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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

Dose-dense chemotherapy

High-dose chemotherapy, stage II and III disease

High-dose chemotherapy, stage IV disease

Ablative allogeneic transplants and cell therapy for stage IV disease

Non-myeloablative reduced intensity conditioning allogeneic transplants, stage IV

The future

References

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.

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).

23. Van Hoef MEHM. Clinical development of non-myeloablative transplants: application as integrated treatment strategy. Hematol Journal. 2002;3(suppl 1):161 (abst 534).

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.

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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"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) "19371" ["VALUE"]=> array(2) { ["TEXT"]=> string(55) "Марлис Е.Г.М. Ван Гуф" ["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

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

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

Keywords

breast cancer, semi-high-dose, autologous, reduced intensity, conditioning, allogeneic, dose-dense treatment, chemotherapy

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

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

Марлис Е.Г.М. Ван Гуф

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Ключевые слова

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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

1. Sources of unrelated donors

2. Current URD-HSCT activity

2.1. Number of URD-HSCTs

2.2. Disease indication

2.3. Clinical outcomes of URD-HSCT

3. Advances in URD-HSCT

3.1. Conditioning regimens

3.2. Prophylaxis regimens for aGVHD

4. Trends and perspective for HSCT in China

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

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.

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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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. 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Хе Хуанг, Хаовен Сяо, Хуалюй Фу

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 Xiao^1,2, 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

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 Xiao^1,2, Huarui Fu¹

Keywords

hematopoietic stem cell transplantation, HSCT, unrelated donor, China

Keywords

hematopoietic stem cell transplantation, HSCT, unrelated donor, China

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Хе Хуанг, Хаовен Сяо, Хуалюй Фу

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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

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

Figure 1. Serum Free kappa light chain assay

Discussion

Acknowledgements

The authors have declared that no competing interests exist.

References

3. Dhodapkar MV, Merlini G, Solomon A. Biology and therapy of immunoglobulin deposition diseases. Hematol Oncol Clin North Am. 1997;11:89-110.

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.

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" ["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

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

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

Keywords

Autologous stem cell transplantation (ASCT), End stage renal failure, Monoclonal Immunoglobulin Deposition Disease (MIDD), Renal allograft, Serum free light chains, Melphalan

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

Тарун Банзал, Рашид Хоссейн, Уильям МкКейн, Джон А. Сноуден

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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. 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Ключевые слова

" } } } [3]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(2) "84" ["~IBLOCK_SECTION_ID"]=> string(2) "84" ["ID"]=> string(4) "1474" ["~ID"]=> string(4) "1474" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(135) "The use of autologous mesenchymal bone marrow stem cells absorbed in fibrin clot for the regeneration of injured lower jawbones in rats" ["~NAME"]=> string(135) "The use of autologous mesenchymal bone marrow stem cells absorbed in fibrin clot for the regeneration of injured lower jawbones in rats" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(22) "11/22/2017 12:25:06 pm" ["~TIMESTAMP_X"]=> string(22) "11/22/2017 12:25:06 pm" ["DETAIL_PAGE_URL"]=> string(135) "/en/archive/tom-3-nomer-1-8/stati/the-use-of-autologous-mesenchymal-bone-marrow-stem-cells-absorbed-in-fibrin-clot-for-the-regeneratio/" ["~DETAIL_PAGE_URL"]=> string(135) "/en/archive/tom-3-nomer-1-8/stati/the-use-of-autologous-mesenchymal-bone-marrow-stem-cells-absorbed-in-fibrin-clot-for-the-regeneratio/" ["LIST_PAGE_URL"]=> string(12) "/en/archive/" ["~LIST_PAGE_URL"]=> string(12) "/en/archive/" ["DETAIL_TEXT"]=> string(54084) "

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).

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).

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*⁴^{, 7, 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

1. Anitua E, Sanchez M, Nurden A, et al. New insights into and novel applications for platelet-rich fibrin therapies. Trends in Biotechnology. 2006:24(5):227-234. doi:10.1016/j.tibtech.2006.02.010.

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.

3. Chanda D, Kumar S and Ponnazhagan S. Therapeutic potential of adult bone marrow-derived mesenchymal stem cells in diseases of the skeleton. Journal of Cellular Biochemistry. 2010:111(2):249-257. doi:10.1002/jcb.22701.

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.

12. Neumann K, Dehne T, Endres M, et al. Chondrogenic differentiation capacity of human mesenchymal progenitor cells derived from subchondral cortico-spongious bone. Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society. 2008:26(11):1449-1456.

13. Niemeyer P, Fechner K, Milz S, et al. Comparison of mesenchymal stem cells from bone marrow and adipose tissue for bone regeneration in a critical size defect of the sheep tibia and the influence of platelet-rich plasma. Biomaterials. 2010:31(13):3572-3579.

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.

" ["~DETAIL_TEXT"]=> string(54084) "

Introduction

Materials and methods

Results

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

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*⁴^{, 7, 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

Discussion

Conclusion

Acknowledgements

References

1. Anitua E, Sanchez M, Nurden A, et al. New insights into and novel applications for platelet-rich fibrin therapies. Trends in Biotechnology. 2006:24(5):227-234. doi:10.1016/j.tibtech.2006.02.010.

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.

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.

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Maiborodin, Andrew I. Shevela, Vera A. Matveeva, Ivan S. Kolesnikov, Michail N. Drovosekov, Michail S. Toder, Tatyana V. Perrin" ["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" ["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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Keywords

bone damage, rat jaw, bone repair, mesenchymal stem cells, autologous bone marrow, regeneration

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

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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; p_U >0.05). Second, they received higher number of input cells (0.74 ± 0.15 vs 0.59 ± 0.17 х 10⁶/kg; p_U >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; p_U =0.015) and strong tendency to an increase of vascular endothelial growth factor (VEGF; from 190 ± 41 to 240 ± 40 pg/ml; p_U =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.

References

1. Aarum J, Sandberg K, Haeberlein SL, Persson MA. Migration and differentiation of neural precursor cells can be directed by microglia. Proc Natl Acad Sci USA. 2003; 100:15983-15988. doi:10.1073/pnas.2237050100.

2. Arenillas JF, Sobrino T, Castillo J, Davalos A. The role of angiogenesis in damage and recovery from ischemic stroke. Curr Treat Options Cardiovasc Med. 2007;9:205–212.

3. Asher RA, Morgenstern DA, Moon LD and Fawcett JW. Chondroitin sulphate proteoglycans: inhibitory components of the glial scar. Prog Brain Res. 2001;132:611–619.

4. Back SA, Luo NL, Mallinson RA, O'Malley JP, Wallen LD, Frei B, Morrow JD, Petito CK, Roberts CT Jr, Murdoch GH, Montine TJ. Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes. Ann Neurol. 2005;58:108–120.

5. Cerebral Palsy, Toso L, Poggi S, Park J, Einat H, Roberson R, Dunlap V, Woodard J, Abebe D, Spong CY. Inflammatory-mediated model of cerebral palsy with developmental sequelae. Am J Obstet Gynecology. 2005;193(3 Pt 2):933-941.

6. Chen L, Huang H, Xi H, Xie Z, Liu R, Jiang Z, Zhang F, Liu Y, Chen D,Wang Q,Wang H, Ren Y, Zhou C. Intracranial Transplant of Olfactory Ensheathing Cells in Children and Adolescents With Cerebral Palsy: A Randomized Controlled Clinical Trial. Cell Transplantation. 2010;19:185–191.

7. Chernykh ER, Shevela EY, Sakhno LV, Tikhonova MA, Petrovsky YL, Ostanin AA. The generation and properties of human M2-like macrophages: potential candidates for CNS repair? Cellular Therapy and Transplantation 2010;2:e.000080.01. doi:10.3205/ctt-2010-en-000080.01.

8. Domeniconi M, Cao Z, Spencer T, Sivasankaran R, Wang K, Nikulina E, Kimura N, Cai H, Deng K, Gao Y, He Z, Filbin M. Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron. 2002;35:283-290.

9. Fitch MT, Silver J. Activated macrophages and the blood-brain barrier: inflammation after CNS injury leads to increases in putative inhibitory molecules. Exp Neurol. 1997;148:587-603.

10. Freire-de-Lima CG, Xiao YQ, Gardai SJ, Bratton DL, Schiemann WP, and Henson PM. Apoptotic cells, through transforming growth factor-β, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages. J Biol Chem. 2006;281:38376-38384. doi:10.1074/jbc.M605146200.

11. Ferraro GB, Alabed YZ, Fournier AE. Molecular Targets to Promote Central Nervous System Regeneration. Current Neurovascular Research. 2004;1:61-75.

12. Glod J, Kobiler D, Noel M, et al. Monocytes form a vascular barrier and participate in vessel repair after brain injury. Blood. 2006;107:940-946. doi:10.1182/blood-2004-11-4403.

13. Goldman SA, Schanz S, Windrem MS. Stem cell-based strategies for treating pediatric disorders of myelin. Human molecular genetics. 2008;17(R1):R76-83. doi:10.1093/hmg/ddn052.

14. Golpon HA, Fadok VA, Taraseviciene-Stewart L, et al. Life after corpse engulfment: phagocytosis of apoptotic cells leads to VEGF secretion and cell growth. The FASEB Journal. 2004;18:1716-1718. doi:10.1096/fj.04-1853fje 15345697.

15. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 2005;5:953-964.

16. Hendrix S, Nitsch R. The role of T helper cells in neuroprotection and regeneration Journal of Neuroimmunology. 2007;184:100-112.

17. Hohlfeld R, Kerschensteiner M, Meinl E. Dual role of inflammation in CNS disease. Neurology. 2007;68(Suppl 3):S58-S63.

18. Ingram TTS. A historical review of the definition and classification of the cerebral palsies. In: Stanley FJ, Alberman E, eds. The Epidemiology of Cerebral Palsy. London, England: Heinemann. 1984:1-11.

19. Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WEF, Kolbeck R, Hoppe E, Oropeza-Wekerle R-L, Bartke I, Stadelmann C, Lassman H, Wekerle H, Hohlfeld R. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: A neuroprotective role of inflammation? J Exp Med. 1999;189:865-870.

20. Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci. 2009;29:13435-13444. doi:10.1523/JNEUROSCI.3257-09.2009.

21. Kotter MR, Zhao C, van Rooijen N, Franklin RJ. Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol Dis. 2005;18:166-175.

22. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677-686.

23. McPhail LT, Stirling DP, Tetzlaff W, Kwiecien JM, Ramer MS. The contribution of activated phagocytes and myelin degeneration to axonal retraction/dieback following spinal cord injury. Eur J Neurosci. 2004;20:1984-1994.

24. Moalem G, Gdalyahu A, Shani Y, Otten U, Lazarovici P, Cohen IR, Schwartz M. Production of neurotrophins by activated T cells: implications for neuroprotective autoimmunity. J Autoimmunity. 2000;15:331-345.

25. Mosser DM. The many faces of macrophage activation. J Leukocyte Biol. 2003;73:209-212.

26. Nakajima K, Kohsaka S. Microglia: neuroprotective and neurotrophic cells in the central nervous system. Curr Drug Targets Cardiovasc Haematol Disord. 2004;4:65-84.

27. O’Shea TM. Diagnosis, treatment, and prevention of cerebral palsy. Clinical obstetrics and gynecology. 2008;51:816-828.

28. Pellegrino L. Cerebral palsy. In: Batshaw ML, Ed. When Your Child Has a Disability: The Complete Sourcebook of Daily and Medical Care. Baltimore, MD: Paul H. Brookes Publishing Co; 2000:275-287.

29. Pharoah PO. Epidemiology of cerebral palsy: a review. Journal of the Royal Society of medicine. 1981;74(7):516-520.

30. Rehman J, Li J, Orschell CM, March KL. Peripheral blood "endothelial progenitor cells" are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation. 2003;107:1164-1169.

31. Rimaniol A-C, HaÏk S, Martin M, Le Grand R, Boussin FD, Dereuddre-Bosquet N, Gras G and Dormont D. High-Affinity Glutamate Transport in Macrophages. J Immunol. 2000;164:5430-5438.

32. Russell DJ, Rosenbaum PL, Cadman DT, et al. The Gross Motor Function Measure: a means to evaluate the effects of physical therapy. Dev Med Child Neurol. 1989;31:341-352.

33. Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G, Rolls A, Mack M, Pluchino S, Martino G, Jung S, Schwartz M. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Medicine. 2009;6:1-16. doi:10.1371/journal.pmed.1000113.

34. Tzartos JS, Friese MA, Craner MJ, et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is asso ciated with active disease in multiple sclerosis. Am J Pathol. 2008;172(1):146-155. doi:10.2353/ajpath.2008.070690.

35. Uyttenhove C, Sommereyns C, Theate I, Michiels T, Van Snick J. Anti-IL-17A autovaccination prevents clinical and histological manifestations of experimental autoimmune encephalomyelitis. Ann NY Acad Sci. 2007;1110:330-336.

36. Westbom L, Hagglund G, Nordmark E. Cerebral palsy in a total population of 4-11 year olds in Southern Sweden. Prevalence and distribution according to different CP classification systems. BMC pediatrics. 2007;7:41. doi:10.1186/1471-2431-7-41.

37. Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, van Bruggen N, Chopp M. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain J Clin Invest. 2000;106(7):829-838. doi:10.1172/JCI9369.

38. Ziv Y, Avidan H, Pluchino S, Martino G, Schwartz M. Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proc Natl Acad Sci USA. 2006;103:13174-13179. doi:10.1073/pnas.0603747103.

" ["~DETAIL_TEXT"]=> string(54111) "

Introduction

Patients and methods

Study design

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

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

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

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

Discussion

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.

References

2. Arenillas JF, Sobrino T, Castillo J, Davalos A. The role of angiogenesis in damage and recovery from ischemic stroke. Curr Treat Options Cardiovasc Med. 2007;9:205–212.

3. Asher RA, Morgenstern DA, Moon LD and Fawcett JW. Chondroitin sulphate proteoglycans: inhibitory components of the glial scar. Prog Brain Res. 2001;132:611–619.

9. Fitch MT, Silver J. Activated macrophages and the blood-brain barrier: inflammation after CNS injury leads to increases in putative inhibitory molecules. Exp Neurol. 1997;148:587-603.

11. Ferraro GB, Alabed YZ, Fournier AE. Molecular Targets to Promote Central Nervous System Regeneration. Current Neurovascular Research. 2004;1:61-75.

12. Glod J, Kobiler D, Noel M, et al. Monocytes form a vascular barrier and participate in vessel repair after brain injury. Blood. 2006;107:940-946. doi:10.1182/blood-2004-11-4403.

13. Goldman SA, Schanz S, Windrem MS. Stem cell-based strategies for treating pediatric disorders of myelin. Human molecular genetics. 2008;17(R1):R76-83. doi:10.1093/hmg/ddn052.

15. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 2005;5:953-964.

16. Hendrix S, Nitsch R. The role of T helper cells in neuroprotection and regeneration Journal of Neuroimmunology. 2007;184:100-112.

17. Hohlfeld R, Kerschensteiner M, Meinl E. Dual role of inflammation in CNS disease. Neurology. 2007;68(Suppl 3):S58-S63.

22. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677-686.

25. Mosser DM. The many faces of macrophage activation. J Leukocyte Biol. 2003;73:209-212.

26. Nakajima K, Kohsaka S. Microglia: neuroprotective and neurotrophic cells in the central nervous system. Curr Drug Targets Cardiovasc Haematol Disord. 2004;4:65-84.

27. O’Shea TM. Diagnosis, treatment, and prevention of cerebral palsy. Clinical obstetrics and gynecology. 2008;51:816-828.

28. Pellegrino L. Cerebral palsy. In: Batshaw ML, Ed. When Your Child Has a Disability: The Complete Sourcebook of Daily and Medical Care. Baltimore, MD: Paul H. Brookes Publishing Co; 2000:275-287.

29. Pharoah PO. Epidemiology of cerebral palsy: a review. Journal of the Royal Society of medicine. 1981;74(7):516-520.

31. Rimaniol A-C, HaÏk S, Martin M, Le Grand R, Boussin FD, Dereuddre-Bosquet N, Gras G and Dormont D. High-Affinity Glutamate Transport in Macrophages. J Immunol. 2000;164:5430-5438.

32. Russell DJ, Rosenbaum PL, Cadman DT, et al. The Gross Motor Function Measure: a means to evaluate the effects of physical therapy. Dev Med Child Neurol. 1989;31:341-352.

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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) "" ["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) "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. <h3>Ключевые слова</h3> М2-макрофаги, церебральный паралич, цитокины, нейротрофические фактор " ["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; p_U=0,015) и выраженной тенденции к возрастанию концентрации фактора роста эндотелия сосудов (с 190 ± 41 до 240 ± 40 pg/ml; p_U=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

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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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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; p_U=0.015) and a strong tendency to enlargement of vascular endothelial growth factor (from 190 ± 41 to 240 ± 40 pg/ml; p_U=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" ["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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Keywords

M2-macrophages, cerebral palsy, cytokines, neurotrophic factors

Keywords

M2-macrophages, cerebral palsy, cytokines, neurotrophic factors

" } ["DOI"]=> array(37) { ["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) "19555" ["VALUE"]=> string(29) "10.3205/ctt-2011-en-000092.01" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(29) "10.3205/ctt-2011-en-000092.01" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(29) "10.3205/ctt-2011-en-000092.01" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["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) "40" ["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) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19556" ["VALUE"]=> string(74) "Autologous M2-like macrophage applications in children with cerebral palsy" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(74) "Autologous M2-like macrophage applications in children with cerebral palsy" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(74) "Autologous M2-like macrophage applications in children with cerebral palsy" } ["ORGANIZATION_EN"]=> array(37) { ["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) "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: <a href="javascript:linkTo_UnCryptMailto('qempxs.gx_pefDqemp2vy');">ct_lab@spam is badmail.ru</a> " ["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

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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). 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. <h3>Ключевые слова</h3> М2-макрофаги, церебральный паралич, цитокины, нейротрофические фактор " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5052) "

Ключевые слова

М2-макрофаги, церебральный паралич, цитокины, нейротрофические фактор

Ключевые слова

М2-макрофаги, церебральный паралич, цитокины, нейротрофические фактор

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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

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)

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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Introduction

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

Hematopoietic stem cell transplantation

Cell isolation and generation of DC

Hematopoietic chimerism analysis

Statistics

Results

Discussion

Conflict of Interest

The authors of this paper declare no financial or personal conflict of interest.

Acknowledgements

References

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.

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.

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) "Sandra Lange1, Simone Altmann1, Heike Vogel2, Volker Weirich3, Mathias Freund1, Christian Junghanss1" ["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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Keywords

allogeneic hematopoietic stem cell transplantation, nonmyeloablative, vaccination, dendritic cells, dog, chimerism, engraftment

Keywords

allogeneic hematopoietic stem cell transplantation, nonmyeloablative, vaccination, dendritic cells, dog, chimerism, engraftment

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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) } } } }

Articles

Tutorial: Treatment and hematopoietic cell transplantation for breast cancer: the past, the present, is there a future?

Marlies E.H.M. van Hoef, MD, PhD

He Huang¹, Haowen Xiao^1,2, Huarui Fu¹

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

Tarun Bansal², Rashed Hossain¹, William McKane², John A Snowden¹

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

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

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

Articles

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

Keywords

breast cancer, semi-high-dose, autologous, reduced intensity, conditioning, allogeneic, dose-dense treatment, chemotherapy

Articles

Unrelated donors for hematopoietic stem cell transplantation in the People's Republic of China

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He Huang¹, Haowen Xiao^1,2, Huarui Fu¹

Keywords

hematopoietic stem cell transplantation, HSCT, unrelated donor, China

Articles

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

Download PDF version

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

Keywords

Autologous stem cell transplantation (ASCT), End stage renal failure, Monoclonal Immunoglobulin Deposition Disease (MIDD), Renal allograft, Serum free light chains, Melphalan

Articles

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

Keywords

bone damage, rat jaw, bone repair, mesenchymal stem cells, autologous bone marrow, regeneration

Articles

Autologous M2-like macrophage applications in children with cerebral palsy

Download PDF version

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

Keywords

M2-macrophages, cerebral palsy, cytokines, neurotrophic factors

Articles

Sandra Lange¹, Simone Altmann¹, Heike Vogel², Volker Weirich³, Mathias Freund¹, Christian Junghanss¹

Keywords

allogeneic hematopoietic stem cell transplantation, nonmyeloablative, vaccination, dendritic cells, dog, chimerism, engraftment