell niches, bone marrow stroma

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В эссе представлены проблемные аспекты трансплантации гемопоэтических стволовых клеток, возможности увеличения энграфмента с позиции фундаментальных представлений о клеточных нишах и современных данных о строме костного мозга реципиента и донора с учетом результатов собственных исследований. 

Ключевые слова

трансплантация гемопоэтических стволовых клеток, клеточные ниши, строма костного мозга

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Restoration of bone marrow niches is the basis of optimization of HSC engraftment

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Ilya Ya. Bozo

Moscow Dental University, OJSC "Human Stem Cells Institute", Moscow, Russia

Correspondence
Ilya Ya. Bozo, Moscow Dental University, OJSC "Human Stem Cells Institute", 3/2 Gubkina str., 119991, Moscow, Russia; Phone: +7965147-12-77, Fax: +7495646-80-76
E-mail: bozo.ilya@spam is badgmail.com 

The essay presents the problematic aspects of hematopoietic stem cell transplantation, from the position of fundamental notions about cell niches and contemporary data on the bone marrow stroma of recipient and donor, taking into account the results of one’s own research.

Keywords

hematopoietic stem cells (HSCs) transplantation, cell niches, bone marrow stroma

Short contributions

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Константин У. Слободнюк

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Минимальная остаточная болезнь (МОД) у больных с диагнозом острого миелобластного лейкоза (ОМЛ) может выявляться различными методами. Знание уровней МОД весьма важно для (1) стратификации больных по группамриска, и (2) для мониторинга эффективности лечения. Разработаны процедуры проточной цитометрии для идентификации поверхностных и внутриклеточных антигенов в клетках. Они стали исключительно полезным способом определения клеток костного мозга,  с иммунофенотипом, ассоциированным с лейкозом, и они осществимы практически у всех больных с ОМЛ. Данное краткое сообщение касается, в основном, оценки МОД при ОМЛ с помощью многоцветной проточной цитометрии.

Ключевые слова

острый миелобластный лейкоз, многоцветная проточная цитометрия, иммунофенотип, ассоциация с лейкозом

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Konstantin U. Slobodnyuk

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Center for laboratory diagnostics, Pavlov State Medical University, St. Petersburg, Russia

Correspondence
Konstantin U. Slobodnyuk, Center for laboratory diagnostics, Pavlov State Medical University, 6/8 Lev Tolstoy Str., St. Petersburg, 199022, Russia
E-mail: k.slobodnyuk@spam is badgmail.com 

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Minimal residual disease (MRD) in patients diagnosed with acute myeloid leukemia (AML) can be detected by different methods. Knowing the MRD value is highly important for (i) stratification of patients in to risk groups and (ii) monitoring treatment's efficiency. Flow cytometry procedures have been developed to identify surface and intracellular antigens in cells. It has become an extremely useful tool for detecting the leukemia-associated immunophenotype of leukemia cells in bone marrow and it can be provided to virtually all patients with acute myeloid leukemia. This short report focuses on the assessment of AML MRD with multicolor flow cytometry. 

Keywords

acute myeloid leukemia, multicolor flow cytometry, leukemia-associated immunophenotype

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Detection of minimal residual disease in patients with acute myeloid leukemia with multicolor flow cytometry

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Konstantin U. Slobodnyuk

Center for laboratory diagnostics, Pavlov State Medical University, St. Petersburg, Russia

Correspondence
Konstantin U. Slobodnyuk, Center for laboratory diagnostics, Pavlov State Medical University, 6/8 Lev Tolstoy Str., St. Petersburg, 199022, Russia
E-mail: k.slobodnyuk@spam is badgmail.com 

Minimal residual disease (MRD) in patients diagnosed with acute myeloid leukemia (AML) can be detected by different methods. Knowing the MRD value is highly important for (i) stratification of patients in to risk groups and (ii) monitoring treatment's efficiency. Flow cytometry procedures have been developed to identify surface and intracellular antigens in cells. It has become an extremely useful tool for detecting the leukemia-associated immunophenotype of leukemia cells in bone marrow and it can be provided to virtually all patients with acute myeloid leukemia. This short report focuses on the assessment of AML MRD with multicolor flow cytometry. 

Keywords

acute myeloid leukemia, multicolor flow cytometry, leukemia-associated immunophenotype

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Хе Хуанг, Хаовен Сяо, Хуалюй Фу

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Число трансплантаций гемопоэтических стволовых клеток (ТГСК) в Китае резко возросло, особенно по сравнению с концом 90-х годов. Поскольку в Китае введена политика "одна семья-один ребенок", все больше альтернативных доноров, например, неродственных (НРД), привлекаются для лечения больных, требующих трансплантации и не имеющих HLA-идентичного донора из числа сибсов. Значительное возрастание числа неродственных ТГСК, проводимых в Китае, отмечено после того, как в 2001 году было официально начато обслуживание по китайской Программе доноров костного мозга, что привело к быстрому росту пула доноров. Наиболее частым показанием для неродственной ТГСК являются онкогематологические заболевания. Успехи в технологии HLA-типирования, сниженние интенсивности режимов кондиционирования и стратегии профилактики РТПХ в большой мере улучшили исходы и расширили пригодность неродственной ТГСК для пациентов. По мере быстрого экономического развития Китая, будет больше возможностей для развития потенциала ТГСК.

Ключевые слова

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He Huang1, Haowen Xiao1,2, Huarui Fu1

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1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, P R China;
2Department of Haematology, Guangzhou Liuhuaqiao Hospital, Guangzhou, Guangdong province, P R China

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The number of hematopoietic stem cell transplantations (HSCT) in China has increased dramatically, especially since the late 1990s. As the one child policy has been implemented in China, more and more alternative donors such as unrelated donors (URD) have been used for patients who need transplantation without a human leukocyte antigen (HLA) identical sibling donor. A dramatic increase in the number of URD-HSCTs performed in China was observed after the Chinese Marrow Donor Program started servicing the public in 2001, resulting in the rapid expansion of the donor pool. The most common indication is hematological malignancies in URD-HSCT. Advances in HLA-typing techniques, a reduced intensity conditioning regimen, and prophylaxis strategy for GVHD have greatly improved the outcome and expanded patient eligibility for URD-HSCT. With rapid the economic development in China there will be much development potential for HSCT.

Keywords

hematopoietic stem cell transplantation, HSCT, unrelated donor, China

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Unrelated donors for hematopoietic stem cell transplantation in the People's Republic of China

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He Huang1, Haowen Xiao1,2, Huarui Fu1

1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, P R China;
2Department of Haematology, Guangzhou Liuhuaqiao Hospital, Guangzhou, Guangdong province, P R China

The number of hematopoietic stem cell transplantations (HSCT) in China has increased dramatically, especially since the late 1990s. As the one child policy has been implemented in China, more and more alternative donors such as unrelated donors (URD) have been used for patients who need transplantation without a human leukocyte antigen (HLA) identical sibling donor. A dramatic increase in the number of URD-HSCTs performed in China was observed after the Chinese Marrow Donor Program started servicing the public in 2001, resulting in the rapid expansion of the donor pool. The most common indication is hematological malignancies in URD-HSCT. Advances in HLA-typing techniques, a reduced intensity conditioning regimen, and prophylaxis strategy for GVHD have greatly improved the outcome and expanded patient eligibility for URD-HSCT. With rapid the economic development in China there will be much development potential for HSCT.

Keywords

hematopoietic stem cell transplantation, HSCT, unrelated donor, China

Articles

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Елена Р. Черных, Марина Ю. Кафанова, Екатерина Я. Шевела, Елена И. Адонина, Людмила В. Сахно, Марина А. Тихонова, Александр А. Останин

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Повреждение центральной нервной системы (ЦНС) сопровождается развитием иммуноопосредованных воспалительных реакций, которые оказывают существенное влияние на выживаемость и регенерацию нервных клеток. Роль воспаления, индуцированного  главным образом макрофагами, противоречива,  поскольку макрофаги могут проявлять как нейротоксическую активность в отношении нейронов и клеток глии, так и способствовать репарации нервной ткани. Оппозитные эффекты макрофагов могут быть обусловлены их функциональной гетерогенностью. Так классические провоспалительные макрофаги (М1) являются тканедеструктивными, а противовоспалительные макрофаги (М2) участвуют в репарации тканей. Кроме того, М2 макрофаги индуцируют преимущественно Th2 ответ, который  в наибольшей степени способствует восстановлению ЦНС. Используя культуральные условия  с дефицитом ростовых факторов, мы разработали метод получения М2-подобных макрофагов и исследовали безопасность и клиническую эффективность эндолюмбального введения  этих клеток в лечении детей с церебральным параличом (ЦП). 

В исследование были отобраны 9 детей в возрасте от 2 до 8 лет с тяжелыми формами ЦП. Эндолюмбальное введение М2-подобных макрофагов  сопровождалось развитием цитокиновых реакций у 10 (62,5%) детей. Локальных или системных аллергических реакций немедленного типа, а также гематом или инфекционных осложнений, связанных  с введением клеток, не отмечалось. Через три месяца после лечения уровень спастичности в нижних конечностях (балл по шкале Эшворта) снизился с 3,9 ± 0,2 до 3,1 ± 0,2 (p<0,01). Уровень двигательной активности по шкале GMFM (Gross Motor Function Measure) возрос с 12,1 ± 9,0 до 60 ± 19 баллов (p<0,01). У трех из шести детей было отмечено полное прекращение судорожного синдрома, у четырех детей отмечено улучшение ментальных функций (способность понимать обращенную речь и говорить). Трансплантация М2-подобных макрофагов путем люмбальной пункции не сопровождалась возрастанием  уровня интерлейкина-17 и интерферона-γ в сыворотке крови, однако приводила к достоверному увеличению  нейроторофического фактора головного мозга (с 695 ± 60 до 1183 ± 153 пг/мл; pU=0,015) и выраженной тенденции к возрастанию концентрации фактора роста эндотелия сосудов (с 190 ± 41 до 240 ± 40 pg/ml; pU=0,07).

Полученные нами данные свидетельствуют о том, что эндолюмбальное ведение М2-подобных макрофагов является безопасным и улучшает неврологический статус у детей с ЦП. Однако для более полной оценки терапевтического потенциала этих клеток у детей с ЦП необходимы дальнейшие рандомизированные контролируемые проспективные исследования с оценкой отдаленных эффектов.

Ключевые слова

М2-макрофаги, церебральный паралич, цитокины, нейротрофические фактор

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Elena R. Chernykh, Marina Yu. Kafanova, Ekaterina Ya. Shevela, Elena I. Adonina, Lyudmila V. Sakhno, Marina A. Tikhonova, Alexander A. Ostanin

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 19575 [VALUE] => Array ( [TEXT] => <p class="bodytext">Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology of Russian Academy on Medical Sciences, Siberian Branch, Novosibirsk, 630099, Russia </p> <br> <p class="bodytext"><b>Correspondence</b><br> Elena Chernykh, Head of Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology RAMS SB, Yadrintsevskaya str., 14, Novosibirsk, 630099, Russia <br> Phone: +7(383)2360329, Fax: +7(383)2227028 <br> E-mail: <a href="javascript:linkTo_UnCryptMailto('qempxs.gx_pefDqemp2vy');">ct_lab@<span style="display:none;">spam is bad</span>mail.ru</a> </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology of Russian Academy on Medical Sciences, Siberian Branch, Novosibirsk, 630099, Russia


Correspondence
Elena Chernykh, Head of Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology RAMS SB, Yadrintsevskaya str., 14, Novosibirsk, 630099, Russia
Phone: +7(383)2360329, Fax: +7(383)2227028
E-mail: ct_lab@spam is badmail.ru

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Following injury to the central nervous system (CNS), immune-mediated inflammation profoundly affects the ability of neural cells to survive and to regenerate. The role of inflammation, comprises mostly of macrophages, is controversial, since macrophages can both induce neuronal and glial toxicity and promote tissue repair. The opposite effects of macrophages may be conditioned by their functional heterogeneity. Thus, classical pro-inflammatory macrophages (M1) are tissue-destructive, while anti-inflammatory (M2) macrophages mediate tissue repair. In addition, M2 macrophages predominantly induce the Th2 response, which is particularly beneficial in CNS repair. Using growth factor deficiency conditions we have generated M2-like macrophages and evaluated the safety and clinical efficacy of endolumbar introduction of these cells in treatment of children with cerebral palsy (CP). Sixteen children from 2.0 to 8.0 years old with severe forms of CP were enrolled in this trial. Endolumbar administration of M2-like cells was accompanied by cytokine reactions in 10 (62.5%) persons. There was no evidence of local and systemic immediate hypersensitivity reactions, hematoma or infection complications related to cell transplantation. At 3 months after therapy the average Ashworth score decreased from 3.9 ± 0.2 to 3.1 ± 0.2 in the lower extremities (p<0.01). Gross Motor Function Measure (GMFM) test improved from 12.1 ± 9.0 to 60 ± 19 points (p<0.01). Three of six children experienced seizures arrest, and four children improved mental functions (improvement of speech and understanding). M2-like macrophage introduction was not accompanied by an increase of serum levels of interferon-gamma and interleukin-17, but resulted in significant enhancement of brain-derived neurotrophic factor (from 695 ± 60 to 1183 ± 153 pg/ml; pU=0.015) and a strong tendency to enlargement of vascular endothelial growth factor (from 190 ± 41 to 240 ± 40 pg/ml; pU=0.07). Our data indicate that transplantation of M2-like macrophages via lumbar puncture is safe and improves neurological status in children with CP. However, to better define the therapeutic effect of these cells in CP, randomized controlled prospective trials and long-term follow-up are required.

Keywords

M2-macrophages, cerebral palsy, cytokines, neurotrophic factors

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Autologous M2-like macrophage applications in children with cerebral palsy

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Elena R. Chernykh, Marina Yu. Kafanova, Ekaterina Ya. Shevela, Elena I. Adonina, Lyudmila V. Sakhno, Marina A. Tikhonova, Alexander A. Ostanin

Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology of Russian Academy on Medical Sciences, Siberian Branch, Novosibirsk, 630099, Russia


Correspondence
Elena Chernykh, Head of Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology RAMS SB, Yadrintsevskaya str., 14, Novosibirsk, 630099, Russia
Phone: +7(383)2360329, Fax: +7(383)2227028
E-mail: ct_lab@spam is badmail.ru

Following injury to the central nervous system (CNS), immune-mediated inflammation profoundly affects the ability of neural cells to survive and to regenerate. The role of inflammation, comprises mostly of macrophages, is controversial, since macrophages can both induce neuronal and glial toxicity and promote tissue repair. The opposite effects of macrophages may be conditioned by their functional heterogeneity. Thus, classical pro-inflammatory macrophages (M1) are tissue-destructive, while anti-inflammatory (M2) macrophages mediate tissue repair. In addition, M2 macrophages predominantly induce the Th2 response, which is particularly beneficial in CNS repair. Using growth factor deficiency conditions we have generated M2-like macrophages and evaluated the safety and clinical efficacy of endolumbar introduction of these cells in treatment of children with cerebral palsy (CP). Sixteen children from 2.0 to 8.0 years old with severe forms of CP were enrolled in this trial. Endolumbar administration of M2-like cells was accompanied by cytokine reactions in 10 (62.5%) persons. There was no evidence of local and systemic immediate hypersensitivity reactions, hematoma or infection complications related to cell transplantation. At 3 months after therapy the average Ashworth score decreased from 3.9 ± 0.2 to 3.1 ± 0.2 in the lower extremities (p<0.01). Gross Motor Function Measure (GMFM) test improved from 12.1 ± 9.0 to 60 ± 19 points (p<0.01). Three of six children experienced seizures arrest, and four children improved mental functions (improvement of speech and understanding). M2-like macrophage introduction was not accompanied by an increase of serum levels of interferon-gamma and interleukin-17, but resulted in significant enhancement of brain-derived neurotrophic factor (from 695 ± 60 to 1183 ± 153 pg/ml; pU=0.015) and a strong tendency to enlargement of vascular endothelial growth factor (from 190 ± 41 to 240 ± 40 pg/ml; pU=0.07). Our data indicate that transplantation of M2-like macrophages via lumbar puncture is safe and improves neurological status in children with CP. However, to better define the therapeutic effect of these cells in CP, randomized controlled prospective trials and long-term follow-up are required.

Keywords

M2-macrophages, cerebral palsy, cytokines, neurotrophic factors

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Igor V. Maiborodin, Andrew I. Shevela, Vera A. Matveeva, Ivan S. Kolesnikov, Michail N. Drovosekov, Michail S. Toder, Tatyana V. Perrin

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Center of New Medical Technologies (Director - Prof. A.I. Shevela), Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS, 630090, Novosibirsk, Russia


Correspondence
Center of New Medical Technologies (Director - Prof. A.I. Shevela), Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS, 630090, Novosibirsk, Russia
E-mail: imai@spam is badmail.ru 

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According to scientific literature data, the application of mesenchymal stem cells leads to faster regeneration of injured bones and an increase in bone density. The regeneration processes at the site of a rat’s damaged bottom jawbone after the administration of the following substances: (1) autologous platelet-enriched fibrin clot (PEFC); (2) a suspension of autologous marrow-derived mesenchymal stem cells (AMSC) in a culture medium; and (3) PEFC with absorbed AMSC were studied with light microscopy and x-ray densitometry. Morphological examination showed that the development of red bone marrow in the bone callus occurs much earlier after AMSC application than during natural bone restoration. The formation of marrow-containing bone cavities after AMSC introduction is associated with decreased local tissue density at the 4th and 5th weeks of observation. The revealed changes are detectable in all observations, thus confirming the acceleration of the regenerative events in damaged bone tissue. The combination of PEFC with AMSC achieved the best results. After one week the hole in the lower jawbone was mostly filled with the regenerated bone tissue. It is very likely that in this case the synthesis of fibrin and stem cell characteristics optimized bone regeneration. Apparently, the bone formation started in the center of the defect, it did not start from the edges. Stem cells in the fibrin clot spread in the space of defect and filled it evenly. As a result, the most rapid and successful regeneration of the bone tissue defect was achieved.

Keywords

bone damage, rat jaw, bone repair, mesenchymal stem cells, autologous bone marrow, regeneration

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The use of autologous mesenchymal bone marrow stem cells absorbed in fibrin clot for the regeneration of injured lower jawbones in rats

Igor V. Maiborodin, Andrew I. Shevela, Vera A. Matveeva, Ivan S. Kolesnikov, Michail N. Drovosekov, Michail S. Toder, Tatyana V. Perrin

Center of New Medical Technologies (Director - Prof. A.I. Shevela), Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS, 630090, Novosibirsk, Russia


Correspondence
Center of New Medical Technologies (Director - Prof. A.I. Shevela), Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS, 630090, Novosibirsk, Russia
E-mail: imai@spam is badmail.ru 

According to scientific literature data, the application of mesenchymal stem cells leads to faster regeneration of injured bones and an increase in bone density. The regeneration processes at the site of a rat’s damaged bottom jawbone after the administration of the following substances: (1) autologous platelet-enriched fibrin clot (PEFC); (2) a suspension of autologous marrow-derived mesenchymal stem cells (AMSC) in a culture medium; and (3) PEFC with absorbed AMSC were studied with light microscopy and x-ray densitometry. Morphological examination showed that the development of red bone marrow in the bone callus occurs much earlier after AMSC application than during natural bone restoration. The formation of marrow-containing bone cavities after AMSC introduction is associated with decreased local tissue density at the 4th and 5th weeks of observation. The revealed changes are detectable in all observations, thus confirming the acceleration of the regenerative events in damaged bone tissue. The combination of PEFC with AMSC achieved the best results. After one week the hole in the lower jawbone was mostly filled with the regenerated bone tissue. It is very likely that in this case the synthesis of fibrin and stem cell characteristics optimized bone regeneration. Apparently, the bone formation started in the center of the defect, it did not start from the edges. Stem cells in the fibrin clot spread in the space of defect and filled it evenly. As a result, the most rapid and successful regeneration of the bone tissue defect was achieved.

Keywords

bone damage, rat jaw, bone repair, mesenchymal stem cells, autologous bone marrow, regeneration

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Тарун Банзал, Рашид Хоссейн, Уильям МкКейн, Джон А. Сноуден

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Болезнь депозитов моноклональных иммуноглобулинов (БДМИ) практически всегда поражает почки и нередко приводит к полной почечной недостаточности (ПН). Трансплантация почки как метод лечения при этом обычно не рассматривается, так как болезнь практически всегда рецидивирует, в силу чего вероятность приживления аллотрансплантата очень низкая. Мы приводим результат лечения 36-летней больной, которой после курса индукционной химиотерапии ввели высокую дозу мелфалана и аутологичные стволовые клетки, а затем ей пересадили почку сестры. В течение последующего более чем 2-летнего наблюдения не было отмечено ни признаков отторжения аллотрансплантата и каких-либо связанных с трансплантацией типичных осложнений, ни рецидива БДМИ. Данное клиническое  наблюдение даёт основание рассматривать приведенный метод лечения приемлемым для больных БДМИ, осложнённой конечной стадией ПН, однако, больные для этого должны быть тщательно отобраны.

Ключевые слова

трансплантация аутологичных стволовых клеток, конечная стадия почечной недостаточности, болезнь депозитов моноклональных иммуноглобулинов, БДМИ, аллотрансплантат почки, свободные цепи иммуноглобулинов в сыворотке крови, мелфалан

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Tarun Bansal2, Rashed Hossain1, William McKane2, John A Snowden1

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1Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK;
2Department of Renal Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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Monoclonal immunoglobulin deposition disease (MIDD) nearly always has renal involvement and frequently leads to end stage renal failure (ESRF). Renal transplantation is not usually considered due to an almost universal recurrence of the disease and poor survival of the renal allograft. We report the case of a 36-year-old female who was treated with induction chemotherapy followed by high dose melphalan and autologous stem cell transplantation and subsequently received a live related renal transplant from her sister. She had no rejection or major post transplant complications, and showed no signs of recurrence of disease after over 2 years of follow up. Our case suggests this mode of therapy could be considered in carefully selected patients with ESRF due to MIDD.

Keywords

Autologous stem cell transplantation (ASCT), End stage renal failure, Monoclonal Immunoglobulin Deposition Disease (MIDD), Renal allograft, Serum free light chains, Melphalan

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Safety and efficacy of high dose melphalan and autologous stem cell transplantation prior to renal allograft in end-stage renal failure secondary to Monoclonal Immunoglobulin Deposition Disease

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Tarun Bansal2, Rashed Hossain1, William McKane2, John A Snowden1

1Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK;
2Department of Renal Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

Monoclonal immunoglobulin deposition disease (MIDD) nearly always has renal involvement and frequently leads to end stage renal failure (ESRF). Renal transplantation is not usually considered due to an almost universal recurrence of the disease and poor survival of the renal allograft. We report the case of a 36-year-old female who was treated with induction chemotherapy followed by high dose melphalan and autologous stem cell transplantation and subsequently received a live related renal transplant from her sister. She had no rejection or major post transplant complications, and showed no signs of recurrence of disease after over 2 years of follow up. Our case suggests this mode of therapy could be considered in carefully selected patients with ESRF due to MIDD.

Keywords

Autologous stem cell transplantation (ASCT), End stage renal failure, Monoclonal Immunoglobulin Deposition Disease (MIDD), Renal allograft, Serum free light chains, Melphalan

Articles

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Марлис Е.Г.М. Ван Гуф

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Авторы [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_RU] => Array ( [ID] => 26 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Организации [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 26 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => [VALUE] => [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 19372 [VALUE] => Array ( [TEXT] => <p class="bodytext">В конце прошлого века для лечения рака молочной железы были широко внедрены в практику программы интенсивной химиотерапии. Ряд авторов сообщили о схемах лечения с применением более плотного по частоте введения или более высоких доз химиопрепаратов. Кроме того, были начаты клинические исследования по сочетанию высокодозной химиотерапии и трансплантации аутологичных стволовых клеток больным раком молочной железы II-IV стадий. Первые результаты аллогенной трансплантации гемопоэтических клеток при раке молочной железы в последнем десятилетии 1900-х годов свидетельствовали о положительном иммунном эффекте такого подхода и способствовали началу подобных клинических исследований на небольших группах больных. <br /><br />В данной работе обсуждаются результаты нескольких исследований эффективности высокодозной химиотерапии и трансплантации аутологичных стволовых клеток, а также аллогенной трансплантации при раке молочной железы. </p> <h3>Ключевые слова</h3> <p>рак молочной железы, средневысокие дозы, аутологичный, сниженная интенсивность, кондиционирование, аллогенный, уплотнение режима введения препаратов, химиотерапия  </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

В конце прошлого века для лечения рака молочной железы были широко внедрены в практику программы интенсивной химиотерапии. Ряд авторов сообщили о схемах лечения с применением более плотного по частоте введения или более высоких доз химиопрепаратов. Кроме того, были начаты клинические исследования по сочетанию высокодозной химиотерапии и трансплантации аутологичных стволовых клеток больным раком молочной железы II-IV стадий. Первые результаты аллогенной трансплантации гемопоэтических клеток при раке молочной железы в последнем десятилетии 1900-х годов свидетельствовали о положительном иммунном эффекте такого подхода и способствовали началу подобных клинических исследований на небольших группах больных. 

В данной работе обсуждаются результаты нескольких исследований эффективности высокодозной химиотерапии и трансплантации аутологичных стволовых клеток, а также аллогенной трансплантации при раке молочной железы.

Ключевые слова

рак молочной железы, средневысокие дозы, аутологичный, сниженная интенсивность, кондиционирование, аллогенный, уплотнение режима введения препаратов, химиотерапия 

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Marlies E.H.M. van Hoef, MD, PhD

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Transplant Creations, www.transplantcreations.com, Amsterdam, The Netherlands


Correspondence
Marlies E.H.M. Van Hoef, MD, PhD, Transplant Creations, P.O. Box 51342, 1007 EH Amsterdam, The Netherlands
Phone: +31-6-12433616
E-mail: mvanhoef@spam is badtransplantcreations.com

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 19377 [VALUE] => Array ( [TEXT] => <p class="bodytext">At the end of the past century chemotherapy for breast cancer was characterized by dose intensification. Several authors reported on dose-dense (more frequent) and dose-intense (high-dose) treatment. In addition, studies of high-dose chemotherapy and autologous stem transplantation for stage II to IV breast cancer were started. The first results of allogeneic hematopoietic cell transplantation for breast cancer revealed a positive immune effect and encouraged a handful of small case studies in the last decade of the last century.<br />This article summarizes the results of several studies using high-dose chemotherapy and autologous stem cell transplantation, as well as the results of studies using allogeneic transplantation for breast cancer. </p> <h3>Keywords</h3><p> breast cancer, semi-high-dose, autologous, reduced intensity, conditioning, allogeneic, dose-dense treatment, chemotherapy </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

At the end of the past century chemotherapy for breast cancer was characterized by dose intensification. Several authors reported on dose-dense (more frequent) and dose-intense (high-dose) treatment. In addition, studies of high-dose chemotherapy and autologous stem transplantation for stage II to IV breast cancer were started. The first results of allogeneic hematopoietic cell transplantation for breast cancer revealed a positive immune effect and encouraged a handful of small case studies in the last decade of the last century.
This article summarizes the results of several studies using high-dose chemotherapy and autologous stem cell transplantation, as well as the results of studies using allogeneic transplantation for breast cancer.

Keywords

breast cancer, semi-high-dose, autologous, reduced intensity, conditioning, allogeneic, dose-dense treatment, chemotherapy

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Tutorial: Treatment and hematopoietic cell transplantation for breast cancer: the past, the present, is there a future?

Download PDF version

Marlies E.H.M. van Hoef, MD, PhD

Transplant Creations, www.transplantcreations.com, Amsterdam, The Netherlands


Correspondence
Marlies E.H.M. Van Hoef, MD, PhD, Transplant Creations, P.O. Box 51342, 1007 EH Amsterdam, The Netherlands
Phone: +31-6-12433616
E-mail: mvanhoef@spam is badtransplantcreations.com

At the end of the past century chemotherapy for breast cancer was characterized by dose intensification. Several authors reported on dose-dense (more frequent) and dose-intense (high-dose) treatment. In addition, studies of high-dose chemotherapy and autologous stem transplantation for stage II to IV breast cancer were started. The first results of allogeneic hematopoietic cell transplantation for breast cancer revealed a positive immune effect and encouraged a handful of small case studies in the last decade of the last century.
This article summarizes the results of several studies using high-dose chemotherapy and autologous stem cell transplantation, as well as the results of studies using allogeneic transplantation for breast cancer.

Keywords

breast cancer, semi-high-dose, autologous, reduced intensity, conditioning, allogeneic, dose-dense treatment, chemotherapy

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Sandra Lange1, Simone Altmann1, Heike Vogel2, Volker Weirich3, Mathias Freund1, Christian Junghanss1

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1Department of Internal Medicine, Medical Clinic III – Hematoloy, Oncology, Palliative Medicine; 2Department of Radiation Oncology; 3Institute of Legal Medicine, Medical Faculty, University of Rostock, Rostock, Germany

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The canine nonmyeloablative hematopoietic stem cell transplantation (HSCT) model allows the establishment of mixed hematopoietic chimerism following 2 Gy total body irradiation (TBI) conditioning, but in general fails to do so after 1 Gy TBI. Several studies have used this model to investigate cellular-based therapies as well as pharmaceutical-based approaches in their ability to support engraftment. In the present study we investigated the impact of an intravenous administration of host derived dendritic cells (DC) during (day 0) and/or 1 week post transplantation on long-term engraftment in a canine HSCT model. Dogs were transplanted after conditioning with 1 Gy TBI and received immunosuppression consisting of 15 mg/kg cyclosporin A BID PO (days -1 to +35) in combination with 20 mg/kg mycophenolate mofetil BID PO (days 0 to +27). All dogs transiently engrafted but eventually rejected the graft by a median 56–84 days. Therefore, additional DC administration failed to significantly improve graft survival compared to historical controls. However, administration of DC twice seemed to be superior to a single administration when looking at their ability to support initial engraftment. Future studies might therefore aim at more frequent DC administrations to support successful HSCT in this setting.

Keywords

allogeneic hematopoietic stem cell transplantation, nonmyeloablative, vaccination, dendritic cells, dog, chimerism, engraftment

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Graft enrichment with host-derived mature dendritic cells does not allow long-term engraftment in canine DLA-identical hematopoietic stem cell transplantation recipients after conditioning with 1 Gy TBI

Sandra Lange1, Simone Altmann1, Heike Vogel2, Volker Weirich3, Mathias Freund1, Christian Junghanss1

1Department of Internal Medicine, Medical Clinic III – Hematoloy, Oncology, Palliative Medicine; 2Department of Radiation Oncology; 3Institute of Legal Medicine, Medical Faculty, University of Rostock, Rostock, Germany

The canine nonmyeloablative hematopoietic stem cell transplantation (HSCT) model allows the establishment of mixed hematopoietic chimerism following 2 Gy total body irradiation (TBI) conditioning, but in general fails to do so after 1 Gy TBI. Several studies have used this model to investigate cellular-based therapies as well as pharmaceutical-based approaches in their ability to support engraftment. In the present study we investigated the impact of an intravenous administration of host derived dendritic cells (DC) during (day 0) and/or 1 week post transplantation on long-term engraftment in a canine HSCT model. Dogs were transplanted after conditioning with 1 Gy TBI and received immunosuppression consisting of 15 mg/kg cyclosporin A BID PO (days -1 to +35) in combination with 20 mg/kg mycophenolate mofetil BID PO (days 0 to +27). All dogs transiently engrafted but eventually rejected the graft by a median 56–84 days. Therefore, additional DC administration failed to significantly improve graft survival compared to historical controls. However, administration of DC twice seemed to be superior to a single administration when looking at their ability to support initial engraftment. Future studies might therefore aim at more frequent DC administrations to support successful HSCT in this setting.

Keywords

allogeneic hematopoietic stem cell transplantation, nonmyeloablative, vaccination, dendritic cells, dog, chimerism, engraftment

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