Introduction
Prof. J. L. Chertkov (1927–2009) devoted most of his efforts to understanding the mechanisms of hematopoiesis. He was interested in the developmental fate of hematopoietic stem cells (HSC), and the result of his investigations became the theory of clonal succession of HSC, which was published in several papers [1-4]. The data showed that long-term hematopoiesis is maintained by a large number of simultaneously functioning small, short-lived (1 to 3 months) clones that usually grow locally with little or no dispersion between different regions of the hematopoietic system. Only 10% of clones are long-lived and can function during the whole life of the animal. Furthermore, clones that disappear are never detected again. The data suggests that normal hematopoiesis is supported by the sequential recruitment of marrow repopulating cells into a differentiation mode.
In the mid 1970s, together with A. J. Friedenstein, Joseph Chertkov laid the foundation for experimentation into the differences between HSC and precursor cells in the hematopoietic microenvironment. He postulated that an understanding of the interrelationship between the stem cells of hematopoiesis and regulatory stromal microenvironment is necessary for an investigation of the process of hematopoiesis. To analyze the stromal precursor cells J. L. Chertkov used a functional assay where the microenvironment is addressed as the territory where hematopoiesis takes place and therefore could be estimated by the number of hematopoietic cells maintained on it. The method of ectopic hematopoietic foci formation provides a separate hematopoietic territory built de novo via special stromal precursor cells. Cells capable of transferring the hematopoietic microenvironment were referred to by Chertkov as hematopoietic microenvironment-transferring units (HMTU) [5].
In 1991 A. Caplan defined stem cells capable of giving rise to skeletal tissues – cartilage, bone, tendon, ligament, marrow stroma, and connective tissue – as mesenchymal stem cells (MSC) [6]. The term MSC was used in the fields of cytotherapy and tissue engineering widely and not always correctly; therefore the International Society of Cellular Therapy postulated the use of the term MSC only for cells that fulfilled the stem cell criteria: multipotentiality and self-renewal [7]. All works of Prof. Chertkov clearly demonstrate that HMTU and MSC are synonyms. Therefore we will use the term MSC for cells described by J. L. Chertkov as HMTU.
The compilation of the works by J. L. Chertkov characterizes MSCs both quantitatively and qualitatively, based on their functional properties. MSCs were shown to have a high proliferative potential, to be able to develop multilineage progeny, and form a fully functional hematopoietic microenvironment. The compartment of stromal precursor cells was shown to have a hierarchical structure, and inducible precursor cells were characterized. The radiosensitivity of MSCs and their progeny was estimated and it was then possible to calculate the direct number of MSC in the murine femur.
Materials and Methods
Mice
Female and male C57BL/6 (B6), CBA, CBAT6T6, (CBAxC57BL/6) F1 hybrid (CB), and (CBAT6T6xC57BL/6) F1 hybrid (CBT) mice 8–25 wks of age at the beginning of the study were used. Care was taken that the groups to be compared originated from the same batch of animals housed under the same conditions.
Irradiation of mice
In some of the experiments the recipient mice were irradiated with 400 or 700 rad from a 137Cs IPK irradiator 3 to 4 hrs before bone marrow (BM) implantation. Both doses produced the same effect on the size of the ectopic foci. The irradiator consisted of four 137Cs sources set in a quadrilateral arrangement about the site of exposure.
In order to obtain blood sera containing stroma-stimulating activity, the mice were irradiated with 6–12 Gy (in the latter case the protective dose of BM cells was injected i.v.).
Bone marrow irradiation
In the case of an in vivo irradiation the mice were irradiated and sacrificed immediately thereafter. The femurs were removed and stored on ice until transplantation. For in vitro irradiation the femurs were exposed either to γ-rays from an IPK irradiator with the absorbed dose rate of 500 rad/min or to fast neutrons generated by the Obninsk BR-10 research reactor. The mean energy of fast neutrons was 0.85MeV, the power of the tissue Kerma 128 rad/min, and the ratio of neutron to γ-ray doses at the point of exposure of the bones was approximately 20:1. The γ-ray component was ignored in calculating the dose-response curves, and all neutron doses represent the rad dose of the neutron component. In all experiments, the period between bone resection and the implantation of the bone marrow did not exceed 5 hrs. The sequence of implantation of femurs exposed to various doses was always randomized.
Chimeras
The mice were exposed to 12–13 Gy and reconstituted with syngeneic or allogeneic BM in doses indicated in the corresponding part of the text. In general, 1/3–1/4 of the femoral equivalent was injected (standard chimeras). Secondary chimeras were obtained when irradiated recipients were reconstituted with hematopoietic cells of standard chimeras; the cells were collected no earlier than 2 months after the creation of the standard chimeras. Tertiary chimeras were obtained when the irradiated recipients were reconstituted with hematopoietic cells of secondary chimeras; the cells were also collected no earlier than 2 months after the creation of the secondary chimeras. Double chimeras were obtained when the standard chimeras were exposed to a dose of 12–13 Gy 2–5 months after creation of the chimera, and reconstituted with hematopoietic cells of normal mice. The stromal precursors were studied 3–9 months after creation of the chimeras.
Bone marrow or adherent cell layer implantation
Implantation was performed under the renal capsule of anesthetized mice. The femurs were freed of muscle, the epiphyses cut away, and the bones stored on ice until used. The BM was pressed out of the femur with a stylet or thick needle with a blunt end. In anesthetized mice a small tear was made in the renal capsule and a bone marrow plug or adherent cell layer (ACL) from long-term bone marrow culture placed under it with a small spatula. The ACL was removed from the flask bottom with a rubber policeman and implanted under the renal capsule without conversion to a single-cell suspension. In cases of ectopic foci reimplantation the whole focus was removed from the kidney and implanted under the renal capsule of the recipient. In cases where suspended BM was implanted, the 0.5 ml of suspension (made by repeated passage through a 23-gauge needle) containing 1–2x107 cells was precipitated via centrifugation onto a Millipore HA filter (0.45 micron). The filter was folded so that the cells were inside it and then was transplanted under the renal capsule of the recipient mice. The size of the foci produced was determined after 1–1.5 months by counting the number of nucleated hematopoietic cells in them. The ossicle containing BM was removed from the kidney, and the cells were scraped off the bone with a scalpel into medium 199 or α-MEM and prepared as a single cell suspension by passing it repeatedly through a syringe fitted with a 21-gauge needle. In some experiments the cellularity of the foci was determined in the pool of all foci in each group; consequently, the standard error cannot be calculated. In general the error in such experiments was about 20%.
Bone marrow ablation
After anesthesia, a small incision was made over the knee joint, and the medullary cavity of the femur was entered and curetted using a dental root-canal broach. This was followed by the insertion of a 23-gauge needle into the medullary cavity of the curetted femur, which was then irrigated vigorously with 1 ml of medium 199.
Determination of the proliferative activity of stromal precursors in vivo
The S-phase specific cytostatic compound methotrexate (MTX) was injected intraperitoneally in a single dose of 0.25 mg/g. This dose of MTX was lethal and therefore 4 hrs after its injection the bone marrow or ectopic site was transferred into a normal recipient.
Long-term bone marrow culture
The marrow cells or the cells of an ectopic hematopoietic focus were cultivated by the method described by Dexter et al. [8]. The cells were flushed out with 10 ml of complete medium into a 25cm2 flask without converting them to a single-cell suspension. In the case of cultivation of suspended BM cells, 1 femur was suspended by repeated passage through a 21-gauge needle and then seeded onto the 25cm2 flask. When cultivated in a 24-well plate, 2 femurs were explanted per plate, also without conversion into a single-cell suspension. Fisher medium supplemented with L-glutamine, antibiotics (all Flow Labs), 25% serum (2:1, horse: fetal calf sera, Gibco and Flow Labs) and 10-6M hydrocortisone sodium hemisuccinate (Sigma) were used. The culture was kept at 330C and 5% of CO2 with weekly replacement of 50% of the medium.
The “wound” was performed by scraping 1/2of the adherent cell layer (ACL) with the rubber policeman.
Determination of the proliferative activity of stromal precursors in vitro
Hydroxyurea was added to a long-term bone marrow culture (LTBMC) at the concentration of 13mM (1mg/ml) for periods from 2 hr to 7 days. To stop the function of hydroxyurea the ACLs were washed 3 times with 5 ml of medium 199 with 2% of FCS.
Cytokine treatment
Cytokines (recombinant rat SCF (Amgen) and recombinant human G-CSF (Neupogen 48, Amgen)) were dissolved into the 0.9% NaCl solution with 0.1% of BSA and injected once a day under the skin for 6, 10, or 17 days. G-CSF was used at the concentration of 250 mkg/kg, and SCF at 34 mkg/kg. The control group was injected with 0.9% NaCl solution with 0.1% of BSA only. Twenty hours or 1 month after the last injection, BM from the femurs of the control and cytokine-treated mice was implanted under the renal capsule of the syngeneic mice. In order to define the effect of G-CSF on foci formation the mice were implanted with the syngeneic BM 1 day before beginning the G-CSF courses, which lasted 10 or 17 days.
Sera from irradiated mice
Blood was obtained from the femoral vein not earlier than 1 week after the irradiation. After the clot retraction sera were centrifuged (3000 rpm), supernatant was sterilized by filtration through 0.22 µm filters.
Analysis of various organs of irradiated mice for stroma-stimulating activity
Bone marrow, thymus, bones, liver, and spleen of irradiated mice were implanted into intact mice under the skin or renal capsule. Suspended spleen cells were injected intravenously to the mice previously treated with heparin (50 U/mouse). Intact BM was implanted simultaneously under the renal capsule of these mice.
Karyotype analysis
The origin of the hematopoietic cells in the focus was determined according to the presence or absence of Y-chromosomes, using the G-banding technique.
Histology
The kidneys were removed and fixed in Carnoy’s solution, decalcified, embedded in paraffin and cut into series of 5 µm sections. The preparations were stained with Pappenheim, Giemsa, and hematoxylin-eosin stains.
Statistics
The radiosensitivity curves were fitted to the data via linear regression analysis, from which the D0s, standard errors, and extrapolation numbers were calculated. The concentration of MSC in the femur was calculated using Poisson’s distribution. When not otherwise noted, the data were analyzed with Student’s t-test.
Results and Discussion
Methods of in vitro and in vivo mesenchymal stem cells analysis
In the case of bone marrow (BM) implantation under the renal capsule of the syngeneic animal, the hematopoietic cells leave the graft, whereas the stromal precursors form the new hematopoietic stroma, which is then repopulated by host cells [9, 10]. The same processes take place after implantation of an adherent cell layer from 3–4 wk bone marrow cultures. The beginning of vessel formation was evident by 12 h after implantation. The blood supply to the implant was established 24–48 h after implantation. Characteristic connective tissue lacunae form, and clusters of connective tissue cells were seen from day 4–5, as well as strands of fibroblasts and sometimes the beginning of cartilage development, which was replaced by osteogenesis. By day 6 the implant on the side toward the kidney contained many dead cells with pyknotic nuclei, many erythrocytes, and colonies of hemopoietic cells with blasts cells in the center. On the top and sides of the implant cancellous bone formation was observed. Within the foci there were individual osteoblasts in broad cavities with developing bone trabeculae around them. Osteogenesis was very intensive and 1–2 days later large areas of de novo formed bone could be observed. After 11 days, the typical bone marrow structures such as sinusoids, adipocytes, and areas of hemopoietic cells of different lines of differentiation were represented, and by the end of the second week a well-developed ectopic hemopoietic foci was created [11].
Polymorphic hemopoiesis is maintained for many weeks in long-term cultures of adult mouse bone marrow, and all the main categories of hematopoietic cell precursors, hematopoietic stem cells among others, are identified. Such cultures are characterized by the formation of an adherent cell layer (ACL) of a complex composition containing fibroblastoid cells, giant adipocytes, endothelial cells, and macrophages. The ACL acts as the hematopoietic microenvironment necessary for support of proliferation and differentiation of the hematopoietic cells. It is natural, therefore, to assume that the microenvironment is created by the same precursors as in culture and in vivo, i.e., MSCs capable of transferring the hematopoietic environment and creating ectopic hematopoietic foci upon transplantation.
The transplantation of ACLs from 3–4-week-old cultures of syngeneic animals led to the creation of ectopic foci with the size of the foci formed from a fresh bone marrow plug (5–15x106 nucleated cells). Hematopoietic cells of all differentiation lineages were seen in the foci. The relative CFU-S content was the same as that in the bone marrow (11.4±3.4 per 105 cells) and did not differ from that in the foci produced from bone marrow plug [12]. Thus, cultivation in the long-term culture did not affect stromal precursor dramatically.
The importance of intercellular contacts for appropriate MSC function
Importantly, the bone marrow plug (or cells from long-term bone marrow culture) should be implanted under the renal capsule as a whole, while carefully avoiding converting it into a suspension. Implantation of cells as a suspension under the renal capsule means that no ectopic hematopoietic foci form [13] (for example with cells from long-term bone marrow cultures see Table 1).
Table 1. Transfer of hematopoietic microenvironment via cultures of bone marrow either in fragments or in cell suspension
№ of experiment | Method of implantation | Culture age, weeks | Number of cultures implanted | Foci size, x106 cells |
|---|---|---|---|---|
1 | Suspension | 7 | 4 | 0 |
2 | Suspension | 5 | 2 | 0 |
Fragments | 5 | 2 | 9.3 | |
3 | Suspension | 4 | 2 | 0 |
Fragments | 4 | 2 | 8.0 |
Simultaneous i.v. injection of bone marrow cells to donors did not affect the size of the foci formed from either irradiated donors, or donors with previously curetted bone marrow; meaning that mesenchymal stem cell (MSCs) numbers in the femurs were not affected by the injected cells [14].
One of the most important factors providing for the formation of a full-grown hematopoietic microenvironment in vitro is the explantation of the BM as a whole, or in fragments, but not as a suspension [8]. When the BM is seeded as a suspension, cells do not form the complex stromal layer; on the contrary, cells form a thin monolayer with fibroblast colonies. No hematopoiesis is observed in such layers. Therefore the dissociation of bone marrow cells changes their differentiation potential. Stromal progenitors do not fulfill the variety of cellular differentiations leading to the formation of complex structures of a hematopoietic microenvironment in culture. Thus, the intercellular connections are of most importance for the preserving of the MSC’s features.
When explanted in fragments, bone marrow stromal cells, initially occupying a tiny part of the cultivation flask, built hematopoietic stromal structures on the whole flask surface. During this process they do not lose (or constantly renew) essential intercellular contacts. In order to find out whether this ability is present in the cells from a completely formed cell layer a “wound” was inflicted on the 3-week-old ACL. One week later fibroblastoid cells were observed only rarely on the wound site. No complex ACL was formed. Completely different results were obtained when the “wound” was inflicted on a 1-week-old cell layer, it being in the formation process. One week later the wound site was covered with typical for ACL stromal cells so tightly that it was hardly definable. The ACL regenerated not only morphologically but also functionally as was demonstrated by the ectopic foci formation (Table 2).
Table 2. Size of the foci formed by intact 3-week-old or regenerated ACL (ACL was wounded after 1 week of cultivation)
ACL | Number of cultures | Foci size, x106 cells |
|---|---|---|
Intact part | 4 | 3.8 |
Regenerated part | 4 | 1.2 |
Thus, the intercellular contacts are of highest importance for the stromal progenitors’ differentiation during the processes of building the hematopoietic microenvironment. Stromal progenitor cells are able to keep the intercellular contacts while forming the microenvironment in vitro, and lose this ability when the functional adherent cell layer is formed [13].
The origin of stromal and hematopoietic cells in chimeras and the ectopic foci
Discriminant analysis showed that only MSCs of recipient origin are present in chimera bone marrow 6 and 12 months after irradiation and injection of hematopoietic cells (3–5x106) (Table 3).
Table 3. Discriminant analysis of hemopoietic stromal progenitor origin in B6-in-CBF chimeras
Time after irradiation, months | Number of chimeras tested | Recipient of implanted chimeric bone marrow | Foci formed/number of implants |
|---|---|---|---|
6 | 3 | B6 | 0/2 |
CBF | 4/4 | ||
12 | 18 | B6 | 0/16 |
CBF | 20/20 |
Chimera marrow implanted to non-irradiated mice of the donor strain (B6) was always rejected, and the hematopoietic microenvironment could only be transferred to the recipient strain (CBF) [14]. This means, firstly, that stromal cells in the ectopic hematopoietic foci are of BM donor origin, and secondly, that BM stromal cells injected intravenously for the reconstitution of hematopoiesis after irradiation did not engraft bone marrow stroma of chimeras.
The hematopoietic cells in the ectopic foci were only of recipient origin, as was shown after implantation of adherent cells from B6 female bone marrow cultures under the renal capsule of B6 males (Table 4). The origin of hematopoietic cells in the focus was determined according to the presence or absence of a Y-chromosome [11].
Table 4. The origin of hematopoietic cells in ectopic hemopoietic foci produced by adherent cell layer from long-term bone marrow culture
Donor | Recipient | Cells per focus, x106 | Donor/recipient metaphases | Foci formed/number of implants |
|---|---|---|---|---|
B6 female | B6 male | 24.4 | 0/100 | 2/2 |
B6 female | B6 male | 15.7 | 0/45 | 1/2 |
B6 female | B6 male | 10.4 | 0/40 | 1/2 |
B6 female | B6 male | 13.5 | 0/60 | 1/2 |
B6 female | B6 male | 5.8 | 0/7 | 1/2 |
The results show that stromal progenitors capable of hematopoietic microenvironment transfer cannot be transplanted i.v., and do not take part in MSC regeneration after irradiation. On implantation of BM of intact mice or adherent cell layer from bone marrow cultures under the renal capsule, ectopic hematopoietic foci form, in which the hematopoietic cells belong to the recipient while the stroma is of donor origin.
In order to investigate the origin of stromal cells in ACL, LTBMCs had been established from B6-in-CBF1chimeras, and when stable ACLs had been formed they were carefully scraped as a whole and implanted under the renal capsule in both B6 and CBF1 recipients. This discriminant analysis showed that ACL implantation produced ectopic foci only in the recipient line (CBF1) (Table 5).
Table 5. Discriminant analysis of hematopoietic stromal progenitors originating in adherent cell layer (ACL) of long-term bone marrow cultures of B6-in-CBF1 chimeras
Time after irradiation, months | Number of chimeras tested | Recipient of implanted ACL | Foci formed/number of implants |
|---|---|---|---|
12 | 4 | B6 | 0/4 |
CBF1 | 4/4 |
Thus, MSCs in the ACLs from long-term bone marrow cultures of chimeras are only of recipient origin [14].
Linear interdependency between the foci size and amount of MSCs implanted
Various amounts of medullary tissue ranging from 1/4 to 4 femoral bone marrow plugs were transplanted and the hematopoietic cells were counted in the foci formed 1 month later. The results are shown in Table 6, where it can be seen that despite the small number of implants (3–7), the number of nucleated cells on the whole showed a linear relation with the size of the implanted bone marrow fragment. The correlation coefficient (r) was 0.97±0.014 and the extrapolation number 4.68x10-5 [5].
Table 6. The influence of ectopic marrow implant size on hematopoietic cell number in the foci formed
Experiment № | Size of implant (femoral marrow plug equivalent) | Number of implants | Hematopoietic cells/focus (x106) |
|---|---|---|---|
1 | ¼ | 5 | 2.5 |
1 | 5 | 4.7 | |
2 | ¼ | 5 | 2.6 |
½ | 7 | 3.4 | |
1 | 6 | 10.0 | |
3 | ¼ | 3 | 3.8 |
1 | 4 | 8.1 | |
4 | 1 | 5 | 16.5 |
2 | 4 | 30.3 | |
4 | 3 | 68.0 | |
5 | ¼ | 3 | 68.0 |
½ | 10 | 7.9 | |
1 | 9 | 9.8 |
In summary, stromal cells implanted under the renal capsule of syngeneic animal form a hematopoietic microenvironment only if MSCs are preserved among them, and the size of these hematopoietic foci depends solely on the number of MSC among implanted stromal cells. These results allow MSC to be studied on this model.
The size of ectopic foci is proportional to the amount of ACL implanted. ACL taken from the half of the flask bottom produces a focus that is approximately half that formed by ACL collected from the whole surface of the culture flask: 35.6x106 and 58.1x106 nucleated cells, respectively (correlation coefficient is 0.996±0.005) [12].
When transplanted under the renal capsule of a syngeneic recipient, ACL of cultures of a single femur creates a focus approximately the size of a focus formed in implantation of bone marrow freshly isolated from a single femur. This coincidence suggests that the content of stroma precursors in the culture corresponds to the explanted bone marrow dose but not to other factors, for instance, the surface of the flask bottom. In view of this, the size of foci produced by ACL from 4–6-week-old cultures of 1/2, 1 and 2 femurs was studied (Table 7).
Table 7. Correlation between bone marrow dose plated in LTBMC and the size of the ectopic foci formed
Bone marrow plated per flask (femur equivalent) | Foci formed/Number of implants | Ectopic foci size, x106 cells |
|---|---|---|
½ | 5/7 | 1.7 |
1 | 10/13 | 4 |
2 | 9/10 | 8.3 |
The size of the foci was linearly associated with the dose of the implanted bone marrow (correlation coefficient 0.999±0.001) [12].
Kinetics of stromal precursor cell proliferation in vitro and during ectopic foci formation
The time-course of the stromal precursor repopulation during the process of a creating a site of ectopic hematopoiesis was also studied. In the first 6 hrs after implantation the number of transplantable stromal precursors reduced appreciably, reaching the nadir by the end of the first day (about 20% of the number implanted). Thereafter, there was a phase of regeneration and stromal precursors recovered up to the initial level in 3 weeks. The sensitivity of the stromal precursors to the cytostatics is in good agreement with such kinetics. Normally the stromal precursors do not actually show proliferative activity, which is seen from their insensitivity to MTX. Twenty-four hours after implantation their proliferative activity remains low. During the next 24 hrs the precursors are triggered into the cell cycle synchronously. At this time up to two-thirds of the stromal precursors are killed by the cytostatics. High sensitivity to the cytostatics is observed at 3–4 and 9–10 days after implantation, but not 5–6 days after. It is not clear whether these fluctuations are incidental, or if they are related to the movement of the partially synchronized cell population through the cell cycle. Three weeks later, i.e., when the number of stromal precursors had recovered, their proliferative activity decreased to the initial low level, and remained on that level [15].
Stromal precursors also proliferate during the formation of the adherent cell layer in the LTBMC. Considering the fact that hydroxyurea affects precursors from day 2 until day 11, it seems that these cells change their proliferative status slowly, for more than 24 hours. Thus, both the implantation of BM in vivo, leading to the building of a new hematopoietic microenvironment and hematopoietic foci formation, and the explantation of BM in vitro, leading to the building of a hematopoietic microenvironment in the form of an adherent cell layer in LTBMC, are accompanied by identical changes in the proliferative status of stromal precursors. In the first 24 hours after the transfer they remain at mitotic rest, then, during the next 2 days they mobilize into the cell cycle substantially and synchronically. For the next 2 weeks they are highly active in proliferation. Afterwards, despite continuous growth of ectopic foci or ACLs, the stromal precursors do not proliferate. This is reflected in the absence of increase in the number of stromal precursors both in vivo and in vitro after 3 weeks of formation of the microenvironment.
Characteristics of stromal progenitors in vivo and in vitro
De novo formation of a stromal microenvironment after the implantation of MSC under the renal capsule
In bone marrow implantation the hematopoietic cells leave the graft, whereas the stromal precursors form a new hematopoietic stroma, which is then repopulated by host cells. The cellularity of the hematopoietic focus is proportional to the initial implant size, i.e., to the content of the stromal precursors in it. On retransplantation of the intact ectopic site, hemopoietic cells again leave the implant, as they do after the primary implantation of the bone marrow plug. Twenty-four hours after retransplantation no more than about 3% of the CFU-S remain in the focus (Table 8) [15].
Table 8. Cellularity and CFU-S content of an ectopic site of hematopoiesis as a function of time after retransplantation
Time after retransplantation, days | Number of implants | Cellularity of ectopic foci, x106 | CFU-S per ectopic foci |
|---|---|---|---|
Before | 5 | 12.1 | 3842±545 |
1 | 6 | 3.3 | 107±16 |
4 | 6 | 1.8 | 148±18 |
7 | 5 | 4.5 | 641±90 |
10 | 6 | 7.9 | 1501±329 |
The replacement of the hematopoietic cells by the recipient cells in the retransplanted focus was also confirmed karyologically [16]. Hence, it appears that when the formed site of ectopic hematopoiesis is retransplanted, the hematopoietic microenvironment is created de novo.
Self-renewal ability of MSC
The results permitted the study of the capacity of MSCs for repeated formation of ectopic foci. Nine passages failed to produce any reduction in size of the newly formed hematopoietic foci (Table 9).
Table 9. Cellularity of ectopic bone marrow foci on repeated transplantation
Transfer number | Cells in the foci, x106 |
|---|---|
1 | 12.5 |
2 | 17.2 |
3 | 20.6 |
4 | 21.3 |
5 | 22.9 |
6 | 19.8 |
7 | 35.2 |
8 | 24.7 |
9 | 11.5 |
During the serial transfer of the ectopic hematopoietic tissue without ossicles, a complete loss of the ability to form the hematopoietic focus was already apparent at the third passage. In this case no more than half of the stromal precursors remained on the ossicle (when the bone marrow is pressed out of the femur only 10–15% of the stroma precursors remain on the bone), which was verified by separate implantation of the ossicle and hematopoietic tissue from focus [15].
The self-maintenance ability of the stromal precursors was also studied in a model in which the medullary cavity was repeatedly curetted. Four successive curettages were carried out, and in each over 90% of the stromal precursors were washed out of the femur. After each curettage, the complement of stromal precursors recovered over 1–1.5 months up to 50–60% of the initial and after the fourth curettage up to 20%. Subsequent curettages proved impossible because the whole medullary cavity was filled with newly formed bone [15].
The capacity for self-maintenance of stromal precursors from cultures was studied by repeated transfer of ectopic hemopoietic foci created by them in intermediate to final recipients (Table 10).
Table 10. Self-maintenance ability of hematopoietic stromal precursors from long-term bone marrow cultures
Experiment № | Intermediate recipients | Final recipients | ||
|---|---|---|---|---|
Foci/number of implants | Cellularity, x106 | Foci/number of implants | Cellularity, x106 | |
1 | 4/4 | 12.1 | 4/4 | 1.8 |
2 | 3/4 | 2.9 | 3/3 | 0.6 |
The self-maintenance of MSCs from LTBMC proved to be low and the size of the secondary foci was 10–15% of that of foci in the intermediate recipients [11]. Thus, MSCs are maintained in LTBMC and are capable of creating a hematopoietic microenvironment on transplantation. However, self-maintenance of these precursors from LTBMC is essentially diminished.
The data obtained have demonstrated a high ability of self-maintenance of the cells transferring the hematopoietic microenvironment. Twenty-four hours after BM implantation about 10% of the stromal precursors survive. The population of the precursors in the femur is reduced to approximately the same degree after bone marrow curettage. During regeneration the stromal precursors increase to 60–100% of the initial level, hence they must undergo three or four mitoses. This is consistent with the rise in their sensitivity to S-phase specific cytostatics for the first 2 weeks after implantation. Taking into consideration that on the serial transfer of hematopoietic tissue without ossicles or on serial curettage three or four cycles of regeneration are possible, the stromal precursors are able to undergo no less than 10–12 mitoses. This value is rather underestimated since calculating the loss of precursors for differentiation was not taken into account. The high self-maintenance ability, on the one hand, and the ability to form a fully differentiated bone marrow stromal tissue on the other, suggests that the cells transferring the hematopoietic microenvironment are true mesenchymal stem cells.
Radiosensitivity of MSCs
The hematopoietic stroma function of the femoral bone marrow exposed in vitro to 500 to 2700 rad of γ-rays was also studied, using the ectopic foci formation method. Irradiation of bones with 500 rad caused no noticeable damage to the MSCs’ ability to form a hematopoietic microenvironment. Higher doses produced an exponential decrease in MSCs. The D0 estimated from linear regression (regression equation: log survival=-0.000977x+0.7200) of this portion of the curve is 444±5 rad and the extrapolation number (n) is 5.2. The results for in vitro neutron irradiation of bone marrow agreed (regression equation: log survival=-0.002697x+0.1506). A small shoulder was evident followed by an exponential survival having D0 and n of 161±19 rad and 1.4, respectively [5].
The radiosensitivity of MSCs from 5-week-old LTBMC seemed very similar to that of non-cultivated ones (regression equation: log survival=-0.089x+0.3744; D0 was 486±15 rad and n was 2.4) [17].
When high doses of irradiation were used, implantation proved unsuccessful in some cases and no ossicles with hematopoiesis were formed. One may assume that not a single MSC is preserved in such implants. The independent and random character of radiation damage of cells suggests that the existence or nonexistence of MSCs in the implant is governed by Poisson’s distribution. In this case the data on the proportion of transplant failures (P0) allow the mean MSC content in the implant (x) to be calculated using the equation x=- ln P0. The total MSC content in the femoral bone marrow can be found by taking into account the fraction that survived exposure to the given dose. These data are shown in Table 11 [5] where it is seen that the results were quite consistent on the whole.
Table 11. The effect of g irradiation on the hematopoietic microenvironment transferring MSCs in murine femoral bone marrow
Irradiation dose, rad | Implant failure/total number of implants | MSC/implant (- ln P0) | Survival fraction | MSC per femur |
|---|---|---|---|---|
2100 | 6/22 | 1.3 | 0.033 | 39.9 |
2200 | 12/20 | 0.511 | 0.025 | 20.3 |
2200 | 9/21 | 0.847 | 0.013 | 65.4 |
2500 | 7/19 | 0.999 | 0.012 | 86.3 |
2700 | 17/20 | 0.163 | 0.007 | 23.3 |
2700 | 15/19 | 0.236 | 0.003 | 78.7 |
The mean number of MSCs calculated from the proportion of transplant failures after high doses of irradiation was 52.3±11.6 per femoral bone marrow plug.
The results show that MSCs are much more radioresistant than hematopoietic stem cells, for which D0 is about 100 rad. The second feature of MSCs is their marked capability to recover from sublethal γ-ray damage, which is characterized by a extrapolation number (5.2). In the case of neutron irradiation the extrapolation number is 1.4, which is evidence that MSCs are incapable of recovery from sublethal neutron-induced damage [5].
Despite their high radioresistance MSCs were still sensitive to irradiation. After lethal irradiation and syngeneic bone marrow transplantation of CBF1 mice, the MSCs were reduced to 1/5 of the initial level and slowly regenerated to subnormal level in 6 months. The number of bone marrow cells used for reconstitution of the primary recipient did not affect MSC regeneration (Table 12) [14].
Table 12. Hematopoietic stromal precursors in lethally irradiated CBF1 mice reconstituted with different doses of syngeneic bone marrow cells
Chimera’s characteristics | Ectopic hemopoietic foci produced by femoral marrow plug implantation from reconstituted mice | |||
|---|---|---|---|---|
Cell injected | Time after reconstitution, months | Foci formed/number of implants | Foci cellularity, x106 | Ossicle weight, mg |
2x105 | 2 | 8/8 | 4.0 | 1.4 |
7.4x107 | 2 | 8/8 | 4.8 | 1.4 |
2x105 | 6 | 8/8 | 5.5 | 2.0 |
7.4x107 | 6 | 8/8 | 5.4 | 2.1 |
control | -- | 12/12 | 10.7 | 1.6 |
Two to six months after irradiation, the content of stromal progenitors in the mouse femur was, judging from the cellularity of the foci produced by them, 40–50% of the initial level in both groups of mice reconstituted both in minimal protective dose of marrow cells (2x105) and with a hundredfold dose. Thus, MSCs could be affected by high doses of irradiation and in such cases they are not able to regenerate completely.
Influence of the quality of hematopoiesis on MSCs’ proliferative potential
MSCs were compared in chimeras and double chimeras. Hematopoietic foci formed in standard recipients via BM from chimeras were approximately 2 times smaller when compared with foci formed from BM of non-irradiated mice, and 2 times bigger compared to foci formed from BM from double chimeras. These data confirm that stromal precursors are radiosensitive and unable to recover from radiation damage completely. Interestingly, secondary and tertiary chimeras’ BM formed the same small ectopic foci as double chimeras did, while the dose of irradiation affected the stroma of secondary and tertiary chimeras was 2 times lower than of double chimeras [18]. When BM from all types of chimeras tested were explanted in LTBMC, and after 3–4 weeks of cultivation were implanted under the renal capsule of syngeneic mice, foci formed from ACLs from chimeras’ BM were 75%, foci formed from ACLs from double chimeras’ BM were 20%, and ACLs from secondary and tertiary chimeras were approximately 40% by size from ACLs from non-irradiated mice. The secondary and tertiary chimeras’ stromal precursors were irradiated only once while hematopoietic cells had undergone 2 or 3 rounds of intensive proliferation during reconstitution of hematopoiesis. Thus, judging by the grade of irradiation damage, stromal cells from secondary and tertiary chimeras were similar to ordinary chimeras. Nevertheless, secondary and tertiary chimeras’ stromal precursors turned out to be affected more deeply than the same cells in ordinary chimeras. The data indicates that the stroma’s damage was determined not only by the irradiation dosage but by the quality of hematopoietic cells proliferating on it [18].
Hierarchical organization of the MSC compartment: existence of more mature than MSC-inducible precursor cells
In BM implantation, the ectopic hemopoietic focus is larger in an irradiated recipient than in a non-irradiated one in a dose-dependent manner (Table 13) [19].
Table 13. The size of the ectopic foci in irradiated recipients
Dose of irradiation | Foci size, % of control |
|---|---|
0 | 100 ± 18.8 |
1.5-2.5 | 156 ± 20 |
4.0-6.0 | 200 ± 37.5 |
7.0-8.0 | 210 ± 31.2 |
10.0-13.0 | 290 ± 68.7 |
In subsequent passages the size of the focus did not increase further (Table 14, compare with Table 9).
Table 14. Cellularity of ectopic bone marrow foci on repeated transplantation into irradiated recipients
Transfer number | Cells in the foci, x106 |
|---|---|
1 | 15.9 |
2 | 18.1 |
3 | 31.0 |
4 | 18.2 |
5 | 38.4 |
6 | 28.4 |
7 | 35.2 |
8 | 20.1 |
Hence, one may conclude that in the irradiated recipient the number of stromal precursors in an ectopic focus does not correspond to the large size of the focus. This was demonstrated more directly by implantation of similar bone marrow fragments into non-irradiated and irradiated (chimeric) recipients, subsequently testing the content of the stromal precursors in the sites formed by their retransplantation to non-irradiated recipients. In these experiments the primary focus formed in chimeras exceeded that in the non-irradiated ones by a factor of 2.2 (27.3x106 and 12.5x106). The content of the stromal precursors in both was essentially the same since the cellularities of the foci formed on transfer to the non-irradiated recipients were 10.93x106 and 11.83x106, respectively [15]. Stromal precursors from a culture also react to stimulation from the irradiated recipient, the response being much stronger than in implantation of freshly isolated bone marrow: the foci were 5–7 times larger in the irradiated recipients than in the non-irradiated ones (35.1±8x106 versus 5.3±1.2x106) (Table 15) [11].
Table 15. Size of ectopic foci produced by adherent cell layer from LTBMC in non-irradiated and irradiated recipients
Experiment № | Culture age, weeks | Non-irradiated recipients | Irradiated recipients | ||
|---|---|---|---|---|---|
| Foci formed/number of implants | Cellularity, x106 | Cellularity, x106 | Cellularity, x106 | |
1 | 2 | 2/2 | 0.7 | 2/2 | 22.5 |
2 | 4 | 0/2 | -- | 2/2 | 30.5 |
3 | 4 | 2/2 | 8.0 | 1/2 | 7.6 |
4 | 4 | 2/2 | 5.7 | 2/2 | 35.5 |
5 | 5 | 2/2 | 9.3 | 2/2 | 55.0 |
6 | 6 | 6/6 | 2.9 | 2/2 | 105.0 |
7 | 9 | 4/4 | 4.8 | 4/4 | 12.5 |
Similar results were obtained when LTBMC were established from different amounts of bone marrow (1/2, 1, 2 femurs). All cultures proved to be alike in hematopoiesis maintenance, though the MSC content in them corresponded to the dose of plated bone marrow (see Table 7). At the same time, in irradiated recipients all cultures produced foci approximately the same size (37.1, 42.7 and 38.3x106 correspondingly) [12].
The effect of hydroxyurea was estimated by the size of ectopic foci formed from treated ACLs in irradiated and non-irradiated recipients [20]. The results were similar in both types of recipients. So one may conclude that during the ACL formation both types of stromal precursors actively proliferate. MSCs functioning during the transfer into non-irradiated recipients and the more mature precursors taking part in the foci formation in the irradiated recipients.
The data suggest that the compartment of the hemopoietic stromal precursors is heterogenic and includes cells of at least two differentiation levels. Those less differentiated, MSCs able to transfer a hematopoietic microenvironment are marked by a relatively high self-maintenance, do not respond to the systemic demand of the irradiated recipient, and create a microenvironment, the size of which is proportional to the number of transferred MSCs. More mature precursors are marked by poor self-maintenance; they respond to the systemic demand of the irradiated recipient and, in the culture, to the surface of the flask bottom, and are not transplantable via in vivo transfer.
Summarizing the data presented above, the compartment of stromal bone marrow cells has a hierarchical structure. There are true mesenchymal stem cells (MSCs) capable of both self-maintaining and differentiating into all stromal lineages, and more mature inducible stromal precursors, which keep the ability for multipotential differentiations while losing their self-renewing ability. MSCs are mainly in mitotic rest and are not sensitive to the systemic demand, while more mature precursors proliferate more easily in the case of systemic requirements.
More mature inducible stromal precursors are sensitive to the unknown factor(s) released after irradiation. When injected during foci formation sera from irradiated mice also stimulate these precursors, resulting in increased size of the foci formed – the size of the foci was 19.5±1. 8x106 compared with 14±1.5x106 in control mice [19]. Addition of sera from irradiated mice to the LTBMC also increases the number of stromal cells in the ACLs (Table 16) [21].
Table 16. Influence of the sera from irradiated mice on the number of cells in the ACLs from LTMBC
Group | Cell number per well, х 103 |
|---|---|
control (no additional serum) | 118 ± 4 |
2% of sera from non-irradiated mice | 131 ± 7 |
0.5% of sera from irradiated mice | 160 ± 4 |
1 % of sera from irradiated mice | 185 ± 5 |
2 % of sera from irradiated mice | 206 ± 5 |
In order to define the organ producing the unknown factor(s), various organs of irradiated mice were co-transplanted simultaneously with the implantation of the BM plug under the renal capsule. Intravenous injection of irradiated sera as well as implantation of 5–6 irradiated bones under the skin enhanced the growth of stromal cells in the foci formed (Table 17) [21].
Table 17. Analysis of the various organs of irradiated mice for their stroma-stimulating activity
Recipients | The organ from irradiated mice, transplantation site | Foci size, х 106 |
|---|---|---|
intact (non-irradiated) | 9.0 ± 1.7 | |
irradiated | 21.1 ± 6.2 | |
intact | BM from 6 femurs, under the skin | 8.6 ± 2.3 |
intact | 5–6 femurs, under the skin | 22.0 ± 4.1 |
intact | Thymus, under the renal capsule | 14.8 ± 3.4 |
intact | Equivalent of ½ of the spleen, intravenously | 10.5 ± 1.2 |
intact | 1/3 of the spleen, under the renal capsule | 11.8 ± 3.3 |
intact | the spleen, under the skin | 13.1 ± 2.8 |
intact | 1/3 of the liver, under the skin | 14.8 ± 3.2 |
intact | Sera from irradiated mice, intravenously | 20.1 ± 1.5 |
intact | Sera from non-irradiated mice, intravenously | 14.0 ± 2.8 |
Thus, the unknown factor(s) stimulating the growth of stromal inducible precursor cells are produced in the irradiated bones and secreted into the blood serum.
The regulation of MSCs in vivo by hematopoietic growth factors
Regulation of MSCs by soluble factors remains obscure. During the formation of the hematopoietic microenvironment MSCs are affected by G-CSF. When recipients of BM were injected over 10 or 17 days beginning from the day after implantation of BM under the renal capsule it dramatically decreased size of the foci formed (Table 18).
Table 18. Influence of G-CSF on the ectopic foci formation from the bone marrow of intact mice
G-CSF treatment | Bone marrow implantation | Foci retransplantation | ||||
|---|---|---|---|---|---|---|
Implant number | Cellularity, x106 | Ossicle weight, mg | Implant number | Cellularity, x106 | Ossicle weight, mg | |
Control | 4 | 8.3±1.7 | 2.2±0.4 | 4 | 16.2±3.3 | 2.3±0.5 |
10 days | 4 | 5.3±0.7 | 2.7±0.7 | 4 | 9.0±1.8 | 1.9±0.5 |
17 days | 6 | 3.4±0.6 | 2.0±0.4 | 6 | 1.7±0.3 | 1.3±0.4 |
Obviously, when administered during the active proliferation and differentiation of MSC, G-SCF inhibits their proliferation (judging from the decreased size of the foci formed); moreover, it diminishes the number of MSCs themselves as was shown by retransplantation of the foci [22].
Conversely, cytokine treatment of the MSCs in their steady-state (in the intact bone marrow increases the number of these stromal precursors (Table 19).
Table 19. Size of the ectopic foci formed from the bone marrow of mice treated with cytocines
Group | Bone marrow implantation | Foci retransplantation | ||||
|---|---|---|---|---|---|---|
Implant number | Cellularity, x106 | Ossicle weight, mg | Implant number | Cellularity, x106 | Ossicle weight, mg | |
Control | 9 | 6.5±1.0 | 2.0±0.2 | 4 | 5.9±1.2 | 2.6±0.4 |
G-CSF, 6 days | 4 | 7.4±2.2 | 1.1±0.2 | |||
G-CSF, 10 days | 3 | 10.7±2.0 | 1.0±0.2 | 3 | 11.3±2.9 | 3.0±0.6 |
G-CSF, 17 days | 4 | 9.2±1.0 | 3.3±0.7 | 3 | 13.3±2.8 | 3.5±0.7 |
G-CSF+SCF, 6 days | 4 | 6.4±1.6 | 2.2±0.5 | |||
G-CSF+SCF, 10 days | 4 | 12.8±1.5 | 2.4±0.6 | |||
G-CSF+SCF, 17 days | 4 | 18.4±3.9 | 1.7±0.5 | 5 | 19.5±4.2 | 3.2±0.6 |
The combination of G-CSF with SCF and the longest treatment (for 17 days) had a maximal effect on the MSC number in the bone marrow of treated mice. In the case of G-CSF treatment this effect was transient and did not last for a month, in the case of cytokine combination, however, the increase in the number of MSCs was stable for at least a month. Cytokine treatment did not affect the osteogenic potential of MSCs either during stroma formation or in the intact bone marrow [22].
Thus, during the building of ectopic hematopoietic foci when stromal precursors are proliferating and differentiating, pharmacological concentrations of G-CSF inhibit the process of foci formation and diminish the number of stromal precursors in them. When affecting the mature non-proliferating bone marrow stroma, cytokines increase the number of MSCs.
Conclusions
Summarizing the works of J. L. Chertkov, it is possible to describe the main features of MSCs. These cells are capable of transferring a hematopoietic microenvironment due to both their high proliferative potential and their ability to differentiate into all bone marrow stromal lineages, including bone, cartilage, and marrow stromal cells. MSCs are more radioresistant than HSCs but they still suffer from radiation and their damage could not be fully recovered. Impaired hematopoiesis also influences the MSCs. The compartment of MSCs and stromal precursor cells is organized hierarchically. Therefore, J. L. Chertkov described the main features of MSCs from many sides using the functional assay.
Acknowledgements
Irina Shipounova and Nina Drize for preparing the compilation of Chertkov’s works on hematopoietic stromal microenvironment.
Gurevich O. A., Udalov G. A., Samoylina N. L., Samoylova R. S., Lemeneva N. L., Todria T. V., Olovnikova N. I., Olshanskaya Y. V., Shiponova (Nifontova) I. N., Ershler M. A. and Drize N. I. as co-authors of his works.
References
3. Olovnikova NI, Drize NJ, Ershler MA, Nifontova IN, Belkina EV, Nikolaeva TN, Proskurina NV, Chertkov JL. Developmental fate of hematopoietic stem cells: the study of individual hematopoietic clones at the level of antigen-responsive B lymphocytes. Hematol J. 2003;4(2):146-150.
4. Drize NJ, Olshanskaya YV, Gerasimova LP, Manakova TE, Samoylina NL, Todria TV, Chertkov JL. Lifelong hematopoiesis in both reconstituted and sublethally irradiated mice is provided by multiple sequentially recruited stem cells. Exp Hematol. 2001;29(6):786-794.
5. Chertkov JL, Gurevitch OA. Radiosensitivity of progenitor cells of the hematopoietic microenvironment. Radiat Res. 1979;79(1):177-186.
6. Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991;9(5):641-650.
7. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy. 2005;7(5):393-395.
8. Dexter TM, Allen TD, Lajtha LG. Conditions controlling the proliferation of haemopoietic stem cells in vitro. J Cell Physiol. 1977;91(3):335-344.
9. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230-247.
10. Udalov GA, Gurevich OA, Chertkov IL. Origin of hematopoietic cells in a syngenous and semisyngenous focus of heterotopic hematopoiesis. Biull Eksp Biol Med. 1977;83(5):584-586.
11. Chertkov JL, Drize NJ, Gurevitch OA, Udalov GA. Hemopoietic stromal precursors in long-term culture of bone marrow: I. Precursor characteristics, kinetics in culture, and dependence on quality of donor hemopoietic cells in chimeras. Exp Hematol. 1983;11(3):231-242.
12. Chertkov JL, Drize NJ, Gurevich OA. Hemopoietic microenvironment and hemopoietic stroma precursors. Recent advances in haematology immunology and blood transfusion : proceedings of the plenary sessions of the joint meeting of the 19th Congress of the International Society of Haematology and the 17th Congress of the International Society of Blood Transfusion, Budapest, August 1-7, 1982, Eds. Susan R. Hollán; International Society of Haematology, 12,1983;133-147.
13. Gurevich OA, Drize NI, Chertkov IL. Importance of cell contacts for the differentiation of the precursor cells of hematopoietic stroma in long-term bone marrow cultures. Biull Eksp Biol Med. 1982;94(8):97-100.
14. Chertkov JL, Drize NJ, Gurevitch OA, Samoylova RS. Origin of hemopoietic stromal progenitor cells in chimeras. Exp Hematol. 1985;13(11):1217-1222.
15. Chertkov JL, Gurevitch OA. Self-maintenance ability and kinetics of haemopoietic stroma precursors. Cell Tissue Kinet. 1980;13(5):535-541.
16. Chertkov JL, Gurevich OA, Udalov GA. Role of bone marrow stroma in the phenomenon of hybrid resistance. Biull Eksp Biol Med 1979 Apr; 87(4):337-40.
17. Gurevich OA, Chertkov JL. Radiosensitivity of hemopoietic stroma precursors from long-term bone marrow culture. Radiobiology. 1983;23(4):521-523.
18. Gurevich OA, Drize NI, Udalov GA, Chertkov IL. Effect of hematopoiesis on progenitor bone marrow stromal cells. Biull Eksp Biol Med. 1982;94(10):115-117.
19. Chertkov JL, Gurevitch OA. Hematopoietic stem cell and its microenvironment. Moscow, Meditzina 1984. Russian.
20. Gurevich OA, Drize NJ, Chertkov JL. Proliferation of cells-precursors of hematopoietic microenvironment in murine long-term bone marrow culture. Bull Exp Biol Med. 1984;XCVIII(11):612-614.
21. Drize NI, Ershler MA, Chertkov IL. Radiation-induced hemopoietic cell growth factor: detection in a culture. Bull Exp Biol Med. 2001;132(6):1213-1215.
22. Drize NJ, Chertkov JL. Influence of cytokine (G-CSF and SCF) treatment on the murine precursors of hematopoietic stroma. Bull Exp Biol Med. 1998;125(2):204-206.
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Introduction
Prof. J. L. Chertkov (1927–2009) devoted most of his efforts to understanding the mechanisms of hematopoiesis. He was interested in the developmental fate of hematopoietic stem cells (HSC), and the result of his investigations became the theory of clonal succession of HSC, which was published in several papers [1-4]. The data showed that long-term hematopoiesis is maintained by a large number of simultaneously functioning small, short-lived (1 to 3 months) clones that usually grow locally with little or no dispersion between different regions of the hematopoietic system. Only 10% of clones are long-lived and can function during the whole life of the animal. Furthermore, clones that disappear are never detected again. The data suggests that normal hematopoiesis is supported by the sequential recruitment of marrow repopulating cells into a differentiation mode.
In the mid 1970s, together with A. J. Friedenstein, Joseph Chertkov laid the foundation for experimentation into the differences between HSC and precursor cells in the hematopoietic microenvironment. He postulated that an understanding of the interrelationship between the stem cells of hematopoiesis and regulatory stromal microenvironment is necessary for an investigation of the process of hematopoiesis. To analyze the stromal precursor cells J. L. Chertkov used a functional assay where the microenvironment is addressed as the territory where hematopoiesis takes place and therefore could be estimated by the number of hematopoietic cells maintained on it. The method of ectopic hematopoietic foci formation provides a separate hematopoietic territory built de novo via special stromal precursor cells. Cells capable of transferring the hematopoietic microenvironment were referred to by Chertkov as hematopoietic microenvironment-transferring units (HMTU) [5].
In 1991 A. Caplan defined stem cells capable of giving rise to skeletal tissues – cartilage, bone, tendon, ligament, marrow stroma, and connective tissue – as mesenchymal stem cells (MSC) [6]. The term MSC was used in the fields of cytotherapy and tissue engineering widely and not always correctly; therefore the International Society of Cellular Therapy postulated the use of the term MSC only for cells that fulfilled the stem cell criteria: multipotentiality and self-renewal [7]. All works of Prof. Chertkov clearly demonstrate that HMTU and MSC are synonyms. Therefore we will use the term MSC for cells described by J. L. Chertkov as HMTU.
The compilation of the works by J. L. Chertkov characterizes MSCs both quantitatively and qualitatively, based on their functional properties. MSCs were shown to have a high proliferative potential, to be able to develop multilineage progeny, and form a fully functional hematopoietic microenvironment. The compartment of stromal precursor cells was shown to have a hierarchical structure, and inducible precursor cells were characterized. The radiosensitivity of MSCs and their progeny was estimated and it was then possible to calculate the direct number of MSC in the murine femur.
Materials and Methods
Mice
Female and male C57BL/6 (B6), CBA, CBAT6T6, (CBAxC57BL/6) F1 hybrid (CB), and (CBAT6T6xC57BL/6) F1 hybrid (CBT) mice 8–25 wks of age at the beginning of the study were used. Care was taken that the groups to be compared originated from the same batch of animals housed under the same conditions.
Irradiation of mice
In some of the experiments the recipient mice were irradiated with 400 or 700 rad from a 137Cs IPK irradiator 3 to 4 hrs before bone marrow (BM) implantation. Both doses produced the same effect on the size of the ectopic foci. The irradiator consisted of four 137Cs sources set in a quadrilateral arrangement about the site of exposure.
In order to obtain blood sera containing stroma-stimulating activity, the mice were irradiated with 6–12 Gy (in the latter case the protective dose of BM cells was injected i.v.).
Bone marrow irradiation
In the case of an in vivo irradiation the mice were irradiated and sacrificed immediately thereafter. The femurs were removed and stored on ice until transplantation. For in vitro irradiation the femurs were exposed either to γ-rays from an IPK irradiator with the absorbed dose rate of 500 rad/min or to fast neutrons generated by the Obninsk BR-10 research reactor. The mean energy of fast neutrons was 0.85MeV, the power of the tissue Kerma 128 rad/min, and the ratio of neutron to γ-ray doses at the point of exposure of the bones was approximately 20:1. The γ-ray component was ignored in calculating the dose-response curves, and all neutron doses represent the rad dose of the neutron component. In all experiments, the period between bone resection and the implantation of the bone marrow did not exceed 5 hrs. The sequence of implantation of femurs exposed to various doses was always randomized.
Chimeras
The mice were exposed to 12–13 Gy and reconstituted with syngeneic or allogeneic BM in doses indicated in the corresponding part of the text. In general, 1/3–1/4 of the femoral equivalent was injected (standard chimeras). Secondary chimeras were obtained when irradiated recipients were reconstituted with hematopoietic cells of standard chimeras; the cells were collected no earlier than 2 months after the creation of the standard chimeras. Tertiary chimeras were obtained when the irradiated recipients were reconstituted with hematopoietic cells of secondary chimeras; the cells were also collected no earlier than 2 months after the creation of the secondary chimeras. Double chimeras were obtained when the standard chimeras were exposed to a dose of 12–13 Gy 2–5 months after creation of the chimera, and reconstituted with hematopoietic cells of normal mice. The stromal precursors were studied 3–9 months after creation of the chimeras.
Bone marrow or adherent cell layer implantation
Implantation was performed under the renal capsule of anesthetized mice. The femurs were freed of muscle, the epiphyses cut away, and the bones stored on ice until used. The BM was pressed out of the femur with a stylet or thick needle with a blunt end. In anesthetized mice a small tear was made in the renal capsule and a bone marrow plug or adherent cell layer (ACL) from long-term bone marrow culture placed under it with a small spatula. The ACL was removed from the flask bottom with a rubber policeman and implanted under the renal capsule without conversion to a single-cell suspension. In cases of ectopic foci reimplantation the whole focus was removed from the kidney and implanted under the renal capsule of the recipient. In cases where suspended BM was implanted, the 0.5 ml of suspension (made by repeated passage through a 23-gauge needle) containing 1–2x107 cells was precipitated via centrifugation onto a Millipore HA filter (0.45 micron). The filter was folded so that the cells were inside it and then was transplanted under the renal capsule of the recipient mice. The size of the foci produced was determined after 1–1.5 months by counting the number of nucleated hematopoietic cells in them. The ossicle containing BM was removed from the kidney, and the cells were scraped off the bone with a scalpel into medium 199 or α-MEM and prepared as a single cell suspension by passing it repeatedly through a syringe fitted with a 21-gauge needle. In some experiments the cellularity of the foci was determined in the pool of all foci in each group; consequently, the standard error cannot be calculated. In general the error in such experiments was about 20%.
Bone marrow ablation
After anesthesia, a small incision was made over the knee joint, and the medullary cavity of the femur was entered and curetted using a dental root-canal broach. This was followed by the insertion of a 23-gauge needle into the medullary cavity of the curetted femur, which was then irrigated vigorously with 1 ml of medium 199.
Determination of the proliferative activity of stromal precursors in vivo
The S-phase specific cytostatic compound methotrexate (MTX) was injected intraperitoneally in a single dose of 0.25 mg/g. This dose of MTX was lethal and therefore 4 hrs after its injection the bone marrow or ectopic site was transferred into a normal recipient.
Long-term bone marrow culture
The marrow cells or the cells of an ectopic hematopoietic focus were cultivated by the method described by Dexter et al. [8]. The cells were flushed out with 10 ml of complete medium into a 25cm2 flask without converting them to a single-cell suspension. In the case of cultivation of suspended BM cells, 1 femur was suspended by repeated passage through a 21-gauge needle and then seeded onto the 25cm2 flask. When cultivated in a 24-well plate, 2 femurs were explanted per plate, also without conversion into a single-cell suspension. Fisher medium supplemented with L-glutamine, antibiotics (all Flow Labs), 25% serum (2:1, horse: fetal calf sera, Gibco and Flow Labs) and 10-6M hydrocortisone sodium hemisuccinate (Sigma) were used. The culture was kept at 330C and 5% of CO2 with weekly replacement of 50% of the medium.
The “wound” was performed by scraping 1/2of the adherent cell layer (ACL) with the rubber policeman.
Determination of the proliferative activity of stromal precursors in vitro
Hydroxyurea was added to a long-term bone marrow culture (LTBMC) at the concentration of 13mM (1mg/ml) for periods from 2 hr to 7 days. To stop the function of hydroxyurea the ACLs were washed 3 times with 5 ml of medium 199 with 2% of FCS.
Cytokine treatment
Cytokines (recombinant rat SCF (Amgen) and recombinant human G-CSF (Neupogen 48, Amgen)) were dissolved into the 0.9% NaCl solution with 0.1% of BSA and injected once a day under the skin for 6, 10, or 17 days. G-CSF was used at the concentration of 250 mkg/kg, and SCF at 34 mkg/kg. The control group was injected with 0.9% NaCl solution with 0.1% of BSA only. Twenty hours or 1 month after the last injection, BM from the femurs of the control and cytokine-treated mice was implanted under the renal capsule of the syngeneic mice. In order to define the effect of G-CSF on foci formation the mice were implanted with the syngeneic BM 1 day before beginning the G-CSF courses, which lasted 10 or 17 days.
Sera from irradiated mice
Blood was obtained from the femoral vein not earlier than 1 week after the irradiation. After the clot retraction sera were centrifuged (3000 rpm), supernatant was sterilized by filtration through 0.22 µm filters.
Analysis of various organs of irradiated mice for stroma-stimulating activity
Bone marrow, thymus, bones, liver, and spleen of irradiated mice were implanted into intact mice under the skin or renal capsule. Suspended spleen cells were injected intravenously to the mice previously treated with heparin (50 U/mouse). Intact BM was implanted simultaneously under the renal capsule of these mice.
Karyotype analysis
The origin of the hematopoietic cells in the focus was determined according to the presence or absence of Y-chromosomes, using the G-banding technique.
Histology
The kidneys were removed and fixed in Carnoy’s solution, decalcified, embedded in paraffin and cut into series of 5 µm sections. The preparations were stained with Pappenheim, Giemsa, and hematoxylin-eosin stains.
Statistics
The radiosensitivity curves were fitted to the data via linear regression analysis, from which the D0s, standard errors, and extrapolation numbers were calculated. The concentration of MSC in the femur was calculated using Poisson’s distribution. When not otherwise noted, the data were analyzed with Student’s t-test.
Results and Discussion
Methods of in vitro and in vivo mesenchymal stem cells analysis
In the case of bone marrow (BM) implantation under the renal capsule of the syngeneic animal, the hematopoietic cells leave the graft, whereas the stromal precursors form the new hematopoietic stroma, which is then repopulated by host cells [9, 10]. The same processes take place after implantation of an adherent cell layer from 3–4 wk bone marrow cultures. The beginning of vessel formation was evident by 12 h after implantation. The blood supply to the implant was established 24–48 h after implantation. Characteristic connective tissue lacunae form, and clusters of connective tissue cells were seen from day 4–5, as well as strands of fibroblasts and sometimes the beginning of cartilage development, which was replaced by osteogenesis. By day 6 the implant on the side toward the kidney contained many dead cells with pyknotic nuclei, many erythrocytes, and colonies of hemopoietic cells with blasts cells in the center. On the top and sides of the implant cancellous bone formation was observed. Within the foci there were individual osteoblasts in broad cavities with developing bone trabeculae around them. Osteogenesis was very intensive and 1–2 days later large areas of de novo formed bone could be observed. After 11 days, the typical bone marrow structures such as sinusoids, adipocytes, and areas of hemopoietic cells of different lines of differentiation were represented, and by the end of the second week a well-developed ectopic hemopoietic foci was created [11].
Polymorphic hemopoiesis is maintained for many weeks in long-term cultures of adult mouse bone marrow, and all the main categories of hematopoietic cell precursors, hematopoietic stem cells among others, are identified. Such cultures are characterized by the formation of an adherent cell layer (ACL) of a complex composition containing fibroblastoid cells, giant adipocytes, endothelial cells, and macrophages. The ACL acts as the hematopoietic microenvironment necessary for support of proliferation and differentiation of the hematopoietic cells. It is natural, therefore, to assume that the microenvironment is created by the same precursors as in culture and in vivo, i.e., MSCs capable of transferring the hematopoietic environment and creating ectopic hematopoietic foci upon transplantation.
The transplantation of ACLs from 3–4-week-old cultures of syngeneic animals led to the creation of ectopic foci with the size of the foci formed from a fresh bone marrow plug (5–15x106 nucleated cells). Hematopoietic cells of all differentiation lineages were seen in the foci. The relative CFU-S content was the same as that in the bone marrow (11.4±3.4 per 105 cells) and did not differ from that in the foci produced from bone marrow plug [12]. Thus, cultivation in the long-term culture did not affect stromal precursor dramatically.
The importance of intercellular contacts for appropriate MSC function
Importantly, the bone marrow plug (or cells from long-term bone marrow culture) should be implanted under the renal capsule as a whole, while carefully avoiding converting it into a suspension. Implantation of cells as a suspension under the renal capsule means that no ectopic hematopoietic foci form [13] (for example with cells from long-term bone marrow cultures see Table 1).
Table 1. Transfer of hematopoietic microenvironment via cultures of bone marrow either in fragments or in cell suspension
№ of experiment | Method of implantation | Culture age, weeks | Number of cultures implanted | Foci size, x106 cells |
|---|---|---|---|---|
1 | Suspension | 7 | 4 | 0 |
2 | Suspension | 5 | 2 | 0 |
Fragments | 5 | 2 | 9.3 | |
3 | Suspension | 4 | 2 | 0 |
Fragments | 4 | 2 | 8.0 |
Simultaneous i.v. injection of bone marrow cells to donors did not affect the size of the foci formed from either irradiated donors, or donors with previously curetted bone marrow; meaning that mesenchymal stem cell (MSCs) numbers in the femurs were not affected by the injected cells [14].
One of the most important factors providing for the formation of a full-grown hematopoietic microenvironment in vitro is the explantation of the BM as a whole, or in fragments, but not as a suspension [8]. When the BM is seeded as a suspension, cells do not form the complex stromal layer; on the contrary, cells form a thin monolayer with fibroblast colonies. No hematopoiesis is observed in such layers. Therefore the dissociation of bone marrow cells changes their differentiation potential. Stromal progenitors do not fulfill the variety of cellular differentiations leading to the formation of complex structures of a hematopoietic microenvironment in culture. Thus, the intercellular connections are of most importance for the preserving of the MSC’s features.
When explanted in fragments, bone marrow stromal cells, initially occupying a tiny part of the cultivation flask, built hematopoietic stromal structures on the whole flask surface. During this process they do not lose (or constantly renew) essential intercellular contacts. In order to find out whether this ability is present in the cells from a completely formed cell layer a “wound” was inflicted on the 3-week-old ACL. One week later fibroblastoid cells were observed only rarely on the wound site. No complex ACL was formed. Completely different results were obtained when the “wound” was inflicted on a 1-week-old cell layer, it being in the formation process. One week later the wound site was covered with typical for ACL stromal cells so tightly that it was hardly definable. The ACL regenerated not only morphologically but also functionally as was demonstrated by the ectopic foci formation (Table 2).
Table 2. Size of the foci formed by intact 3-week-old or regenerated ACL (ACL was wounded after 1 week of cultivation)
ACL | Number of cultures | Foci size, x106 cells |
|---|---|---|
Intact part | 4 | 3.8 |
Regenerated part | 4 | 1.2 |
Thus, the intercellular contacts are of highest importance for the stromal progenitors’ differentiation during the processes of building the hematopoietic microenvironment. Stromal progenitor cells are able to keep the intercellular contacts while forming the microenvironment in vitro, and lose this ability when the functional adherent cell layer is formed [13].
The origin of stromal and hematopoietic cells in chimeras and the ectopic foci
Discriminant analysis showed that only MSCs of recipient origin are present in chimera bone marrow 6 and 12 months after irradiation and injection of hematopoietic cells (3–5x106) (Table 3).
Table 3. Discriminant analysis of hemopoietic stromal progenitor origin in B6-in-CBF chimeras
Time after irradiation, months | Number of chimeras tested | Recipient of implanted chimeric bone marrow | Foci formed/number of implants |
|---|---|---|---|
6 | 3 | B6 | 0/2 |
CBF | 4/4 | ||
12 | 18 | B6 | 0/16 |
CBF | 20/20 |
Chimera marrow implanted to non-irradiated mice of the donor strain (B6) was always rejected, and the hematopoietic microenvironment could only be transferred to the recipient strain (CBF) [14]. This means, firstly, that stromal cells in the ectopic hematopoietic foci are of BM donor origin, and secondly, that BM stromal cells injected intravenously for the reconstitution of hematopoiesis after irradiation did not engraft bone marrow stroma of chimeras.
The hematopoietic cells in the ectopic foci were only of recipient origin, as was shown after implantation of adherent cells from B6 female bone marrow cultures under the renal capsule of B6 males (Table 4). The origin of hematopoietic cells in the focus was determined according to the presence or absence of a Y-chromosome [11].
Table 4. The origin of hematopoietic cells in ectopic hemopoietic foci produced by adherent cell layer from long-term bone marrow culture
Donor | Recipient | Cells per focus, x106 | Donor/recipient metaphases | Foci formed/number of implants |
|---|---|---|---|---|
B6 female | B6 male | 24.4 | 0/100 | 2/2 |
B6 female | B6 male | 15.7 | 0/45 | 1/2 |
B6 female | B6 male | 10.4 | 0/40 | 1/2 |
B6 female | B6 male | 13.5 | 0/60 | 1/2 |
B6 female | B6 male | 5.8 | 0/7 | 1/2 |
The results show that stromal progenitors capable of hematopoietic microenvironment transfer cannot be transplanted i.v., and do not take part in MSC regeneration after irradiation. On implantation of BM of intact mice or adherent cell layer from bone marrow cultures under the renal capsule, ectopic hematopoietic foci form, in which the hematopoietic cells belong to the recipient while the stroma is of donor origin.
In order to investigate the origin of stromal cells in ACL, LTBMCs had been established from B6-in-CBF1chimeras, and when stable ACLs had been formed they were carefully scraped as a whole and implanted under the renal capsule in both B6 and CBF1 recipients. This discriminant analysis showed that ACL implantation produced ectopic foci only in the recipient line (CBF1) (Table 5).
Table 5. Discriminant analysis of hematopoietic stromal progenitors originating in adherent cell layer (ACL) of long-term bone marrow cultures of B6-in-CBF1 chimeras
Time after irradiation, months | Number of chimeras tested | Recipient of implanted ACL | Foci formed/number of implants |
|---|---|---|---|
12 | 4 | B6 | 0/4 |
CBF1 | 4/4 |
Thus, MSCs in the ACLs from long-term bone marrow cultures of chimeras are only of recipient origin [14].
Linear interdependency between the foci size and amount of MSCs implanted
Various amounts of medullary tissue ranging from 1/4 to 4 femoral bone marrow plugs were transplanted and the hematopoietic cells were counted in the foci formed 1 month later. The results are shown in Table 6, where it can be seen that despite the small number of implants (3–7), the number of nucleated cells on the whole showed a linear relation with the size of the implanted bone marrow fragment. The correlation coefficient (r) was 0.97±0.014 and the extrapolation number 4.68x10-5 [5].
Table 6. The influence of ectopic marrow implant size on hematopoietic cell number in the foci formed
Experiment № | Size of implant (femoral marrow plug equivalent) | Number of implants | Hematopoietic cells/focus (x106) |
|---|---|---|---|
1 | ¼ | 5 | 2.5 |
1 | 5 | 4.7 | |
2 | ¼ | 5 | 2.6 |
½ | 7 | 3.4 | |
1 | 6 | 10.0 | |
3 | ¼ | 3 | 3.8 |
1 | 4 | 8.1 | |
4 | 1 | 5 | 16.5 |
2 | 4 | 30.3 | |
4 | 3 | 68.0 | |
5 | ¼ | 3 | 68.0 |
½ | 10 | 7.9 | |
1 | 9 | 9.8 |
In summary, stromal cells implanted under the renal capsule of syngeneic animal form a hematopoietic microenvironment only if MSCs are preserved among them, and the size of these hematopoietic foci depends solely on the number of MSC among implanted stromal cells. These results allow MSC to be studied on this model.
The size of ectopic foci is proportional to the amount of ACL implanted. ACL taken from the half of the flask bottom produces a focus that is approximately half that formed by ACL collected from the whole surface of the culture flask: 35.6x106 and 58.1x106 nucleated cells, respectively (correlation coefficient is 0.996±0.005) [12].
When transplanted under the renal capsule of a syngeneic recipient, ACL of cultures of a single femur creates a focus approximately the size of a focus formed in implantation of bone marrow freshly isolated from a single femur. This coincidence suggests that the content of stroma precursors in the culture corresponds to the explanted bone marrow dose but not to other factors, for instance, the surface of the flask bottom. In view of this, the size of foci produced by ACL from 4–6-week-old cultures of 1/2, 1 and 2 femurs was studied (Table 7).
Table 7. Correlation between bone marrow dose plated in LTBMC and the size of the ectopic foci formed
Bone marrow plated per flask (femur equivalent) | Foci formed/Number of implants | Ectopic foci size, x106 cells |
|---|---|---|
½ | 5/7 | 1.7 |
1 | 10/13 | 4 |
2 | 9/10 | 8.3 |
The size of the foci was linearly associated with the dose of the implanted bone marrow (correlation coefficient 0.999±0.001) [12].
Kinetics of stromal precursor cell proliferation in vitro and during ectopic foci formation
The time-course of the stromal precursor repopulation during the process of a creating a site of ectopic hematopoiesis was also studied. In the first 6 hrs after implantation the number of transplantable stromal precursors reduced appreciably, reaching the nadir by the end of the first day (about 20% of the number implanted). Thereafter, there was a phase of regeneration and stromal precursors recovered up to the initial level in 3 weeks. The sensitivity of the stromal precursors to the cytostatics is in good agreement with such kinetics. Normally the stromal precursors do not actually show proliferative activity, which is seen from their insensitivity to MTX. Twenty-four hours after implantation their proliferative activity remains low. During the next 24 hrs the precursors are triggered into the cell cycle synchronously. At this time up to two-thirds of the stromal precursors are killed by the cytostatics. High sensitivity to the cytostatics is observed at 3–4 and 9–10 days after implantation, but not 5–6 days after. It is not clear whether these fluctuations are incidental, or if they are related to the movement of the partially synchronized cell population through the cell cycle. Three weeks later, i.e., when the number of stromal precursors had recovered, their proliferative activity decreased to the initial low level, and remained on that level [15].
Stromal precursors also proliferate during the formation of the adherent cell layer in the LTBMC. Considering the fact that hydroxyurea affects precursors from day 2 until day 11, it seems that these cells change their proliferative status slowly, for more than 24 hours. Thus, both the implantation of BM in vivo, leading to the building of a new hematopoietic microenvironment and hematopoietic foci formation, and the explantation of BM in vitro, leading to the building of a hematopoietic microenvironment in the form of an adherent cell layer in LTBMC, are accompanied by identical changes in the proliferative status of stromal precursors. In the first 24 hours after the transfer they remain at mitotic rest, then, during the next 2 days they mobilize into the cell cycle substantially and synchronically. For the next 2 weeks they are highly active in proliferation. Afterwards, despite continuous growth of ectopic foci or ACLs, the stromal precursors do not proliferate. This is reflected in the absence of increase in the number of stromal precursors both in vivo and in vitro after 3 weeks of formation of the microenvironment.
Characteristics of stromal progenitors in vivo and in vitro
De novo formation of a stromal microenvironment after the implantation of MSC under the renal capsule
In bone marrow implantation the hematopoietic cells leave the graft, whereas the stromal precursors form a new hematopoietic stroma, which is then repopulated by host cells. The cellularity of the hematopoietic focus is proportional to the initial implant size, i.e., to the content of the stromal precursors in it. On retransplantation of the intact ectopic site, hemopoietic cells again leave the implant, as they do after the primary implantation of the bone marrow plug. Twenty-four hours after retransplantation no more than about 3% of the CFU-S remain in the focus (Table 8) [15].
Table 8. Cellularity and CFU-S content of an ectopic site of hematopoiesis as a function of time after retransplantation
Time after retransplantation, days | Number of implants | Cellularity of ectopic foci, x106 | CFU-S per ectopic foci |
|---|---|---|---|
Before | 5 | 12.1 | 3842±545 |
1 | 6 | 3.3 | 107±16 |
4 | 6 | 1.8 | 148±18 |
7 | 5 | 4.5 | 641±90 |
10 | 6 | 7.9 | 1501±329 |
The replacement of the hematopoietic cells by the recipient cells in the retransplanted focus was also confirmed karyologically [16]. Hence, it appears that when the formed site of ectopic hematopoiesis is retransplanted, the hematopoietic microenvironment is created de novo.
Self-renewal ability of MSC
The results permitted the study of the capacity of MSCs for repeated formation of ectopic foci. Nine passages failed to produce any reduction in size of the newly formed hematopoietic foci (Table 9).
Table 9. Cellularity of ectopic bone marrow foci on repeated transplantation
Transfer number | Cells in the foci, x106 |
|---|---|
1 | 12.5 |
2 | 17.2 |
3 | 20.6 |
4 | 21.3 |
5 | 22.9 |
6 | 19.8 |
7 | 35.2 |
8 | 24.7 |
9 | 11.5 |
During the serial transfer of the ectopic hematopoietic tissue without ossicles, a complete loss of the ability to form the hematopoietic focus was already apparent at the third passage. In this case no more than half of the stromal precursors remained on the ossicle (when the bone marrow is pressed out of the femur only 10–15% of the stroma precursors remain on the bone), which was verified by separate implantation of the ossicle and hematopoietic tissue from focus [15].
The self-maintenance ability of the stromal precursors was also studied in a model in which the medullary cavity was repeatedly curetted. Four successive curettages were carried out, and in each over 90% of the stromal precursors were washed out of the femur. After each curettage, the complement of stromal precursors recovered over 1–1.5 months up to 50–60% of the initial and after the fourth curettage up to 20%. Subsequent curettages proved impossible because the whole medullary cavity was filled with newly formed bone [15].
The capacity for self-maintenance of stromal precursors from cultures was studied by repeated transfer of ectopic hemopoietic foci created by them in intermediate to final recipients (Table 10).
Table 10. Self-maintenance ability of hematopoietic stromal precursors from long-term bone marrow cultures
Experiment № | Intermediate recipients | Final recipients | ||
|---|---|---|---|---|
Foci/number of implants | Cellularity, x106 | Foci/number of implants | Cellularity, x106 | |
1 | 4/4 | 12.1 | 4/4 | 1.8 |
2 | 3/4 | 2.9 | 3/3 | 0.6 |
The self-maintenance of MSCs from LTBMC proved to be low and the size of the secondary foci was 10–15% of that of foci in the intermediate recipients [11]. Thus, MSCs are maintained in LTBMC and are capable of creating a hematopoietic microenvironment on transplantation. However, self-maintenance of these precursors from LTBMC is essentially diminished.
The data obtained have demonstrated a high ability of self-maintenance of the cells transferring the hematopoietic microenvironment. Twenty-four hours after BM implantation about 10% of the stromal precursors survive. The population of the precursors in the femur is reduced to approximately the same degree after bone marrow curettage. During regeneration the stromal precursors increase to 60–100% of the initial level, hence they must undergo three or four mitoses. This is consistent with the rise in their sensitivity to S-phase specific cytostatics for the first 2 weeks after implantation. Taking into consideration that on the serial transfer of hematopoietic tissue without ossicles or on serial curettage three or four cycles of regeneration are possible, the stromal precursors are able to undergo no less than 10–12 mitoses. This value is rather underestimated since calculating the loss of precursors for differentiation was not taken into account. The high self-maintenance ability, on the one hand, and the ability to form a fully differentiated bone marrow stromal tissue on the other, suggests that the cells transferring the hematopoietic microenvironment are true mesenchymal stem cells.
Radiosensitivity of MSCs
The hematopoietic stroma function of the femoral bone marrow exposed in vitro to 500 to 2700 rad of γ-rays was also studied, using the ectopic foci formation method. Irradiation of bones with 500 rad caused no noticeable damage to the MSCs’ ability to form a hematopoietic microenvironment. Higher doses produced an exponential decrease in MSCs. The D0 estimated from linear regression (regression equation: log survival=-0.000977x+0.7200) of this portion of the curve is 444±5 rad and the extrapolation number (n) is 5.2. The results for in vitro neutron irradiation of bone marrow agreed (regression equation: log survival=-0.002697x+0.1506). A small shoulder was evident followed by an exponential survival having D0 and n of 161±19 rad and 1.4, respectively [5].
The radiosensitivity of MSCs from 5-week-old LTBMC seemed very similar to that of non-cultivated ones (regression equation: log survival=-0.089x+0.3744; D0 was 486±15 rad and n was 2.4) [17].
When high doses of irradiation were used, implantation proved unsuccessful in some cases and no ossicles with hematopoiesis were formed. One may assume that not a single MSC is preserved in such implants. The independent and random character of radiation damage of cells suggests that the existence or nonexistence of MSCs in the implant is governed by Poisson’s distribution. In this case the data on the proportion of transplant failures (P0) allow the mean MSC content in the implant (x) to be calculated using the equation x=- ln P0. The total MSC content in the femoral bone marrow can be found by taking into account the fraction that survived exposure to the given dose. These data are shown in Table 11 [5] where it is seen that the results were quite consistent on the whole.
Table 11. The effect of g irradiation on the hematopoietic microenvironment transferring MSCs in murine femoral bone marrow
Irradiation dose, rad | Implant failure/total number of implants | MSC/implant (- ln P0) | Survival fraction | MSC per femur |
|---|---|---|---|---|
2100 | 6/22 | 1.3 | 0.033 | 39.9 |
2200 | 12/20 | 0.511 | 0.025 | 20.3 |
2200 | 9/21 | 0.847 | 0.013 | 65.4 |
2500 | 7/19 | 0.999 | 0.012 | 86.3 |
2700 | 17/20 | 0.163 | 0.007 | 23.3 |
2700 | 15/19 | 0.236 | 0.003 | 78.7 |
The mean number of MSCs calculated from the proportion of transplant failures after high doses of irradiation was 52.3±11.6 per femoral bone marrow plug.
The results show that MSCs are much more radioresistant than hematopoietic stem cells, for which D0 is about 100 rad. The second feature of MSCs is their marked capability to recover from sublethal γ-ray damage, which is characterized by a extrapolation number (5.2). In the case of neutron irradiation the extrapolation number is 1.4, which is evidence that MSCs are incapable of recovery from sublethal neutron-induced damage [5].
Despite their high radioresistance MSCs were still sensitive to irradiation. After lethal irradiation and syngeneic bone marrow transplantation of CBF1 mice, the MSCs were reduced to 1/5 of the initial level and slowly regenerated to subnormal level in 6 months. The number of bone marrow cells used for reconstitution of the primary recipient did not affect MSC regeneration (Table 12) [14].
Table 12. Hematopoietic stromal precursors in lethally irradiated CBF1 mice reconstituted with different doses of syngeneic bone marrow cells
Chimera’s characteristics | Ectopic hemopoietic foci produced by femoral marrow plug implantation from reconstituted mice | |||
|---|---|---|---|---|
Cell injected | Time after reconstitution, months | Foci formed/number of implants | Foci cellularity, x106 | Ossicle weight, mg |
2x105 | 2 | 8/8 | 4.0 | 1.4 |
7.4x107 | 2 | 8/8 | 4.8 | 1.4 |
2x105 | 6 | 8/8 | 5.5 | 2.0 |
7.4x107 | 6 | 8/8 | 5.4 | 2.1 |
control | -- | 12/12 | 10.7 | 1.6 |
Two to six months after irradiation, the content of stromal progenitors in the mouse femur was, judging from the cellularity of the foci produced by them, 40–50% of the initial level in both groups of mice reconstituted both in minimal protective dose of marrow cells (2x105) and with a hundredfold dose. Thus, MSCs could be affected by high doses of irradiation and in such cases they are not able to regenerate completely.
Influence of the quality of hematopoiesis on MSCs’ proliferative potential
MSCs were compared in chimeras and double chimeras. Hematopoietic foci formed in standard recipients via BM from chimeras were approximately 2 times smaller when compared with foci formed from BM of non-irradiated mice, and 2 times bigger compared to foci formed from BM from double chimeras. These data confirm that stromal precursors are radiosensitive and unable to recover from radiation damage completely. Interestingly, secondary and tertiary chimeras’ BM formed the same small ectopic foci as double chimeras did, while the dose of irradiation affected the stroma of secondary and tertiary chimeras was 2 times lower than of double chimeras [18]. When BM from all types of chimeras tested were explanted in LTBMC, and after 3–4 weeks of cultivation were implanted under the renal capsule of syngeneic mice, foci formed from ACLs from chimeras’ BM were 75%, foci formed from ACLs from double chimeras’ BM were 20%, and ACLs from secondary and tertiary chimeras were approximately 40% by size from ACLs from non-irradiated mice. The secondary and tertiary chimeras’ stromal precursors were irradiated only once while hematopoietic cells had undergone 2 or 3 rounds of intensive proliferation during reconstitution of hematopoiesis. Thus, judging by the grade of irradiation damage, stromal cells from secondary and tertiary chimeras were similar to ordinary chimeras. Nevertheless, secondary and tertiary chimeras’ stromal precursors turned out to be affected more deeply than the same cells in ordinary chimeras. The data indicates that the stroma’s damage was determined not only by the irradiation dosage but by the quality of hematopoietic cells proliferating on it [18].
Hierarchical organization of the MSC compartment: existence of more mature than MSC-inducible precursor cells
In BM implantation, the ectopic hemopoietic focus is larger in an irradiated recipient than in a non-irradiated one in a dose-dependent manner (Table 13) [19].
Table 13. The size of the ectopic foci in irradiated recipients
Dose of irradiation | Foci size, % of control |
|---|---|
0 | 100 ± 18.8 |
1.5-2.5 | 156 ± 20 |
4.0-6.0 | 200 ± 37.5 |
7.0-8.0 | 210 ± 31.2 |
10.0-13.0 | 290 ± 68.7 |
In subsequent passages the size of the focus did not increase further (Table 14, compare with Table 9).
Table 14. Cellularity of ectopic bone marrow foci on repeated transplantation into irradiated recipients
Transfer number | Cells in the foci, x106 |
|---|---|
1 | 15.9 |
2 | 18.1 |
3 | 31.0 |
4 | 18.2 |
5 | 38.4 |
6 | 28.4 |
7 | 35.2 |
8 | 20.1 |
Hence, one may conclude that in the irradiated recipient the number of stromal precursors in an ectopic focus does not correspond to the large size of the focus. This was demonstrated more directly by implantation of similar bone marrow fragments into non-irradiated and irradiated (chimeric) recipients, subsequently testing the content of the stromal precursors in the sites formed by their retransplantation to non-irradiated recipients. In these experiments the primary focus formed in chimeras exceeded that in the non-irradiated ones by a factor of 2.2 (27.3x106 and 12.5x106). The content of the stromal precursors in both was essentially the same since the cellularities of the foci formed on transfer to the non-irradiated recipients were 10.93x106 and 11.83x106, respectively [15]. Stromal precursors from a culture also react to stimulation from the irradiated recipient, the response being much stronger than in implantation of freshly isolated bone marrow: the foci were 5–7 times larger in the irradiated recipients than in the non-irradiated ones (35.1±8x106 versus 5.3±1.2x106) (Table 15) [11].
Table 15. Size of ectopic foci produced by adherent cell layer from LTBMC in non-irradiated and irradiated recipients
Experiment № | Culture age, weeks | Non-irradiated recipients | Irradiated recipients | ||
|---|---|---|---|---|---|
| Foci formed/number of implants | Cellularity, x106 | Cellularity, x106 | Cellularity, x106 | |
1 | 2 | 2/2 | 0.7 | 2/2 | 22.5 |
2 | 4 | 0/2 | -- | 2/2 | 30.5 |
3 | 4 | 2/2 | 8.0 | 1/2 | 7.6 |
4 | 4 | 2/2 | 5.7 | 2/2 | 35.5 |
5 | 5 | 2/2 | 9.3 | 2/2 | 55.0 |
6 | 6 | 6/6 | 2.9 | 2/2 | 105.0 |
7 | 9 | 4/4 | 4.8 | 4/4 | 12.5 |
Similar results were obtained when LTBMC were established from different amounts of bone marrow (1/2, 1, 2 femurs). All cultures proved to be alike in hematopoiesis maintenance, though the MSC content in them corresponded to the dose of plated bone marrow (see Table 7). At the same time, in irradiated recipients all cultures produced foci approximately the same size (37.1, 42.7 and 38.3x106 correspondingly) [12].
The effect of hydroxyurea was estimated by the size of ectopic foci formed from treated ACLs in irradiated and non-irradiated recipients [20]. The results were similar in both types of recipients. So one may conclude that during the ACL formation both types of stromal precursors actively proliferate. MSCs functioning during the transfer into non-irradiated recipients and the more mature precursors taking part in the foci formation in the irradiated recipients.
The data suggest that the compartment of the hemopoietic stromal precursors is heterogenic and includes cells of at least two differentiation levels. Those less differentiated, MSCs able to transfer a hematopoietic microenvironment are marked by a relatively high self-maintenance, do not respond to the systemic demand of the irradiated recipient, and create a microenvironment, the size of which is proportional to the number of transferred MSCs. More mature precursors are marked by poor self-maintenance; they respond to the systemic demand of the irradiated recipient and, in the culture, to the surface of the flask bottom, and are not transplantable via in vivo transfer.
Summarizing the data presented above, the compartment of stromal bone marrow cells has a hierarchical structure. There are true mesenchymal stem cells (MSCs) capable of both self-maintaining and differentiating into all stromal lineages, and more mature inducible stromal precursors, which keep the ability for multipotential differentiations while losing their self-renewing ability. MSCs are mainly in mitotic rest and are not sensitive to the systemic demand, while more mature precursors proliferate more easily in the case of systemic requirements.
More mature inducible stromal precursors are sensitive to the unknown factor(s) released after irradiation. When injected during foci formation sera from irradiated mice also stimulate these precursors, resulting in increased size of the foci formed – the size of the foci was 19.5±1. 8x106 compared with 14±1.5x106 in control mice [19]. Addition of sera from irradiated mice to the LTBMC also increases the number of stromal cells in the ACLs (Table 16) [21].
Table 16. Influence of the sera from irradiated mice on the number of cells in the ACLs from LTMBC
Group | Cell number per well, х 103 |
|---|---|
control (no additional serum) | 118 ± 4 |
2% of sera from non-irradiated mice | 131 ± 7 |
0.5% of sera from irradiated mice | 160 ± 4 |
1 % of sera from irradiated mice | 185 ± 5 |
2 % of sera from irradiated mice | 206 ± 5 |
In order to define the organ producing the unknown factor(s), various organs of irradiated mice were co-transplanted simultaneously with the implantation of the BM plug under the renal capsule. Intravenous injection of irradiated sera as well as implantation of 5–6 irradiated bones under the skin enhanced the growth of stromal cells in the foci formed (Table 17) [21].
Table 17. Analysis of the various organs of irradiated mice for their stroma-stimulating activity
Recipients | The organ from irradiated mice, transplantation site | Foci size, х 106 |
|---|---|---|
intact (non-irradiated) | 9.0 ± 1.7 | |
irradiated | 21.1 ± 6.2 | |
intact | BM from 6 femurs, under the skin | 8.6 ± 2.3 |
intact | 5–6 femurs, under the skin | 22.0 ± 4.1 |
intact | Thymus, under the renal capsule | 14.8 ± 3.4 |
intact | Equivalent of ½ of the spleen, intravenously | 10.5 ± 1.2 |
intact | 1/3 of the spleen, under the renal capsule | 11.8 ± 3.3 |
intact | the spleen, under the skin | 13.1 ± 2.8 |
intact | 1/3 of the liver, under the skin | 14.8 ± 3.2 |
intact | Sera from irradiated mice, intravenously | 20.1 ± 1.5 |
intact | Sera from non-irradiated mice, intravenously | 14.0 ± 2.8 |
Thus, the unknown factor(s) stimulating the growth of stromal inducible precursor cells are produced in the irradiated bones and secreted into the blood serum.
The regulation of MSCs in vivo by hematopoietic growth factors
Regulation of MSCs by soluble factors remains obscure. During the formation of the hematopoietic microenvironment MSCs are affected by G-CSF. When recipients of BM were injected over 10 or 17 days beginning from the day after implantation of BM under the renal capsule it dramatically decreased size of the foci formed (Table 18).
Table 18. Influence of G-CSF on the ectopic foci formation from the bone marrow of intact mice
G-CSF treatment | Bone marrow implantation | Foci retransplantation | ||||
|---|---|---|---|---|---|---|
Implant number | Cellularity, x106 | Ossicle weight, mg | Implant number | Cellularity, x106 | Ossicle weight, mg | |
Control | 4 | 8.3±1.7 | 2.2±0.4 | 4 | 16.2±3.3 | 2.3±0.5 |
10 days | 4 | 5.3±0.7 | 2.7±0.7 | 4 | 9.0±1.8 | 1.9±0.5 |
17 days | 6 | 3.4±0.6 | 2.0±0.4 | 6 | 1.7±0.3 | 1.3±0.4 |
Obviously, when administered during the active proliferation and differentiation of MSC, G-SCF inhibits their proliferation (judging from the decreased size of the foci formed); moreover, it diminishes the number of MSCs themselves as was shown by retransplantation of the foci [22].
Conversely, cytokine treatment of the MSCs in their steady-state (in the intact bone marrow increases the number of these stromal precursors (Table 19).
Table 19. Size of the ectopic foci formed from the bone marrow of mice treated with cytocines
Group | Bone marrow implantation | Foci retransplantation | ||||
|---|---|---|---|---|---|---|
Implant number | Cellularity, x106 | Ossicle weight, mg | Implant number | Cellularity, x106 | Ossicle weight, mg | |
Control | 9 | 6.5±1.0 | 2.0±0.2 | 4 | 5.9±1.2 | 2.6±0.4 |
G-CSF, 6 days | 4 | 7.4±2.2 | 1.1±0.2 | |||
G-CSF, 10 days | 3 | 10.7±2.0 | 1.0±0.2 | 3 | 11.3±2.9 | 3.0±0.6 |
G-CSF, 17 days | 4 | 9.2±1.0 | 3.3±0.7 | 3 | 13.3±2.8 | 3.5±0.7 |
G-CSF+SCF, 6 days | 4 | 6.4±1.6 | 2.2±0.5 | |||
G-CSF+SCF, 10 days | 4 | 12.8±1.5 | 2.4±0.6 | |||
G-CSF+SCF, 17 days | 4 | 18.4±3.9 | 1.7±0.5 | 5 | 19.5±4.2 | 3.2±0.6 |
The combination of G-CSF with SCF and the longest treatment (for 17 days) had a maximal effect on the MSC number in the bone marrow of treated mice. In the case of G-CSF treatment this effect was transient and did not last for a month, in the case of cytokine combination, however, the increase in the number of MSCs was stable for at least a month. Cytokine treatment did not affect the osteogenic potential of MSCs either during stroma formation or in the intact bone marrow [22].
Thus, during the building of ectopic hematopoietic foci when stromal precursors are proliferating and differentiating, pharmacological concentrations of G-CSF inhibit the process of foci formation and diminish the number of stromal precursors in them. When affecting the mature non-proliferating bone marrow stroma, cytokines increase the number of MSCs.
Conclusions
Summarizing the works of J. L. Chertkov, it is possible to describe the main features of MSCs. These cells are capable of transferring a hematopoietic microenvironment due to both their high proliferative potential and their ability to differentiate into all bone marrow stromal lineages, including bone, cartilage, and marrow stromal cells. MSCs are more radioresistant than HSCs but they still suffer from radiation and their damage could not be fully recovered. Impaired hematopoiesis also influences the MSCs. The compartment of MSCs and stromal precursor cells is organized hierarchically. Therefore, J. L. Chertkov described the main features of MSCs from many sides using the functional assay.
Acknowledgements
Irina Shipounova and Nina Drize for preparing the compilation of Chertkov’s works on hematopoietic stromal microenvironment.
Gurevich O. A., Udalov G. A., Samoylina N. L., Samoylova R. S., Lemeneva N. L., Todria T. V., Olovnikova N. I., Olshanskaya Y. V., Shiponova (Nifontova) I. N., Ershler M. A. and Drize N. I. as co-authors of his works.
References
3. Olovnikova NI, Drize NJ, Ershler MA, Nifontova IN, Belkina EV, Nikolaeva TN, Proskurina NV, Chertkov JL. Developmental fate of hematopoietic stem cells: the study of individual hematopoietic clones at the level of antigen-responsive B lymphocytes. Hematol J. 2003;4(2):146-150.
4. Drize NJ, Olshanskaya YV, Gerasimova LP, Manakova TE, Samoylina NL, Todria TV, Chertkov JL. Lifelong hematopoiesis in both reconstituted and sublethally irradiated mice is provided by multiple sequentially recruited stem cells. Exp Hematol. 2001;29(6):786-794.
5. Chertkov JL, Gurevitch OA. Radiosensitivity of progenitor cells of the hematopoietic microenvironment. Radiat Res. 1979;79(1):177-186.
6. Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991;9(5):641-650.
7. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy. 2005;7(5):393-395.
8. Dexter TM, Allen TD, Lajtha LG. Conditions controlling the proliferation of haemopoietic stem cells in vitro. J Cell Physiol. 1977;91(3):335-344.
9. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230-247.
10. Udalov GA, Gurevich OA, Chertkov IL. Origin of hematopoietic cells in a syngenous and semisyngenous focus of heterotopic hematopoiesis. Biull Eksp Biol Med. 1977;83(5):584-586.
11. Chertkov JL, Drize NJ, Gurevitch OA, Udalov GA. Hemopoietic stromal precursors in long-term culture of bone marrow: I. Precursor characteristics, kinetics in culture, and dependence on quality of donor hemopoietic cells in chimeras. Exp Hematol. 1983;11(3):231-242.
12. Chertkov JL, Drize NJ, Gurevich OA. Hemopoietic microenvironment and hemopoietic stroma precursors. Recent advances in haematology immunology and blood transfusion : proceedings of the plenary sessions of the joint meeting of the 19th Congress of the International Society of Haematology and the 17th Congress of the International Society of Blood Transfusion, Budapest, August 1-7, 1982, Eds. Susan R. Hollán; International Society of Haematology, 12,1983;133-147.
13. Gurevich OA, Drize NI, Chertkov IL. Importance of cell contacts for the differentiation of the precursor cells of hematopoietic stroma in long-term bone marrow cultures. Biull Eksp Biol Med. 1982;94(8):97-100.
14. Chertkov JL, Drize NJ, Gurevitch OA, Samoylova RS. Origin of hemopoietic stromal progenitor cells in chimeras. Exp Hematol. 1985;13(11):1217-1222.
15. Chertkov JL, Gurevitch OA. Self-maintenance ability and kinetics of haemopoietic stroma precursors. Cell Tissue Kinet. 1980;13(5):535-541.
16. Chertkov JL, Gurevich OA, Udalov GA. Role of bone marrow stroma in the phenomenon of hybrid resistance. Biull Eksp Biol Med 1979 Apr; 87(4):337-40.
17. Gurevich OA, Chertkov JL. Radiosensitivity of hemopoietic stroma precursors from long-term bone marrow culture. Radiobiology. 1983;23(4):521-523.
18. Gurevich OA, Drize NI, Udalov GA, Chertkov IL. Effect of hematopoiesis on progenitor bone marrow stromal cells. Biull Eksp Biol Med. 1982;94(10):115-117.
19. Chertkov JL, Gurevitch OA. Hematopoietic stem cell and its microenvironment. Moscow, Meditzina 1984. Russian.
20. Gurevich OA, Drize NJ, Chertkov JL. Proliferation of cells-precursors of hematopoietic microenvironment in murine long-term bone marrow culture. Bull Exp Biol Med. 1984;XCVIII(11):612-614.
21. Drize NI, Ershler MA, Chertkov IL. Radiation-induced hemopoietic cell growth factor: detection in a culture. Bull Exp Biol Med. 2001;132(6):1213-1215.
22. Drize NJ, Chertkov JL. Influence of cytokine (G-CSF and SCF) treatment on the murine precursors of hematopoietic stroma. Bull Exp Biol Med. 1998;125(2):204-206.
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Иосиф Л. Чертков, Ольга А. Гуревич, Геннадий А. Удалов, Ирина Н. Шипунова, Нина И. Дризе
" ["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) "18017" ["VALUE"]=> array(2) { ["TEXT"]=> string(2489) "<p>Данная работа суммирует достижения профессора Иосифа Львовича Черткова в изучении клеток-предшественниц кроветворного стромального микроокружения. В своих работах Чертков использовал уникальный функциональный метод анализа стромальных клеток-предшественниц – метод образования очагов эктопического кроветворения под капсулой почки сингенных с донорами костного мозга реципиентов. Было продемонстрировано наличие в костном мозге мезенхимальных стволовых клеток, способных к переносу кроветворного микрооружения, т.е. дифференцировке во все стромальные клеточные линии, и к самоподдержанию, т.е. многократному переносу кроветворного микроокружения. Были изучены радиочувствительность и пролиферативный потенциал мезенхимальных стволовых клеток. Показана важность сохранения межклеточных контактов для построения стромального микроокружения in vitro и in vivo. Выявлена иерархичная структура отдела мезенхимальных стволовых клеток и охарактеризован отдел более дифференцированных, индуцибельных клеток-предшественниц стромального микроокружения. Показано взаимное влияние кроветворных и стромальных клеток. Охарактеризованы некоторые пути регуляции стромальных предшественников. Данная компиляция работ И. Л. Черткова демонстрирует его вклад в изучение регулирующего кроветворение стромального микроокружения костного мозга.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2477) "Данная работа суммирует достижения профессора Иосифа Львовича Черткова в изучении клеток-предшественниц кроветворного стромального микроокружения. В своих работах Чертков использовал уникальный функциональный метод анализа стромальных клеток-предшественниц – метод образования очагов эктопического кроветворения под капсулой почки сингенных с донорами костного мозга реципиентов. Было продемонстрировано наличие в костном мозге мезенхимальных стволовых клеток, способных к переносу кроветворного микрооружения, т.е. дифференцировке во все стромальные клеточные линии, и к самоподдержанию, т.е. многократному переносу кроветворного микроокружения. Были изучены радиочувствительность и пролиферативный потенциал мезенхимальных стволовых клеток. Показана важность сохранения межклеточных контактов для построения стромального микроокружения in vitro и in vivo. Выявлена иерархичная структура отдела мезенхимальных стволовых клеток и охарактеризован отдел более дифференцированных, индуцибельных клеток-предшественниц стромального микроокружения. Показано взаимное влияние кроветворных и стромальных клеток. Охарактеризованы некоторые пути регуляции стромальных предшественников. Данная компиляция работ И. Л. Черткова демонстрирует его вклад в изучение регулирующего кроветворение стромального микроокружения костного мозга.
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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "18032" ["VALUE"]=> array(2) { ["TEXT"]=> string(702) "<p>The manuscript summarizes the works of Prof. Joseph Chertkov that are dedicated to precursor cells in the hematopoietic stromal microenvironment. Unique functional analysis was used in these investigations. The properties of stem cells in the hematopoietic microenvironment such as self-renewal capacity and the ability to differentiate into all stromal lineages are described. The hierarchical structure of stromal precursor cells compartment is proposed. Some elements of the regulatory pathways of stromal precursor cells are described. This compilation reflects the importance of Prof. Chertkov’s contribution to the investigation of stromal precursor cells and hematopoiesis. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(690) "The manuscript summarizes the works of Prof. Joseph Chertkov that are dedicated to precursor cells in the hematopoietic stromal microenvironment. Unique functional analysis was used in these investigations. The properties of stem cells in the hematopoietic microenvironment such as self-renewal capacity and the ability to differentiate into all stromal lineages are described. The hierarchical structure of stromal precursor cells compartment is proposed. Some elements of the regulatory pathways of stromal precursor cells are described. This compilation reflects the importance of Prof. Chertkov’s contribution to the investigation of stromal precursor cells and hematopoiesis.
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В своих работах Чертков использовал уникальный функциональный метод анализа стромальных клеток-предшественниц – метод образования очагов эктопического кроветворения под капсулой почки сингенных с донорами костного мозга реципиентов. Было продемонстрировано наличие в костном мозге мезенхимальных стволовых клеток, способных к переносу кроветворного микрооружения, т.е. дифференцировке во все стромальные клеточные линии, и к самоподдержанию, т.е. многократному переносу кроветворного микроокружения. Были изучены радиочувствительность и пролиферативный потенциал мезенхимальных стволовых клеток. Показана важность сохранения межклеточных контактов для построения стромального микроокружения in vitro и in vivo. Выявлена иерархичная структура отдела мезенхимальных стволовых клеток и охарактеризован отдел более дифференцированных, индуцибельных клеток-предшественниц стромального микроокружения. Показано взаимное влияние кроветворных и стромальных клеток. Охарактеризованы некоторые пути регуляции стромальных предшественников. Данная компиляция работ И. Л. Черткова демонстрирует его вклад в изучение регулирующего кроветворение стромального микроокружения костного мозга.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2477) "Данная работа суммирует достижения профессора Иосифа Львовича Черткова в изучении клеток-предшественниц кроветворного стромального микроокружения. В своих работах Чертков использовал уникальный функциональный метод анализа стромальных клеток-предшественниц – метод образования очагов эктопического кроветворения под капсулой почки сингенных с донорами костного мозга реципиентов. Было продемонстрировано наличие в костном мозге мезенхимальных стволовых клеток, способных к переносу кроветворного микрооружения, т.е. дифференцировке во все стромальные клеточные линии, и к самоподдержанию, т.е. многократному переносу кроветворного микроокружения. Были изучены радиочувствительность и пролиферативный потенциал мезенхимальных стволовых клеток. Показана важность сохранения межклеточных контактов для построения стромального микроокружения in vitro и in vivo. Выявлена иерархичная структура отдела мезенхимальных стволовых клеток и охарактеризован отдел более дифференцированных, индуцибельных клеток-предшественниц стромального микроокружения. Показано взаимное влияние кроветворных и стромальных клеток. Охарактеризованы некоторые пути регуляции стромальных предшественников. Данная компиляция работ И. Л. Черткова демонстрирует его вклад в изучение регулирующего кроветворение стромального микроокружения костного мозга.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2477) "Данная работа суммирует достижения профессора Иосифа Львовича Черткова в изучении клеток-предшественниц кроветворного стромального микроокружения. В своих работах Чертков использовал уникальный функциональный метод анализа стромальных клеток-предшественниц – метод образования очагов эктопического кроветворения под капсулой почки сингенных с донорами костного мозга реципиентов. Было продемонстрировано наличие в костном мозге мезенхимальных стволовых клеток, способных к переносу кроветворного микрооружения, т.е. дифференцировке во все стромальные клеточные линии, и к самоподдержанию, т.е. многократному переносу кроветворного микроокружения. Были изучены радиочувствительность и пролиферативный потенциал мезенхимальных стволовых клеток. Показана важность сохранения межклеточных контактов для построения стромального микроокружения in vitro и in vivo. Выявлена иерархичная структура отдела мезенхимальных стволовых клеток и охарактеризован отдел более дифференцированных, индуцибельных клеток-предшественниц стромального микроокружения. Показано взаимное влияние кроветворных и стромальных клеток. Охарактеризованы некоторые пути регуляции стромальных предшественников. Данная компиляция работ И. Л. Черткова демонстрирует его вклад в изучение регулирующего кроветворение стромального микроокружения костного мозга.
" } } } [1]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(2) "67" ["~IBLOCK_SECTION_ID"]=> string(2) "67" ["ID"]=> string(4) "1347" ["~ID"]=> string(4) "1347" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(85) "Управление библиографическими списками и Web 2.0" ["~NAME"]=> string(85) "Управление библиографическими списками и Web 2.0" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "15.08.2017 14:37:31" ["~TIMESTAMP_X"]=> string(19) "15.08.2017 14:37:31" ["DETAIL_PAGE_URL"]=> string(84) "/ru/archive/tom-2-nomer-2-6/forum/upravlenie-bibliograficheskimi-spiskami-i-web-2-0/" ["~DETAIL_PAGE_URL"]=> string(84) "/ru/archive/tom-2-nomer-2-6/forum/upravlenie-bibliograficheskimi-spiskami-i-web-2-0/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(10941) "Introduction
Reference management software allows researchers to create a personal electronic collection of relevant scholarly publications, and to use this collection to write their own scholarly works. Some of the earliest programs (e.g. Endnote and BibTeX) have now been around for 25 years, and their core functions remain unchanged. The first big change came around 15 years ago when references were no longer typed in by hand, but rather retrieved from the Internet. Another important change started five years ago in the context of what is typically called Web 2.0. Reference managers no longer were used as software on a single desktop computer. They now more often than not are web-based applications (with or without synchronization to a desktop version), and this allows easy sharing of references between several users, computers and/or other web applications. This trend has led to a number of new reference managers, both commercial and freely available.
Reference managers help researchers by performing three basic functions:
1) Searching: find relevant scientific literature,
2) Storing: store the results of that search in a personal database for later retrieval, and
3) Writing: insert references when writing a manuscript.
Although all three functions could also be performed without specialized software, a manual approach is not recommended for managing anything beyond a handful of references. Managing references manually is much slower and prone to errors, e.g., when renumbering all references in a manuscript after inserting a new citation.
In the next sections, we will look at the three basic reference manager functions in more detail, with special emphasis on how the newer Web-based reference managers enhance some of these functions with “social” features.
Searching
All reference managers can import references from bibliographic databases, either by directly searching these databases (PubMed, Scopus, Web of Science, Google Scholar, etc.), and/or via so-called bookmarklets. Bookmarklets are specialized bookmarks for web browsers that retrieve references from web pages, e.g., the result of a PubMed search. Both strategies have their advantages, but for most users there is no real difference. Interesting references are also showing up in other places besides bibliographic databases. Most commonly this is a journal table of contents received via email or RSS reader, but it can also be a blog post or even a Twitter message. In order to retrieve this reference information, users usually first have to follow a link to a bibliographic database or journal web page.
A traditional search strategy typically uses keywords, author and journal names, and publication dates. Because web-based reference managers such as CiteULike or Mendeley store millions of references by thousands of users, they also offer a very powerful “social” search. They can show you the references of users with similar interests, or papers similar to the paper you just imported. This “social” search requires a critical mass of users, but might in a few years surpass traditional search strategies in popularity. Sharing references in private or public groups is already a very popular feature of web-based reference managers. Reading lists — lists of references required for a particular course — are one typical use.
Storing
Reference managers are databases that store references. In the life sciences a reference is typically a journal article, and sometimes a conference abstract, book chapter, or web page. But reference managers can also handle a long list of other references. Among the 48 reference types supported in the latest version of Endnote (Endnote X4), some of the lesser known are online database, audiovisual material, grant, blog, and research dataset. This wider definition of a reference looks not unlike the bookmarks we store with our web browser. Bookmarks can be stored in specialized websites (e.g., delicious), and several of these so-called social bookmarking sites also handle scientific references (CiteULike being the most popular).
Since almost all scholarly publications are now published in electronic form, reference managers (most notably Papers) a few years ago started to not only manage references, but also store the fulltext PDF files associated with them. This is the most convenient way to store these PDF files. And it has another advantage: we can do powerful fulltext searches of the publications stored in our reference manager. Many reference managers can import PDF files and extract the reference information from the PDF file. And some of them have an integrated PDF viewer that allows highlighting of text and note taking.
As reference managers are basically databases, they should allow the user to import and export references (RIS is the best standard file format), find duplicate records, or group references by subject or keyword. Only some reference managers can also group references by author or journal, or list all references cited by a particular reference.
Many reference managers offer a web-based version. This allows users to have the same reference database on more than one computer and to share references with others. Whereas some reference managers (e.g. CiteULike, RefWorks) are only web-based, others (e.g., Mendeley, Endnote, Zotero) synchronize a desktop with a web version. This year we have seen a proliferation of reference management tools for mobile devices such as the iPhone, and also the first reference managers for the iPad.
Writing
Reference managers are a big time saver in manuscript writing. They help in inserting citations into the text and automatically create a bibliography in the desired citation style. Although many reference managers now come with more than 1000 different citation styles, only a few of them (e.g., Endnote or Refworks) allow the user to edit them — an important feature for some users. Not all reference managers have a word processor plugin, and if they do they often only support Microsoft Word and maybe OpenOffice. The built-in reference management features of the latest version of Microsoft Word (Word 2007 or Word 2008 for Macintosh) are very rudimentary and not recommended.
Almost all scientific papers are now written by more than one author. Collaborative online writing tools such as Google Docs or Zoho Writer facilitate the writing process, as authors don’t have to repeatedly send around draft versions of manuscripts via email. Unfortunately no reference manager directly supports these online tools beyond a simple copy and paste.
Links
Connotea
Endnote/Endnote Web
Refworks
Zotero
Mendeley
CiteULike
Jabref
Papers
Citavi
Table 1. Some popular reference managers with Web 2.0 features
(Animation by Viktoriya Levenko)
Conclusions
Reference management software is currently undergoing a lot of exciting changes, and now is a good time to test some of the programs mentioned in this article. Several of the newer reference managers are free to use, so cost shouldn’t be a reason not to start using such a tool. CiteULike and other web-based tools can be used right away without installing any software; downloading and installing one of the free tools (e.g. Zotero or Mendeley) also takes less than an hour. Every reference manager has strengths and weaknesses; the comparison chart can help with finding the right tool to get started. It is also a good idea to start with a reference manager that your colleagues use. Not only can they help you with questions, but you also want to use the same reference manager when writing a manuscript together.
Acknowledgements
I declare no conflict of interest.
References
1. Hull D. et al. Defrosting the digital library: bibliographic tools for the next generation web. PLoS Comput Biol. 2008;4(10):pp.e1000204
http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000204
2. Innovations in Reference Management Workshop
3. Reference Manager Overview
Introduction
Reference management software allows researchers to create a personal electronic collection of relevant scholarly publications, and to use this collection to write their own scholarly works. Some of the earliest programs (e.g. Endnote and BibTeX) have now been around for 25 years, and their core functions remain unchanged. The first big change came around 15 years ago when references were no longer typed in by hand, but rather retrieved from the Internet. Another important change started five years ago in the context of what is typically called Web 2.0. Reference managers no longer were used as software on a single desktop computer. They now more often than not are web-based applications (with or without synchronization to a desktop version), and this allows easy sharing of references between several users, computers and/or other web applications. This trend has led to a number of new reference managers, both commercial and freely available.
Reference managers help researchers by performing three basic functions:
1) Searching: find relevant scientific literature,
2) Storing: store the results of that search in a personal database for later retrieval, and
3) Writing: insert references when writing a manuscript.
Although all three functions could also be performed without specialized software, a manual approach is not recommended for managing anything beyond a handful of references. Managing references manually is much slower and prone to errors, e.g., when renumbering all references in a manuscript after inserting a new citation.
In the next sections, we will look at the three basic reference manager functions in more detail, with special emphasis on how the newer Web-based reference managers enhance some of these functions with “social” features.
Searching
All reference managers can import references from bibliographic databases, either by directly searching these databases (PubMed, Scopus, Web of Science, Google Scholar, etc.), and/or via so-called bookmarklets. Bookmarklets are specialized bookmarks for web browsers that retrieve references from web pages, e.g., the result of a PubMed search. Both strategies have their advantages, but for most users there is no real difference. Interesting references are also showing up in other places besides bibliographic databases. Most commonly this is a journal table of contents received via email or RSS reader, but it can also be a blog post or even a Twitter message. In order to retrieve this reference information, users usually first have to follow a link to a bibliographic database or journal web page.
A traditional search strategy typically uses keywords, author and journal names, and publication dates. Because web-based reference managers such as CiteULike or Mendeley store millions of references by thousands of users, they also offer a very powerful “social” search. They can show you the references of users with similar interests, or papers similar to the paper you just imported. This “social” search requires a critical mass of users, but might in a few years surpass traditional search strategies in popularity. Sharing references in private or public groups is already a very popular feature of web-based reference managers. Reading lists — lists of references required for a particular course — are one typical use.
Storing
Reference managers are databases that store references. In the life sciences a reference is typically a journal article, and sometimes a conference abstract, book chapter, or web page. But reference managers can also handle a long list of other references. Among the 48 reference types supported in the latest version of Endnote (Endnote X4), some of the lesser known are online database, audiovisual material, grant, blog, and research dataset. This wider definition of a reference looks not unlike the bookmarks we store with our web browser. Bookmarks can be stored in specialized websites (e.g., delicious), and several of these so-called social bookmarking sites also handle scientific references (CiteULike being the most popular).
Since almost all scholarly publications are now published in electronic form, reference managers (most notably Papers) a few years ago started to not only manage references, but also store the fulltext PDF files associated with them. This is the most convenient way to store these PDF files. And it has another advantage: we can do powerful fulltext searches of the publications stored in our reference manager. Many reference managers can import PDF files and extract the reference information from the PDF file. And some of them have an integrated PDF viewer that allows highlighting of text and note taking.
As reference managers are basically databases, they should allow the user to import and export references (RIS is the best standard file format), find duplicate records, or group references by subject or keyword. Only some reference managers can also group references by author or journal, or list all references cited by a particular reference.
Many reference managers offer a web-based version. This allows users to have the same reference database on more than one computer and to share references with others. Whereas some reference managers (e.g. CiteULike, RefWorks) are only web-based, others (e.g., Mendeley, Endnote, Zotero) synchronize a desktop with a web version. This year we have seen a proliferation of reference management tools for mobile devices such as the iPhone, and also the first reference managers for the iPad.
Writing
Reference managers are a big time saver in manuscript writing. They help in inserting citations into the text and automatically create a bibliography in the desired citation style. Although many reference managers now come with more than 1000 different citation styles, only a few of them (e.g., Endnote or Refworks) allow the user to edit them — an important feature for some users. Not all reference managers have a word processor plugin, and if they do they often only support Microsoft Word and maybe OpenOffice. The built-in reference management features of the latest version of Microsoft Word (Word 2007 or Word 2008 for Macintosh) are very rudimentary and not recommended.
Almost all scientific papers are now written by more than one author. Collaborative online writing tools such as Google Docs or Zoho Writer facilitate the writing process, as authors don’t have to repeatedly send around draft versions of manuscripts via email. Unfortunately no reference manager directly supports these online tools beyond a simple copy and paste.
Links
Connotea
Endnote/Endnote Web
Refworks
Zotero
Mendeley
CiteULike
Jabref
Papers
Citavi
Table 1. Some popular reference managers with Web 2.0 features
(Animation by Viktoriya Levenko)
Conclusions
Reference management software is currently undergoing a lot of exciting changes, and now is a good time to test some of the programs mentioned in this article. Several of the newer reference managers are free to use, so cost shouldn’t be a reason not to start using such a tool. CiteULike and other web-based tools can be used right away without installing any software; downloading and installing one of the free tools (e.g. Zotero or Mendeley) also takes less than an hour. Every reference manager has strengths and weaknesses; the comparison chart can help with finding the right tool to get started. It is also a good idea to start with a reference manager that your colleagues use. Not only can they help you with questions, but you also want to use the same reference manager when writing a manuscript together.
Acknowledgements
I declare no conflict of interest.
References
1. Hull D. et al. Defrosting the digital library: bibliographic tools for the next generation web. PLoS Comput Biol. 2008;4(10):pp.e1000204
http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000204
2. Innovations in Reference Management Workshop
3. Reference Manager Overview
Мартин Феннер
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Keywords
reference management, Web 2.0, citation
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Martin Fenner, MD
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Keywords
reference management, Web 2.0, citation
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Reference management software has been used by researchers for more than 20 years to find, store, and organize references, and to write scholarly papers. Recently developed collaborative web-based tools have resulted in a number of interesting new features, and in a number of new reference managers. These developments are changing which reference managers we use, and how we use them.
Keywords
reference management, Web 2.0, citation
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Carl-Neuberg-Str. 1, Hannover Medical School, 30625 Hannover, Germany
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Не так давно появились коллективные сетевые ресурсы, которые открыли новые интересные возможности и способствовали созданию новых приложений по работе с библиографиями. Эти наработки специфичны для каждого отдельного приложения. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(809) "Программное обеспечение по управлению библиографическими списками используется уже более 20 лет для поиска, хранения и систематизации библиографического материала, а также для написания научных статей. Не так давно появились коллективные сетевые ресурсы, которые открыли новые интересные возможности и способствовали созданию новых приложений по работе с библиографиями. Эти наработки специфичны для каждого отдельного приложения.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(809) "Программное обеспечение по управлению библиографическими списками используется уже более 20 лет для поиска, хранения и систематизации библиографического материала, а также для написания научных статей. Не так давно появились коллективные сетевые ресурсы, которые открыли новые интересные возможности и способствовали созданию новых приложений по работе с библиографиями. Эти наработки специфичны для каждого отдельного приложения.
" } } } [2]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(2) "75" ["~IBLOCK_SECTION_ID"]=> string(2) "75" ["ID"]=> string(4) "1363" ["~ID"]=> string(4) "1363" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(195) "Трансплантация гемопоэтических стволовых клеток при тяжёлых аутоиммунных болезнях: успехи и перспективы" ["~NAME"]=> string(195) "Трансплантация гемопоэтических стволовых клеток при тяжёлых аутоиммунных болезнях: успехи и перспективы" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "21.09.2017 14:43:23" ["~TIMESTAMP_X"]=> string(19) "21.09.2017 14:43:23" ["DETAIL_PAGE_URL"]=> string(145) "/ru/archive/tom-2-nomer-2-6/obzornye-stati-/transplantatsiya-gemopoeticheskikh-stvolovykh-kletok-pri-tyazhyelykh-autoimmunnykh-boleznyakh-uspekh/" ["~DETAIL_PAGE_URL"]=> string(145) "/ru/archive/tom-2-nomer-2-6/obzornye-stati-/transplantatsiya-gemopoeticheskikh-stvolovykh-kletok-pri-tyazhyelykh-autoimmunnykh-boleznyakh-uspekh/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(52279) "Introduction
Stem cell therapy for severe autoimmune diseases (AD), generally as hematopoietic stem cell transplantation (HSCT), both allogeneic and autologous, but also more recently as gene therapy-assisted autologous HSCT, has become one of the hottest areas of clinical immunology. It has been developing progressively in the last decades, and has generated “excitement and promise as well as confusion and at times contradictory results in the lay and scientific literature” [6]. The utilization of stem cells to promote regenerative medicine must be distinguished from the purpose of suppressing autoimmune cellular and humoral aggression. This does not mean that both areas aren’t tightly connected, since supplying new pancreatic beta cells to patients with type I diabetes, whether by islet cell transplantation or by boosting their numbers by reprogramming pancreatic acinar cells, cannot resolve the disease if the autoimmune process is not eliminated [61]. In some clinical entities both effects coincide. An appropriate example is aplastic anemia (AA) and some of its minor variants (pure red cell aplasia-PRCA, pure white cell aplasia-PWCA), in which allogeneic HSCT both suppresses autoimmunity and provides new HSC [62]. In all the other autoimmune conditions this double effect has not been demonstrated conclusively.
The utilization of HSCT, overwhelmingly of the autologous modality, has been growing impressively in the last few years, and is still increasing steadily [28, 47]. Autologous HSCT (ASCT) relies on an extensive debulking of the autoaggressive immune system, followed by the re-infusion of the patients’ HSC (commonly identified as CD34+ cells). The allogeneic procedure is based on the substitution of the faulty immune system by a new healthy one, theoretically capable of eradicating the autoimmune clones by means of the classical combination of high-dose immunosuppressive therapy and a Graft-versus-Autoimmunity (GVA) effect, which will be discussed later. Whether this last intervention will be capable of achieving the Holy Grail of self-tolerance [15] is still not established, given the complexity of the pathogenesis of ADs, including the persisting antigenicity of altered “self” proteins [12] and some paradoxical post-transplant relapses despite full donor chimerism, which will be discussed later.
A brief historical recapitulation
Two streams of research, experimental and clinical, are at the origin of the increasing utilization of HSCT, autologous and allogeneic, for SADs [34]. The first animal studies had shown that the transfer of spleen and/or whole marrow cells to immunosuppressed mice could reproduce murine lupus. The culprit cells were shown to be stem or lymphoid progenitors. The next step was to ascertain whether, contrarily, healthy HSC were capable of curing experimental ADs. Human blood SC were capable of suppressing antibody production in lupus mice, perhaps the first demonstration of a curative effect by xenogeneic HSCT. More recently, it has elegantly been shown that the nonmyeloablative transplantation of purified allogeneic HSC not only prevented, but also induced stabilization or reversal of lupus symptoms in NZB mice [50]. Durable mixed chimerism was also efficacious, a point that will be discussed later. A further experimental improvement has been the intra-bone injection of HSC [21].
The resolution of experimental ADs by means of healthy, compatible allo-SCT was to be expected, considering the overwhelming genetic predisposition of inbred strains of mice, which differs from the intricacies of human ADs, in which there is a complex relationship between genetic, environmental and regulatory factors, and where impaired mechanisms of thymic selection interact, in still poorly elucidated ways, with genetic factors. As already mentioned, a GVA effect has been postulated [33], and theoretically dissected in 6 different mechanisms [53], with immune-mediated abrogation of autoreactive clones in the foreground. In practice, donor-derived immune cells are capable of mediating an anti-autoimmune effect either specifically, or as a part of a more general alloimmune reaction. In experimental autoimmune encephalomyelitis (EAE) it was shown that active alloreactivity was associated with the greatest GVA effect [60]. The second stream in favor of allo-SCT came from the clinical observation of patients affected by coincidental diseases, that is patients with ADs having developed a hematologic malignancy for which they received an allo-SCT, and were ultimately cured of both diseases [35]. There were even cases in which allo-BMT transferred the AD of the donor to the recipient, but cured the latter of his former AD.
The rationale for an apparently paradoxical procedure such as autologous HSCT, in which the patients’ immune cells, despite varying degrees of HSC depletion in vitro and/or in vivo, are administered back to them, came from the pioneering studies by van Bekkum and his group, who were able to cure EAE and adjuvant arthritis (AA), both models of human multiple sclerosis (MS) and rheumatoid arthritis (RA), by means of autologous (“pseudoautologous”) HSCT [58]. These results considerably strengthened the philosophy of autologous HSCT for human ADs, even if it was pointed out later that in animal models the abnormality of the antigen-induced type seems to reside in immunocompetent T/B cells but not in the HSC, and therefore ASCT may be curative, while in spontaneous ADs new, unaffected HSC were necessary to achieve a cure [22]. In any case, the utilization of ASCT is now widely accepted for treating severe, refractory ADs.
A powerful immunosuppressive therapy for SADs has been developed at Johns Hopkins University in Baltimore, where such patients are treated with high-dose cyclophosphamide (CY) alone, with an inevitable delay of marrow and blood reconstitution, but with results that do not differ significantly from those obtained by ASCT [5].
Finally, two new approaches appear to be integrating this area. Mesenchymal stem cells (MSC) possess several immunomodulatory properties [44], have been shown to significantly ameliorate Graft-versus-Host Disease [25] (GVHD), and have been considered a valuable therapeutic option for SADs [56]. However the role of this kind of cellular therapy in human AD, whether associated with ASCT or not, is still to be established. Another fascinating approach is based on the idea of achieving antigen-specific tolerance to treat refractory ADs, even if translating such therapies from bench to bedside is still mainly theoretical. An approach combining HSCT and transduction of the culprit self-antigens in autologous HSCs in order to achieve central (thymic) tolerance has been developed by Alderuccio and his group [2], although only in animal experiments with organ-specific autoimmune conditions at this stage.
Autologous transplantation: progress and questions
In contrast to the long interval having taken place between the first allogeneic transplants for animal ADs and translational clinical trials, ASCT quickly followed the experimental investigations. It was proposed by myself for severe SLE in 1993 [36], and then for ADs in general in 1995 [30]. The first transplants were performed for a connective tissue disease [54] and for severe SLE [32]. The following utilization of ASCT for SADs grew almost exponentially, so much so that, besides the continually increasing registered transplants in the EBMT and CIBMTR registries, a recent study by Dominique Farge et al has analyzed 900 patients [14]. Excellent reviews of specific diseases have been published recently, and a monographic issue of Autoimmunity has just been devoted to this theme [28]. Here, I shall focus on the most significant and contemporary questions.
1. Autologous HSCT for ADs has been considered a relatively safe procedure from its inception, but is it becoming safer?
Autoimmune diseases represent an extremely heterogenous spectrum of diseases, and in most of them severe-refractory forms have a poor prognosis and a greatly impaired quality of life. One cannot disagree, however, with Burt’s statement that “Treatment-related mortality needs to be very low for non-malignant diseases”1. Treatment-Related Mortality (TRM) reached 12% in the initial EBMT Registry, decreased to 7 +3% in 2005, and finally did not exceed 5% in the most recent EBMT study [14]. In this last study evidence was also found of a clear center effect, indicating that experienced teams that are well acquainted with the multi-organ involvement of SADs produce superior results. In the case of a single disease such as SLE, a collection of 162 patients transplanted in 30 Centers showed a TRM of 11% [29], However of 200 patients transplanted at Northwestern University, Chicago, the TRM using non-myeloablative conditioning regimens in 200 patients was 1.5% [8]. This does not mean, of course, that TRM cannot grow much higher in very severe conditions such as advanced scleroderma. Scleroderma-related organ disfunction contributed to treatment-related deaths [43]. In conclusion, the answer to this first question is that ASCT may be considered reasonably safe when performed by experienced teams, appropriate conditioning regimens, and on patients who are not too disease-compromised. These data need to be counterbalanced by mortality from disease progression, and require the adoption of inclusion and exclusion criteria for each category of diseases, which cannot be detailed here. Although the inclusion of patients within approved or investigational protocols is the best policy, it must be realized that, in selected patients with advanced, refractory SADs, the decision to perform ASCT will ultimately rely on a combination of clinical acumen, experienced teams, and a good patient-doctor relationship.
2. Which are the most appropriate mobilization and conditioning regimens?
The source of HSCs was initially the bone marrow (BM), but has now changed to the peripheral blood (PB) following mobilization procedures. In the previously mentioned EBMT study of 900 patients the source was PB in 827 cases [43]. The most popular mobilizing regimens generally consist of combinations of cyclophosphamide (CY) and G-CSF [47]. Mobilizing regimens incorporating CY (from 2 to 4g/m2) have the additional, significant advantage of acting as an important therapeutic procedure per se (therapeutic mobilization). In our own experience of 9 SLE patients the achievement of a complete remission (CR) following mobilization with CY 4g/m2 enabled us, in 2 cases, to dispense from performing the initially programmed ASCT.
A variety of conditioning regimens have been utilized, but it could be shown that high-intensity protocols were followed by a lower probability of disease progression, albeit with a higher risk of TRM [16]. The strategy of performing intense immunosuppression without affecting the whole of the hematopoietic system is most generally accepted, taking into account that biologics such as Rituximab have a longer immunosuppressive activity than any chemotherapeutic agent. A combination of both strategies, in which Rituximab 500 mg is given before and after the regular 200 mg/kg CY protocol (the “sandwich technique”), is being currently utilized at Northwestern University, Chicago (USA). Anti-CD20 immunotherapy for the control of relapse following ASCT in patients with rheumatoid arthritis (RA) had been already utilized with success [41], and the strategy of using an additional immunotherapy in this area is attractive. Unfortunately a devastating complication, progressive multifocal leukoencephalopathy (PML), due to the activation of the John Cunningham virus (JCV), has been reported in a disquieting proportion of patients having been immunosuppressed with biological agents (Natalizumab, Rituximab). A recent review reported 52 patients as having developed PML, 7 of which had received HSCT (3 allogeneic, 4 autologous) for lymphoproliferative diseases [9]. Awareness is obviously needed of the potential for PML among Rituximab-treated patients. Maximal immunosuppression produces greater benefits, but may at the same time be associated with unforeseen iatrogenic complications.
3. What significant changes in the immune system take place following ASCT ? Are we really curing autoimmunity ?
No other aspect of the ASCT-based procedures has been the object of so much research, controversy, enthusiasm, and skepticism. A prolonged depression of CD4+ CD45RA cells is a general finding, and takes place following both ASCT and high-dose immunosuppressive therapy (HDIS) alone. The type of immunomodulation which then follows has been called a “black box” by Muraro and Douek [42], but, thanks to their own and others’ investigations, is becoming increasingly clear. High-dose immunosuppression reduces the population of autoimmune cells to minimal residual autoimmune disease (MRAD). While the cure of oncohematological disease requires the eradication of cancer SC, a different view is entertained for ADs. Two basic mechanisms have been postulated.The first has been defined as a “re-education” of the faulty immune system [1], obtained by restoring a diverse antigen-specific repertoire through reactivation of the thymic output (“thymic rebound”), which has also been shown to persist in adults, albeit in lesser measure. In a recent study of ASCT in 7 SLE patients the Berlin group has found evidence for an overwhelming regeneration of the adoptive immune system and of the B-cell lineage, which became apparently tolerant to self-antigens [3]. The second mechanism is closely related, and consists in the reconstitution of the regulatory T-cell pool following ASCT. Tregs (CD4+ CD25+) expressing the transcription factor Foxp3 are crucial in preventing autoreactivity and restraining autoimmunity throughout life. Experimental and clinical studies have demonstrated the impact of the T regulatory network in inducing post-transplant immune tolerance in SLE [63].
Are these changes sufficient and stable enough to guarantee a rebuilding of the immune system, configured in a way that is less likely to redevelop autoimmunity? The abundant and sophisticated studies undeniably display some controversies. In a first study in autotransplanted MS patients the T cells recognizing myelin basic protein were indeed initially depleted by immunoablation, but then rapidly expanded from the reconstituted T cell repertoire in 12 months [52]. More recently, an early recovery of CD4 T-cell receptor diversity was found after “lymphoablative” conditioning and autologous CD34 cell transplantation in systemic sclerosis (SSc) patients, suggesting that the treatment is not completely T-cell ablative (or, more generally immune SC-ablative), and thus not ultimately curative [51]. This contrasts with another recent study which found that CD34+-selected progenitor cells had limited survival capacity and are therefore unlikely to be a major source of carryover of autoimmune T-cell expansions [11]. However, in a comprehensive recent study analyzing original and pooled data from autotransplanted MS patients, Mondria et al [40] found not only the previously known persistence of CSF oligoclonal bands in 88% of the reported cases, but also the persistence of the soluble lymphocyte activator CD27 – thus concluding that complete eradication of activated lymphocytes from the CNS had not been established, despite an intensive immunosuppressive regimen including ATG, CY and total body irradiation (TBI), in two fractions of 5 Gy a day at days –2 and –1. Active demyelinization and axonal damage have been found to continue after ASCT [39]. Our own clinical experience has included late (and very late) relapses, in a way that suggested a recapitulation of the natural history of lupus. So whether pressing the reset button will turn out to be immunologically curative is still uncertain.
4. What type of benefit, if any, does ASCT confer to severe, progressive, relapsing-refractory ADs?
In a recent, provocative editorial commenting on the utilization of ASCT for SADs, and more specifically for the rheumatic diseases, Illei [23] has posed the question, whether “the glass is half full or half empty”.
The effects of ASCT may be divided into two phases: the early suppression of ongoing, immuno-inflammatory events, and the later resetting of the autoimmune clock, which is closely related to the length and grade of remission. The first effect is clearly due to the immunosuppressive conditioning regimens, and is proportional to the dose intensity, and also independent from HSC rescue. No sophisticated dynamics occur here, besides the well-known combination of immunosuppression and abrogation of its attending inflammation. This first effect is responsible for its dramatic disease-arresting (“nosostatic”) properties, which have been observed in practically all actively aggressive SADs, and most demonstratively in SLE. This change occurs in the aggressive phases of disease, where ASCT may well be the most potent salvage therapy available. A clear distinction of the diverse sensitivity to ASCT according to the phases of disease has been recently made by Shevchenko et al [49], who have divided the transplant strategies for MS into “early”, “conventional” and “salvage-late” procedures. Among the many examples of this early, dramatic therapeutic effect are, besides the cancellation of systemic symptoms, the almost immediate clearance of inflammatory urinary sediments in lupus nephritis, the rapid improvement of nailfold capillaroscopy in SSc [4], and the early abrogation of Gadolinium-enhancing lesions in MS [27]. The striking disappearance of diffuse calcinosis in a child with overlap connective disease [13] and the regression of dermal fibrosis in patients with severe scleroderma [43] may be considered intermediate changes.
The impact of ASCT on SADs in the long run has been discussed in several contributions. In the most important study, Progression Free Survival (PFS), which may be considered as the most accurate estimated outcome of a therapeutic procedure, was 43% at 3 years [14]. Three apparently contrasting aspects emerge: first, that in the overwhelming majority of patients no authentic immunological cure may be realistically expected; second, that dramatic remissions occur, may be life-saving, and even long term. Thirdly, in most relapses the utilization of conventional therapies, to which the patients were formerly refractory, is generally possible.
5. Is ASCT the best available treatment for SADs?
ASCT is a powerful therapeutic procedure for SADs. But can it be regarded as the best treatment available, considering the increasing utilization of new pharmacological, prospective (phase III) clinical trials, which are being actively pursued for SSc (the ASTIS trial in Europe and the SCOT trial in North America), MS (ASTIMS, which is probably the most advanced one), Crohn’s disease (ASTIC), and SLE (ASTIL)? It is clear that this is the only way to obtain a scientifically correct answer. However, the pace of medical progress is such, that by the time that these laborious trials will have reached statistical significance, new agents may have superseded those utilized in the non-transplant arms. Furthermore, in a sizable proportion of these patients' ASCT may be integrated with other therapeutic interventions, including high-dose immunoglobulins (HDIG), biologics and possibly new, “intelligent” molecules.
Allogeneic transplantation facts and questions
More cogently than for the autologous procedure, animal experiments and results from coincidental disease patients had indicated a powerful instrument to cure autoimmunity in Allo-SCT. In an international workshop held in 2005, it was stated that “the potential for a 1-time delivery of a curative therapy is outstanding” [17]. But will it really be so? Many clinical trials are being pursued worldwide, but I shall confine myself only to published material and our personal experience.
Clinical results
A retrospective EBMT study [10] has collected 35 patients having received 38 allogeneic transplants for various ADs, hematological and non-hematological. The donors were identical siblings for 24 patients, matched unrelated donors (MUD) for 3, mismatched related for 2 and syngeneic for 3 patients. Treatment related mortality (TRM) was 22.1% at 2 years and 30.7 at 5, while death due to progression of disease was 3.2% at 2 years and 8.7% at 5. Of the 29 surviving patients 55% achieved complete clinical and laboratory remission, and 24% achieved a partial remission. The consensus is that nonmyeloablative (NST), reduced intensity conditioning regimens (RIC) should be utilized [46].
Immunological aspects
The substitution of an immune system which is behaving badly by a normal, healthy one is the rationale of the allogeneic approach, and its successful achievement is the prerequisite for embarking on a treatment which has been saddled with a 30% mortality after 5 years [17]. Although it is predictable that TRM following Allo-SCT, if further pursued, will probably become lower, both with an improvement of the learning curve and with optimized conditioning regimens, and effective GVHD control, the only legitimate motivation for performing it is achieving a cure.Allo-SCT is traditionally regarded as a “platform for immunotherapy” [24]. An exhaustive analysis of the mechanisms by which it might cure ADs has been performed by Sykes and Nikolic [53], who have placed the previously discussed GVA effect in the foreground. A retrospective study showed, in analogy to an established pattern in oncohematological diseases, that there were more relapses of coincidental ADs in patients transplanted for hematological malignancies with no GVHD, than in those who developed it [19]. However this effect could not be detected in the recent EBMT study [10], and a much greater clinical material would be necessary to obtain significant evidence.Efforts have been made, as already attempted in oncohematological diseases, to separate GVHD from GVA. A potent GVA effect was demonstrated in rat models of EAE. Clinically there is a group of patients who had been allotransplanted for SADs, in whom donor lymphocyte infusions (DLI) were necessary to achieve full donor chimerism, which ultimately ensured complete remissions of the SADs (lit in 11). These results are counterbalanced with others, which are in favor of the hypothesis that mixed chimerism might be capable of inducing long-term remissions [7]. However it has been shown that increasing mixed chimerism is conducive to graft loss in children transplanted for non-malignant disorders [45]. Full chimerism was present in two patients with rheumatoid arthritis [26] and in a 7-year old boy with Evans syndrome, in whom two autologous transplants had been previously unsuccessful [57].
Controversial evidence, however, comes from the analysis of relapsed patients. There appear to be two types of relapses. An example of the first type is the report of a failure of Allo-SCT to arrest disease activity in a patient with MS having been successfully transplanted because of coincidental chronic myeloid leukemia [38]. Even more disquieting are the aforementioned reports of patients with SADs having received Allo-SCT, but having subsequently relapsed despite full donor chimerism. The first and widely acknowledged case was a female patient with rheumatoid arthritis (RA), who received an HLA-identical transplant because of gold-induced aplastic anemia [55] and the second another patient with RA and multiple myeloma (MM), in whom the myeloma was cured but the RA relapsed [31]. The most demonstrative case is the one of a patient with severe Evans syndrome, who was transplanted from his HLA-identical sister but needed a series of DLI in order to achieve full donor chimerism and complete hematological remission. This patient unfortunately relapsed and died with a terminal hemolytic-uremic syndrome 5 years later [20]. The patient was male and had received the bone marrow of his HLA-identical sister. The immunoglobulins (IgG, IgM) eluted from his 100% XX expanded B cells were not the ones eluted from his Coombs-positive cells. It was hypothesized that the autoantibodies might have been secreted by long-lived host plasmacytes surviving in postulated marrow niches [18]. Even allowing for the hypothesis that relapses in donor cells in patients transplanted for leukemia might be less uncommon than generally thought to be, it is still an extremely rare event, having been identified in 14 out of 10,489 transplants in a recent survey [37]. In contrast, 3 relapses in the much smaller group of autoimmune allotransplanted patients inevitably causes some perplexity. Only further careful investigations will hopefully elucidate this unexpected problem.
Syngeneic transplants are a niche event. Three patients with RA received syngeneic transplants following high-dose immunosuppression. The first was a patient with severe seronegative RA, who enjoyed a long-term remission [59]. However a second patient with progressively erosive, rheumatoid factor positive RA, who was treated with high-dose CY and received an unmanipulated peripheral blood graft (PBSCT) from her identical twin sister, had a poor clinical response, associated with serological persistence64. A still unpublished case is the one of 45 year old lady with severe seropositive RA who was transplanted in Genoa from her identical twin sister on July 29, 2005. The conditioning regimen consisted of CY, 160 mg/Kg. Both rheumatoid factor and anti-cyclic citrulline peptide (CCP) titres decreased significantly (CCP from 234 to 2), but there was a clinical relapse with fever, polyarthritis and elevation of ESR, requiring further treatment.
Concluding remarks
Is there, at the time of this writing, sufficient evidence to answer the question, as to whether HSCT, in its various paradigms, is and will be the best available therapy for SADs? There has been a tendency to place the cause of autoimmunity on a faulty immune system, thus assimilating ADs to the neoplastic lymphoproliferative diseases. However most ADs result from a combination of faulty immune systems and antigen (target organ) dysfunctions. The distinction between primary and secondary ADs, the first being sustained by primary immune defaults and the latter by a predominant antigenic trigger, has been considered as helpful for the evaluation of SCT interventions. However the interaction between immune system and target organ antigenicity is extremely tight.
The autologous procedure is being performed worldwide because of its combination of safety and efficacy. It is capable of arresting progressive, otherwise refractory ADs. In addition, if utilized early in appropriate patients, it favorably changes the course of disease, even allowing for varying degrees of regeneration. Whether the autoaggressive immune system is being re-educated or, more simply, reset, is still not fully clarified. With this background, I believe that Illei’s glass [39] is more full than empty, when ASCT is performed in an early stage of disease (fig. 1). However , independently from the results, I believe that there ultimately will be an integration between the two approaches, with careful selection of individual patients.
A word of caution must be said concerning the potential development not only of PML, as already discussed, but also of therapy-related myelodysplasia and leukemia (t-MDS, t-AML), which must be closely watched for when utilizing alkylating drugs and others. Fortunately, there haven’t been such reports in this area, and recourse to ASCT in patients with SADs should not be hindered by the fear of late malignant complications, although careful long-term surveillance is mandatory.
Great expectations have been associated with allogeneic SCT, but its position is still uncertain. Ongoing trials will hopefully offer some answers to the question, or hope, whether the total eradication of a faulty immune system will be sufficient, and whether there is solid evidence of a clinically exploitable GVA effect. The unexpected relapses despite full donor chimerism are still a problem, but further experience is needed.
Summary
Two different sets of investigation are at the origin of hematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (SADs). The experimental evidence consisted in the transfer/cure of animal SADs as murine lupus by means of allogeneic but also, almost paradoxically, autologous HSCT. The clinical arm comes from serendipitous reports of patients allotransplanted for coincidental diseases, and finally cured of both conditions. The encouraging results of ASCT in experimental ADs were enthusiastically translated into human therapy by clinicians hoping to achieve great results without incurring into the rigors associated with the allogeneic procedure.
Well over 1000 ASCT for SADs have been performed worldwide at this time with multiple sclerosis (MS) and connective tissue diseases in the foreground. Transplant-related mortality (TRM) and morbidity have decreased to well under 5%. A dramatic disease-arresting effect is a constant benefit, but the whole course of the disease appears to be influenced favorably. Profound changes of the autoimmune circuitry have been demonstrated, but no authentic eradication of disease (cure?) should realistically be expected. Important multicentric prospective trials are ongoing to compare ASCT to the best available non-transplant therapies, but it may be argued that in the end both approaches will be integrated for single patients, and that new agents will possibly alter present strategies.
Allogeneic STC is eliciting great expectations, but the burden of higher mortality and morbidity with GVHD in the first place, must be considered, even when making recourse to reduced conditioning regimens (RIC). Paradoxical relapses despite complete donor chimerism have been reported. Further experience is clearly needed, but the early enthusiasm for an attractive one-shot therapy must be tempered with a realistic evaluation, at least until new significant breakthroughs have been attained.
Acknowledgements
This article is based on the materials of the perspective article in the International Journal of Clinical Rheumatology 2009; 4(4):395-408.
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Introduction
Stem cell therapy for severe autoimmune diseases (AD), generally as hematopoietic stem cell transplantation (HSCT), both allogeneic and autologous, but also more recently as gene therapy-assisted autologous HSCT, has become one of the hottest areas of clinical immunology. It has been developing progressively in the last decades, and has generated “excitement and promise as well as confusion and at times contradictory results in the lay and scientific literature” [6]. The utilization of stem cells to promote regenerative medicine must be distinguished from the purpose of suppressing autoimmune cellular and humoral aggression. This does not mean that both areas aren’t tightly connected, since supplying new pancreatic beta cells to patients with type I diabetes, whether by islet cell transplantation or by boosting their numbers by reprogramming pancreatic acinar cells, cannot resolve the disease if the autoimmune process is not eliminated [61]. In some clinical entities both effects coincide. An appropriate example is aplastic anemia (AA) and some of its minor variants (pure red cell aplasia-PRCA, pure white cell aplasia-PWCA), in which allogeneic HSCT both suppresses autoimmunity and provides new HSC [62]. In all the other autoimmune conditions this double effect has not been demonstrated conclusively.
The utilization of HSCT, overwhelmingly of the autologous modality, has been growing impressively in the last few years, and is still increasing steadily [28, 47]. Autologous HSCT (ASCT) relies on an extensive debulking of the autoaggressive immune system, followed by the re-infusion of the patients’ HSC (commonly identified as CD34+ cells). The allogeneic procedure is based on the substitution of the faulty immune system by a new healthy one, theoretically capable of eradicating the autoimmune clones by means of the classical combination of high-dose immunosuppressive therapy and a Graft-versus-Autoimmunity (GVA) effect, which will be discussed later. Whether this last intervention will be capable of achieving the Holy Grail of self-tolerance [15] is still not established, given the complexity of the pathogenesis of ADs, including the persisting antigenicity of altered “self” proteins [12] and some paradoxical post-transplant relapses despite full donor chimerism, which will be discussed later.
A brief historical recapitulation
Two streams of research, experimental and clinical, are at the origin of the increasing utilization of HSCT, autologous and allogeneic, for SADs [34]. The first animal studies had shown that the transfer of spleen and/or whole marrow cells to immunosuppressed mice could reproduce murine lupus. The culprit cells were shown to be stem or lymphoid progenitors. The next step was to ascertain whether, contrarily, healthy HSC were capable of curing experimental ADs. Human blood SC were capable of suppressing antibody production in lupus mice, perhaps the first demonstration of a curative effect by xenogeneic HSCT. More recently, it has elegantly been shown that the nonmyeloablative transplantation of purified allogeneic HSC not only prevented, but also induced stabilization or reversal of lupus symptoms in NZB mice [50]. Durable mixed chimerism was also efficacious, a point that will be discussed later. A further experimental improvement has been the intra-bone injection of HSC [21].
The resolution of experimental ADs by means of healthy, compatible allo-SCT was to be expected, considering the overwhelming genetic predisposition of inbred strains of mice, which differs from the intricacies of human ADs, in which there is a complex relationship between genetic, environmental and regulatory factors, and where impaired mechanisms of thymic selection interact, in still poorly elucidated ways, with genetic factors. As already mentioned, a GVA effect has been postulated [33], and theoretically dissected in 6 different mechanisms [53], with immune-mediated abrogation of autoreactive clones in the foreground. In practice, donor-derived immune cells are capable of mediating an anti-autoimmune effect either specifically, or as a part of a more general alloimmune reaction. In experimental autoimmune encephalomyelitis (EAE) it was shown that active alloreactivity was associated with the greatest GVA effect [60]. The second stream in favor of allo-SCT came from the clinical observation of patients affected by coincidental diseases, that is patients with ADs having developed a hematologic malignancy for which they received an allo-SCT, and were ultimately cured of both diseases [35]. There were even cases in which allo-BMT transferred the AD of the donor to the recipient, but cured the latter of his former AD.
The rationale for an apparently paradoxical procedure such as autologous HSCT, in which the patients’ immune cells, despite varying degrees of HSC depletion in vitro and/or in vivo, are administered back to them, came from the pioneering studies by van Bekkum and his group, who were able to cure EAE and adjuvant arthritis (AA), both models of human multiple sclerosis (MS) and rheumatoid arthritis (RA), by means of autologous (“pseudoautologous”) HSCT [58]. These results considerably strengthened the philosophy of autologous HSCT for human ADs, even if it was pointed out later that in animal models the abnormality of the antigen-induced type seems to reside in immunocompetent T/B cells but not in the HSC, and therefore ASCT may be curative, while in spontaneous ADs new, unaffected HSC were necessary to achieve a cure [22]. In any case, the utilization of ASCT is now widely accepted for treating severe, refractory ADs.
A powerful immunosuppressive therapy for SADs has been developed at Johns Hopkins University in Baltimore, where such patients are treated with high-dose cyclophosphamide (CY) alone, with an inevitable delay of marrow and blood reconstitution, but with results that do not differ significantly from those obtained by ASCT [5].
Finally, two new approaches appear to be integrating this area. Mesenchymal stem cells (MSC) possess several immunomodulatory properties [44], have been shown to significantly ameliorate Graft-versus-Host Disease [25] (GVHD), and have been considered a valuable therapeutic option for SADs [56]. However the role of this kind of cellular therapy in human AD, whether associated with ASCT or not, is still to be established. Another fascinating approach is based on the idea of achieving antigen-specific tolerance to treat refractory ADs, even if translating such therapies from bench to bedside is still mainly theoretical. An approach combining HSCT and transduction of the culprit self-antigens in autologous HSCs in order to achieve central (thymic) tolerance has been developed by Alderuccio and his group [2], although only in animal experiments with organ-specific autoimmune conditions at this stage.
Autologous transplantation: progress and questions
In contrast to the long interval having taken place between the first allogeneic transplants for animal ADs and translational clinical trials, ASCT quickly followed the experimental investigations. It was proposed by myself for severe SLE in 1993 [36], and then for ADs in general in 1995 [30]. The first transplants were performed for a connective tissue disease [54] and for severe SLE [32]. The following utilization of ASCT for SADs grew almost exponentially, so much so that, besides the continually increasing registered transplants in the EBMT and CIBMTR registries, a recent study by Dominique Farge et al has analyzed 900 patients [14]. Excellent reviews of specific diseases have been published recently, and a monographic issue of Autoimmunity has just been devoted to this theme [28]. Here, I shall focus on the most significant and contemporary questions.
1. Autologous HSCT for ADs has been considered a relatively safe procedure from its inception, but is it becoming safer?
Autoimmune diseases represent an extremely heterogenous spectrum of diseases, and in most of them severe-refractory forms have a poor prognosis and a greatly impaired quality of life. One cannot disagree, however, with Burt’s statement that “Treatment-related mortality needs to be very low for non-malignant diseases”1. Treatment-Related Mortality (TRM) reached 12% in the initial EBMT Registry, decreased to 7 +3% in 2005, and finally did not exceed 5% in the most recent EBMT study [14]. In this last study evidence was also found of a clear center effect, indicating that experienced teams that are well acquainted with the multi-organ involvement of SADs produce superior results. In the case of a single disease such as SLE, a collection of 162 patients transplanted in 30 Centers showed a TRM of 11% [29], However of 200 patients transplanted at Northwestern University, Chicago, the TRM using non-myeloablative conditioning regimens in 200 patients was 1.5% [8]. This does not mean, of course, that TRM cannot grow much higher in very severe conditions such as advanced scleroderma. Scleroderma-related organ disfunction contributed to treatment-related deaths [43]. In conclusion, the answer to this first question is that ASCT may be considered reasonably safe when performed by experienced teams, appropriate conditioning regimens, and on patients who are not too disease-compromised. These data need to be counterbalanced by mortality from disease progression, and require the adoption of inclusion and exclusion criteria for each category of diseases, which cannot be detailed here. Although the inclusion of patients within approved or investigational protocols is the best policy, it must be realized that, in selected patients with advanced, refractory SADs, the decision to perform ASCT will ultimately rely on a combination of clinical acumen, experienced teams, and a good patient-doctor relationship.
2. Which are the most appropriate mobilization and conditioning regimens?
The source of HSCs was initially the bone marrow (BM), but has now changed to the peripheral blood (PB) following mobilization procedures. In the previously mentioned EBMT study of 900 patients the source was PB in 827 cases [43]. The most popular mobilizing regimens generally consist of combinations of cyclophosphamide (CY) and G-CSF [47]. Mobilizing regimens incorporating CY (from 2 to 4g/m2) have the additional, significant advantage of acting as an important therapeutic procedure per se (therapeutic mobilization). In our own experience of 9 SLE patients the achievement of a complete remission (CR) following mobilization with CY 4g/m2 enabled us, in 2 cases, to dispense from performing the initially programmed ASCT.
A variety of conditioning regimens have been utilized, but it could be shown that high-intensity protocols were followed by a lower probability of disease progression, albeit with a higher risk of TRM [16]. The strategy of performing intense immunosuppression without affecting the whole of the hematopoietic system is most generally accepted, taking into account that biologics such as Rituximab have a longer immunosuppressive activity than any chemotherapeutic agent. A combination of both strategies, in which Rituximab 500 mg is given before and after the regular 200 mg/kg CY protocol (the “sandwich technique”), is being currently utilized at Northwestern University, Chicago (USA). Anti-CD20 immunotherapy for the control of relapse following ASCT in patients with rheumatoid arthritis (RA) had been already utilized with success [41], and the strategy of using an additional immunotherapy in this area is attractive. Unfortunately a devastating complication, progressive multifocal leukoencephalopathy (PML), due to the activation of the John Cunningham virus (JCV), has been reported in a disquieting proportion of patients having been immunosuppressed with biological agents (Natalizumab, Rituximab). A recent review reported 52 patients as having developed PML, 7 of which had received HSCT (3 allogeneic, 4 autologous) for lymphoproliferative diseases [9]. Awareness is obviously needed of the potential for PML among Rituximab-treated patients. Maximal immunosuppression produces greater benefits, but may at the same time be associated with unforeseen iatrogenic complications.
3. What significant changes in the immune system take place following ASCT ? Are we really curing autoimmunity ?
No other aspect of the ASCT-based procedures has been the object of so much research, controversy, enthusiasm, and skepticism. A prolonged depression of CD4+ CD45RA cells is a general finding, and takes place following both ASCT and high-dose immunosuppressive therapy (HDIS) alone. The type of immunomodulation which then follows has been called a “black box” by Muraro and Douek [42], but, thanks to their own and others’ investigations, is becoming increasingly clear. High-dose immunosuppression reduces the population of autoimmune cells to minimal residual autoimmune disease (MRAD). While the cure of oncohematological disease requires the eradication of cancer SC, a different view is entertained for ADs. Two basic mechanisms have been postulated.The first has been defined as a “re-education” of the faulty immune system [1], obtained by restoring a diverse antigen-specific repertoire through reactivation of the thymic output (“thymic rebound”), which has also been shown to persist in adults, albeit in lesser measure. In a recent study of ASCT in 7 SLE patients the Berlin group has found evidence for an overwhelming regeneration of the adoptive immune system and of the B-cell lineage, which became apparently tolerant to self-antigens [3]. The second mechanism is closely related, and consists in the reconstitution of the regulatory T-cell pool following ASCT. Tregs (CD4+ CD25+) expressing the transcription factor Foxp3 are crucial in preventing autoreactivity and restraining autoimmunity throughout life. Experimental and clinical studies have demonstrated the impact of the T regulatory network in inducing post-transplant immune tolerance in SLE [63].
Are these changes sufficient and stable enough to guarantee a rebuilding of the immune system, configured in a way that is less likely to redevelop autoimmunity? The abundant and sophisticated studies undeniably display some controversies. In a first study in autotransplanted MS patients the T cells recognizing myelin basic protein were indeed initially depleted by immunoablation, but then rapidly expanded from the reconstituted T cell repertoire in 12 months [52]. More recently, an early recovery of CD4 T-cell receptor diversity was found after “lymphoablative” conditioning and autologous CD34 cell transplantation in systemic sclerosis (SSc) patients, suggesting that the treatment is not completely T-cell ablative (or, more generally immune SC-ablative), and thus not ultimately curative [51]. This contrasts with another recent study which found that CD34+-selected progenitor cells had limited survival capacity and are therefore unlikely to be a major source of carryover of autoimmune T-cell expansions [11]. However, in a comprehensive recent study analyzing original and pooled data from autotransplanted MS patients, Mondria et al [40] found not only the previously known persistence of CSF oligoclonal bands in 88% of the reported cases, but also the persistence of the soluble lymphocyte activator CD27 – thus concluding that complete eradication of activated lymphocytes from the CNS had not been established, despite an intensive immunosuppressive regimen including ATG, CY and total body irradiation (TBI), in two fractions of 5 Gy a day at days –2 and –1. Active demyelinization and axonal damage have been found to continue after ASCT [39]. Our own clinical experience has included late (and very late) relapses, in a way that suggested a recapitulation of the natural history of lupus. So whether pressing the reset button will turn out to be immunologically curative is still uncertain.
4. What type of benefit, if any, does ASCT confer to severe, progressive, relapsing-refractory ADs?
In a recent, provocative editorial commenting on the utilization of ASCT for SADs, and more specifically for the rheumatic diseases, Illei [23] has posed the question, whether “the glass is half full or half empty”.
The effects of ASCT may be divided into two phases: the early suppression of ongoing, immuno-inflammatory events, and the later resetting of the autoimmune clock, which is closely related to the length and grade of remission. The first effect is clearly due to the immunosuppressive conditioning regimens, and is proportional to the dose intensity, and also independent from HSC rescue. No sophisticated dynamics occur here, besides the well-known combination of immunosuppression and abrogation of its attending inflammation. This first effect is responsible for its dramatic disease-arresting (“nosostatic”) properties, which have been observed in practically all actively aggressive SADs, and most demonstratively in SLE. This change occurs in the aggressive phases of disease, where ASCT may well be the most potent salvage therapy available. A clear distinction of the diverse sensitivity to ASCT according to the phases of disease has been recently made by Shevchenko et al [49], who have divided the transplant strategies for MS into “early”, “conventional” and “salvage-late” procedures. Among the many examples of this early, dramatic therapeutic effect are, besides the cancellation of systemic symptoms, the almost immediate clearance of inflammatory urinary sediments in lupus nephritis, the rapid improvement of nailfold capillaroscopy in SSc [4], and the early abrogation of Gadolinium-enhancing lesions in MS [27]. The striking disappearance of diffuse calcinosis in a child with overlap connective disease [13] and the regression of dermal fibrosis in patients with severe scleroderma [43] may be considered intermediate changes.
The impact of ASCT on SADs in the long run has been discussed in several contributions. In the most important study, Progression Free Survival (PFS), which may be considered as the most accurate estimated outcome of a therapeutic procedure, was 43% at 3 years [14]. Three apparently contrasting aspects emerge: first, that in the overwhelming majority of patients no authentic immunological cure may be realistically expected; second, that dramatic remissions occur, may be life-saving, and even long term. Thirdly, in most relapses the utilization of conventional therapies, to which the patients were formerly refractory, is generally possible.
5. Is ASCT the best available treatment for SADs?
ASCT is a powerful therapeutic procedure for SADs. But can it be regarded as the best treatment available, considering the increasing utilization of new pharmacological, prospective (phase III) clinical trials, which are being actively pursued for SSc (the ASTIS trial in Europe and the SCOT trial in North America), MS (ASTIMS, which is probably the most advanced one), Crohn’s disease (ASTIC), and SLE (ASTIL)? It is clear that this is the only way to obtain a scientifically correct answer. However, the pace of medical progress is such, that by the time that these laborious trials will have reached statistical significance, new agents may have superseded those utilized in the non-transplant arms. Furthermore, in a sizable proportion of these patients' ASCT may be integrated with other therapeutic interventions, including high-dose immunoglobulins (HDIG), biologics and possibly new, “intelligent” molecules.
Allogeneic transplantation facts and questions
More cogently than for the autologous procedure, animal experiments and results from coincidental disease patients had indicated a powerful instrument to cure autoimmunity in Allo-SCT. In an international workshop held in 2005, it was stated that “the potential for a 1-time delivery of a curative therapy is outstanding” [17]. But will it really be so? Many clinical trials are being pursued worldwide, but I shall confine myself only to published material and our personal experience.
Clinical results
A retrospective EBMT study [10] has collected 35 patients having received 38 allogeneic transplants for various ADs, hematological and non-hematological. The donors were identical siblings for 24 patients, matched unrelated donors (MUD) for 3, mismatched related for 2 and syngeneic for 3 patients. Treatment related mortality (TRM) was 22.1% at 2 years and 30.7 at 5, while death due to progression of disease was 3.2% at 2 years and 8.7% at 5. Of the 29 surviving patients 55% achieved complete clinical and laboratory remission, and 24% achieved a partial remission. The consensus is that nonmyeloablative (NST), reduced intensity conditioning regimens (RIC) should be utilized [46].
Immunological aspects
The substitution of an immune system which is behaving badly by a normal, healthy one is the rationale of the allogeneic approach, and its successful achievement is the prerequisite for embarking on a treatment which has been saddled with a 30% mortality after 5 years [17]. Although it is predictable that TRM following Allo-SCT, if further pursued, will probably become lower, both with an improvement of the learning curve and with optimized conditioning regimens, and effective GVHD control, the only legitimate motivation for performing it is achieving a cure.Allo-SCT is traditionally regarded as a “platform for immunotherapy” [24]. An exhaustive analysis of the mechanisms by which it might cure ADs has been performed by Sykes and Nikolic [53], who have placed the previously discussed GVA effect in the foreground. A retrospective study showed, in analogy to an established pattern in oncohematological diseases, that there were more relapses of coincidental ADs in patients transplanted for hematological malignancies with no GVHD, than in those who developed it [19]. However this effect could not be detected in the recent EBMT study [10], and a much greater clinical material would be necessary to obtain significant evidence.Efforts have been made, as already attempted in oncohematological diseases, to separate GVHD from GVA. A potent GVA effect was demonstrated in rat models of EAE. Clinically there is a group of patients who had been allotransplanted for SADs, in whom donor lymphocyte infusions (DLI) were necessary to achieve full donor chimerism, which ultimately ensured complete remissions of the SADs (lit in 11). These results are counterbalanced with others, which are in favor of the hypothesis that mixed chimerism might be capable of inducing long-term remissions [7]. However it has been shown that increasing mixed chimerism is conducive to graft loss in children transplanted for non-malignant disorders [45]. Full chimerism was present in two patients with rheumatoid arthritis [26] and in a 7-year old boy with Evans syndrome, in whom two autologous transplants had been previously unsuccessful [57].
Controversial evidence, however, comes from the analysis of relapsed patients. There appear to be two types of relapses. An example of the first type is the report of a failure of Allo-SCT to arrest disease activity in a patient with MS having been successfully transplanted because of coincidental chronic myeloid leukemia [38]. Even more disquieting are the aforementioned reports of patients with SADs having received Allo-SCT, but having subsequently relapsed despite full donor chimerism. The first and widely acknowledged case was a female patient with rheumatoid arthritis (RA), who received an HLA-identical transplant because of gold-induced aplastic anemia [55] and the second another patient with RA and multiple myeloma (MM), in whom the myeloma was cured but the RA relapsed [31]. The most demonstrative case is the one of a patient with severe Evans syndrome, who was transplanted from his HLA-identical sister but needed a series of DLI in order to achieve full donor chimerism and complete hematological remission. This patient unfortunately relapsed and died with a terminal hemolytic-uremic syndrome 5 years later [20]. The patient was male and had received the bone marrow of his HLA-identical sister. The immunoglobulins (IgG, IgM) eluted from his 100% XX expanded B cells were not the ones eluted from his Coombs-positive cells. It was hypothesized that the autoantibodies might have been secreted by long-lived host plasmacytes surviving in postulated marrow niches [18]. Even allowing for the hypothesis that relapses in donor cells in patients transplanted for leukemia might be less uncommon than generally thought to be, it is still an extremely rare event, having been identified in 14 out of 10,489 transplants in a recent survey [37]. In contrast, 3 relapses in the much smaller group of autoimmune allotransplanted patients inevitably causes some perplexity. Only further careful investigations will hopefully elucidate this unexpected problem.
Syngeneic transplants are a niche event. Three patients with RA received syngeneic transplants following high-dose immunosuppression. The first was a patient with severe seronegative RA, who enjoyed a long-term remission [59]. However a second patient with progressively erosive, rheumatoid factor positive RA, who was treated with high-dose CY and received an unmanipulated peripheral blood graft (PBSCT) from her identical twin sister, had a poor clinical response, associated with serological persistence64. A still unpublished case is the one of 45 year old lady with severe seropositive RA who was transplanted in Genoa from her identical twin sister on July 29, 2005. The conditioning regimen consisted of CY, 160 mg/Kg. Both rheumatoid factor and anti-cyclic citrulline peptide (CCP) titres decreased significantly (CCP from 234 to 2), but there was a clinical relapse with fever, polyarthritis and elevation of ESR, requiring further treatment.
Concluding remarks
Is there, at the time of this writing, sufficient evidence to answer the question, as to whether HSCT, in its various paradigms, is and will be the best available therapy for SADs? There has been a tendency to place the cause of autoimmunity on a faulty immune system, thus assimilating ADs to the neoplastic lymphoproliferative diseases. However most ADs result from a combination of faulty immune systems and antigen (target organ) dysfunctions. The distinction between primary and secondary ADs, the first being sustained by primary immune defaults and the latter by a predominant antigenic trigger, has been considered as helpful for the evaluation of SCT interventions. However the interaction between immune system and target organ antigenicity is extremely tight.
The autologous procedure is being performed worldwide because of its combination of safety and efficacy. It is capable of arresting progressive, otherwise refractory ADs. In addition, if utilized early in appropriate patients, it favorably changes the course of disease, even allowing for varying degrees of regeneration. Whether the autoaggressive immune system is being re-educated or, more simply, reset, is still not fully clarified. With this background, I believe that Illei’s glass [39] is more full than empty, when ASCT is performed in an early stage of disease (fig. 1). However , independently from the results, I believe that there ultimately will be an integration between the two approaches, with careful selection of individual patients.
A word of caution must be said concerning the potential development not only of PML, as already discussed, but also of therapy-related myelodysplasia and leukemia (t-MDS, t-AML), which must be closely watched for when utilizing alkylating drugs and others. Fortunately, there haven’t been such reports in this area, and recourse to ASCT in patients with SADs should not be hindered by the fear of late malignant complications, although careful long-term surveillance is mandatory.
Great expectations have been associated with allogeneic SCT, but its position is still uncertain. Ongoing trials will hopefully offer some answers to the question, or hope, whether the total eradication of a faulty immune system will be sufficient, and whether there is solid evidence of a clinically exploitable GVA effect. The unexpected relapses despite full donor chimerism are still a problem, but further experience is needed.
Summary
Two different sets of investigation are at the origin of hematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (SADs). The experimental evidence consisted in the transfer/cure of animal SADs as murine lupus by means of allogeneic but also, almost paradoxically, autologous HSCT. The clinical arm comes from serendipitous reports of patients allotransplanted for coincidental diseases, and finally cured of both conditions. The encouraging results of ASCT in experimental ADs were enthusiastically translated into human therapy by clinicians hoping to achieve great results without incurring into the rigors associated with the allogeneic procedure.
Well over 1000 ASCT for SADs have been performed worldwide at this time with multiple sclerosis (MS) and connective tissue diseases in the foreground. Transplant-related mortality (TRM) and morbidity have decreased to well under 5%. A dramatic disease-arresting effect is a constant benefit, but the whole course of the disease appears to be influenced favorably. Profound changes of the autoimmune circuitry have been demonstrated, but no authentic eradication of disease (cure?) should realistically be expected. Important multicentric prospective trials are ongoing to compare ASCT to the best available non-transplant therapies, but it may be argued that in the end both approaches will be integrated for single patients, and that new agents will possibly alter present strategies.
Allogeneic STC is eliciting great expectations, but the burden of higher mortality and morbidity with GVHD in the first place, must be considered, even when making recourse to reduced conditioning regimens (RIC). Paradoxical relapses despite complete donor chimerism have been reported. Further experience is clearly needed, but the early enthusiasm for an attractive one-shot therapy must be tempered with a realistic evaluation, at least until new significant breakthroughs have been attained.
Acknowledgements
This article is based on the materials of the perspective article in the International Journal of Clinical Rheumatology 2009; 4(4):395-408.
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Альберто М. Мармонт
" ["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) "18274" ["VALUE"]=> array(2) { ["TEXT"]=> string(2787) "<p class="bodytext">Для обоснования целесообразности трансплантации гемопоэтических стволовых клеток (ТГСК) при тяжёлых аутоиммунных болезнях (ТАБ) приводятся результаты двух различных серий исследований. Экспериментальные доказательства основываются на положительных результатах лечения ТАБ (волчанки) у мышей посредством трансплантации аллогенных, а также, что звучит почти невероятно, аутологичных гемопоэтических стволовых клеток. Клинические доказательства основываются на сообщениях о аллотрансплантациях, сделанных по поводу других заболеваний, в результате чего были успешно вылечены и сопуствующие ТАБ. В настоящее время продолжаются мультицентрические клинические исследования, результаты которых позволят сравнить лечебный эффект трансплантации аллогенных стволовых клеток (ТАСК) с уже наиболее положительно зарекомендовавшими себя схемами лечения ТАБ без применения ТГСК, хотя, не исключено, что в будущем, в каких-то конкретных клинических случаях могут быть использованы оба подхода, и существующая лечебная тактика будет скорректирована при появлении новых лечебных препаратов. На ТАСК возлагаются большие надежды, но никогда нельзя забывать о её последствиях - высокой смертности и осложнениях, прежде всего, в результате РТПХ, даже если для профилактики используют режимы предварительного кондиционирования. </p> <h3>Ключевые слова</h3> <p>аутоиммунные болезни, трансплантация гемопоэтических стволовых клеток, аллогенная трансплантация, аутологичная трансплантация </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2741) "Для обоснования целесообразности трансплантации гемопоэтических стволовых клеток (ТГСК) при тяжёлых аутоиммунных болезнях (ТАБ) приводятся результаты двух различных серий исследований. Экспериментальные доказательства основываются на положительных результатах лечения ТАБ (волчанки) у мышей посредством трансплантации аллогенных, а также, что звучит почти невероятно, аутологичных гемопоэтических стволовых клеток. Клинические доказательства основываются на сообщениях о аллотрансплантациях, сделанных по поводу других заболеваний, в результате чего были успешно вылечены и сопуствующие ТАБ. В настоящее время продолжаются мультицентрические клинические исследования, результаты которых позволят сравнить лечебный эффект трансплантации аллогенных стволовых клеток (ТАСК) с уже наиболее положительно зарекомендовавшими себя схемами лечения ТАБ без применения ТГСК, хотя, не исключено, что в будущем, в каких-то конкретных клинических случаях могут быть использованы оба подхода, и существующая лечебная тактика будет скорректирована при появлении новых лечебных препаратов. На ТАСК возлагаются большие надежды, но никогда нельзя забывать о её последствиях - высокой смертности и осложнениях, прежде всего, в результате РТПХ, даже если для профилактики используют режимы предварительного кондиционирования.
Ключевые слова
аутоиммунные болезни, трансплантация гемопоэтических стволовых клеток, аллогенная трансплантация, аутологичная трансплантация
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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "18282" ["VALUE"]=> array(2) { ["TEXT"]=> string(1109) "<p class="bodytext">Two different sets of investigation are at the origin of hematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (SADs). The experimental evidence consisted in the transfer/cure of animal SADs as murine lupus by means of allogeneic but also, almost paradoxically, autologous HSCT. The clinical arm comes from serendipitous reports of patients allotransplanted for coincidental diseases, and ultimately cured of both conditions. Important multicentric prospective trials are ongoing to compare ASCT to the best available non-transplant therapies, but it may be argued that in the end both approaches will be integrated for single patients, and that new agents will possibly alter present strategies. Allogeneic STC is eliciting great expectations, but the burden of higher mortality and morbidity as a result of GVHD in the first place must be considered, even when making recourse to reduced conditioning regimens (RIC). </p> <h3>Keywords</h3> <p>autoimmune diseases, hematopoietic stem cell transplantation </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1063) "Two different sets of investigation are at the origin of hematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (SADs). The experimental evidence consisted in the transfer/cure of animal SADs as murine lupus by means of allogeneic but also, almost paradoxically, autologous HSCT. The clinical arm comes from serendipitous reports of patients allotransplanted for coincidental diseases, and ultimately cured of both conditions. Important multicentric prospective trials are ongoing to compare ASCT to the best available non-transplant therapies, but it may be argued that in the end both approaches will be integrated for single patients, and that new agents will possibly alter present strategies. Allogeneic STC is eliciting great expectations, but the burden of higher mortality and morbidity as a result of GVHD in the first place must be considered, even when making recourse to reduced conditioning regimens (RIC).
Keywords
autoimmune diseases, hematopoietic stem cell transplantation
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autoimmune diseases, hematopoietic stem cell transplantation
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Экспериментальные доказательства основываются на положительных результатах лечения ТАБ (волчанки) у мышей посредством трансплантации аллогенных, а также, что звучит почти невероятно, аутологичных гемопоэтических стволовых клеток. Клинические доказательства основываются на сообщениях о аллотрансплантациях, сделанных по поводу других заболеваний, в результате чего были успешно вылечены и сопуствующие ТАБ. В настоящее время продолжаются мультицентрические клинические исследования, результаты которых позволят сравнить лечебный эффект трансплантации аллогенных стволовых клеток (ТАСК) с уже наиболее положительно зарекомендовавшими себя схемами лечения ТАБ без применения ТГСК, хотя, не исключено, что в будущем, в каких-то конкретных клинических случаях могут быть использованы оба подхода, и существующая лечебная тактика будет скорректирована при появлении новых лечебных препаратов. На ТАСК возлагаются большие надежды, но никогда нельзя забывать о её последствиях - высокой смертности и осложнениях, прежде всего, в результате РТПХ, даже если для профилактики используют режимы предварительного кондиционирования. </p> <h3>Ключевые слова</h3> <p>аутоиммунные болезни, трансплантация гемопоэтических стволовых клеток, аллогенная трансплантация, аутологичная трансплантация </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2741) "Для обоснования целесообразности трансплантации гемопоэтических стволовых клеток (ТГСК) при тяжёлых аутоиммунных болезнях (ТАБ) приводятся результаты двух различных серий исследований. Экспериментальные доказательства основываются на положительных результатах лечения ТАБ (волчанки) у мышей посредством трансплантации аллогенных, а также, что звучит почти невероятно, аутологичных гемопоэтических стволовых клеток. Клинические доказательства основываются на сообщениях о аллотрансплантациях, сделанных по поводу других заболеваний, в результате чего были успешно вылечены и сопуствующие ТАБ. В настоящее время продолжаются мультицентрические клинические исследования, результаты которых позволят сравнить лечебный эффект трансплантации аллогенных стволовых клеток (ТАСК) с уже наиболее положительно зарекомендовавшими себя схемами лечения ТАБ без применения ТГСК, хотя, не исключено, что в будущем, в каких-то конкретных клинических случаях могут быть использованы оба подхода, и существующая лечебная тактика будет скорректирована при появлении новых лечебных препаратов. На ТАСК возлагаются большие надежды, но никогда нельзя забывать о её последствиях - высокой смертности и осложнениях, прежде всего, в результате РТПХ, даже если для профилактики используют режимы предварительного кондиционирования.
Ключевые слова
аутоиммунные болезни, трансплантация гемопоэтических стволовых клеток, аллогенная трансплантация, аутологичная трансплантация
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2741) "Для обоснования целесообразности трансплантации гемопоэтических стволовых клеток (ТГСК) при тяжёлых аутоиммунных болезнях (ТАБ) приводятся результаты двух различных серий исследований. Экспериментальные доказательства основываются на положительных результатах лечения ТАБ (волчанки) у мышей посредством трансплантации аллогенных, а также, что звучит почти невероятно, аутологичных гемопоэтических стволовых клеток. Клинические доказательства основываются на сообщениях о аллотрансплантациях, сделанных по поводу других заболеваний, в результате чего были успешно вылечены и сопуствующие ТАБ. В настоящее время продолжаются мультицентрические клинические исследования, результаты которых позволят сравнить лечебный эффект трансплантации аллогенных стволовых клеток (ТАСК) с уже наиболее положительно зарекомендовавшими себя схемами лечения ТАБ без применения ТГСК, хотя, не исключено, что в будущем, в каких-то конкретных клинических случаях могут быть использованы оба подхода, и существующая лечебная тактика будет скорректирована при появлении новых лечебных препаратов. На ТАСК возлагаются большие надежды, но никогда нельзя забывать о её последствиях - высокой смертности и осложнениях, прежде всего, в результате РТПХ, даже если для профилактики используют режимы предварительного кондиционирования.
Ключевые слова
аутоиммунные болезни, трансплантация гемопоэтических стволовых клеток, аллогенная трансплантация, аутологичная трансплантация
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High-dose immunosuppressive therapy with hemopoietic stem cell transplantation (HSCT) was already introduced into the management of multiple sclerosis (MS) in 1995 [8]. The method was based on the concept of an immunological “renewal” after (near)-complete eradication of the aberrant immune system responsible for the development of the disease. Experimental hemopoietic transplants in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), performed in Israel and in the Netherlands, showed that the induction of profound and long-lasting immunosuppression followed by allogeneic or syngeneic or (pseudo)-autologous HSCT can actually have a beneficial impact on the course of EAE [3]. At that time, there was a need for new effective treatments for MS; in particular for the rapidly progressing, therapy-resistant cases, as the results of the existing standard therapies, namely interferon-beta and glatiramer acetate, were rather moderate to poor and their effect on the progression of disability was only marginal.
In order to eradicate the immune system and in view of the lack of a purely immunotoxic regimen, the proposal was for MS patients to be treated with high-dose chemotherapeutic agents (carmustin/ etoposide/ araC/ melphalan or busulfan/ cyclophosphamide) or total body irradiation (TBI), in the way patients with lymphoma or leukemia are conditioned for HSCT. To rescue the patient, autologous grafts were used, purged of T cells or CD34+ cell-selected. These were harvested from peripheral blood stem cells mobilized by cyclophosphamide plus G-CSF prior to HSCT. Intravenous anti-lymphocyte globulins (ALG, ATG) were also administered in the peri-transplant period in order to further eradicate any auto-reactive lymphocytes surviving the conditioning regimen or re-infused with the autologous graft. The “debulking” of autoreactive clones followed by reconstitution of the immune system in the presence of auto-antigens was speculated to bring about, apart from the abrogation of inflammation, qualitative changes as well, which might induce a degree of self-tolerance.
Since 1995, a number of centers in the European Union, Russia, Israel, China, USA, Canada, and Latin America have reported their experience in treating progressing, mainly advanced-stage and standard-therapy-resistant MS with high-dose immunosuppression and HSCT [9]. It is estimated that more than 400 patients have so far been treated worldwide, and favorable results have been reported with certain spectacular and long-lasting beneficial outcomes. However, after fourteen years of experience, the number of centers performing HSCT for MS still remains limited and few patients are referred for this kind treatment, which has not yet been accepted as an established therapy for aggressive MS because the neurological communities have constantly kept a skeptical attitude towards it. The reason lies mainly in the toxic complications of HSCT, especially in the risk of mortality associated with the procedure, which may be elevated in improperly selected patients [25]. This attitude has, unfortunately, prevented the accomplishment of comparative studies that were initiated in Europe (ASTIMS) and the USA (MIST, HALTMS) [11] some years ago and have not yet been finalized. In the meantime, other therapies emerged that were claimed to give good results in MS, e.g., mitoxantrone, alemtuzumab, rituximab, and natalizumab.
HSCT has been shown to be a most powerful immunosuppressive and anti-inflammatory treatment. Since 2000, all communications have consistently reported a dramatic, almost 100%, reduction in, or disappearance of, disease activity (inflammation) on magnetic resonance imaging (MRI) which is retained with time and has not been observed as an outcome of any other MS treatment [16, 26, 10, 23]. Also, brain atrophy, which seems to continue after HSCT as a result of edema resolution, slows down after the 2nd post-HSCT year [22, 12]. Consequently, patients with a lot of inflammation in the CNS experience substantial improvement of their disability status. On the other hand, patients with long-standing disease and those with primary progressive MS, i.e., cases in which the neurodegenerative component of the disease prevails, may not respond to HSCT [4]. This has been detected clinically and also in histopathological examinations of autopsy material, which show ongoing demyelination and axonal damage despite marked suppression of inflammation [19].
With regard to the clinical results of HSCT, it must first be noted that the great majority of the patient series treated worldwide had advanced disease with median EDSS scores of 6 to 6.5, while about 20% of the patients had primary progressive MS. All patients had evidence of disease progression over the twelve months preceding HSCT and/or gadolinium-enhancing lesions in MRI. After HSCT, improvement of disability scores by 1 to 4 steps was observed with a great reduction in the yearly relapse rate and a probability of disease progression-free survival (PFS) of 60–80% at three years [9, 25, 11, 10, 18]. At 10 years post-HSCT, PFS was around 65% for secondary and 40% for primary progressive MS (Fassas, unpublished data). Moreover, the patients’ quality of life and the physical and mental health have also been reported to improve [24]. The most dramatic effect, however, was seen in the so-called “malignant” cases of MS, which have a devastating course unresponsive to any standard therapy. In such cases, HSCT has been shown to be life-saving, with meaningful clinical improvement and long-standing disease stabilization [17, 14, 21, 15, 7].
From the immunological point of view, the effects of HSCT, especially the long-term ones on disease stabilization or on reduction in activity, do not seem to derive only from the immunosuppressive effect of the conditioning regimen, i.e., the “debulking” of auto-reactive clones, because MBP-recognizing T cells usually reappear within a year after HSCT [27, 6]. Immunological studies have shown that the speculated immunological remodulation can actually become a fact after HSCT. Expansion of naive CD4+ cells of thymic origin, decrease of memory T cells, reconstitution of broad clonal diversity, and renewal of clonal specificities have been described to occur after HSCT using high-intensity conditioning regimens (e.g. busulfan 16mg/kg.b.wt. or TBI) [20]. These changes may possibly create tolerance or tip the immunological balance towards suppression of autoimmunity and explain the long-standing beneficial effects of HSCT. Recently, there has been a tendency to use “light” conditioning regimens, e.g., cyclophosphamide 200mg/k.b.wt. plus alemtuzumab or ATG in order to diminish the procedure-related mortality risk. Low-intensity conditioning regimens are, too, capable of inducing immune changes, like the renewal of the balance between CD4+25+FoxP3 regulatory and other T cells or like the deviation of a proinflammatory phenotype of autoimmune cells to a tolerant one [2, 1]. There seems to be a difference in the kind of immune reconstitution brought about by the two types of conditioning, high and low, and we still do not know whether this difference might have the same or a different (better or worse) impact on the clinical outcome. It has been reported, however, that, although “light” conditioning regimens do have less toxicity, they are also associated with more autoimmune relapse after HSCT, compared to “strong” regimens [5, 13]. The regimen of cyclophosphamide plus ATG is less toxic than others but does not appear to have the same good impact on MRI compared to the intermediate-intensity BEAM (carmustine/ etoposide/ araC/ melphalan) [18]. The number of relapses after HSCT with cyclophosphamide plus alemtuzumab or ATG appears somewhat elevated [5], and it is still too early to conclude on the long-term effects on disease progression.
HSCT is a toxic treatment with a variety of complications depending on the intensity of the conditioning regimen [9, 25]. Although a patient may undergo HSCT without any problems, it not unusual for infections, organ damage, and transient neurological worsening to develop during the early post-transplant period. Secondary autoimmune phenomena may also appear late after HSCT. In the two EBMT reports of 2002 and 2006, the procedure-related mortality was 6% in 85 cases [9] and 5.3% in 185 cases [25], respectively. However, the mortality has dropped considerably from 7.3% in transplants before the year 2000 to 1.3% after the year 2000 [18]. This is the result of better patient selection, reserving HSCT for younger, ambulatory, not too-disabled patients, and avoiding the use of too “strong” and too intensive conditioning regimens, i.e., ex-vivo plus in-vivo, and lymphocyte depletion.
In summary, the analyses of the EBMT registry cases have shown that HSCT is active in the inflammatory phases of MS and is capable of slowing down the progression of the disease in relapsing/remitting cases and in patients that have recently entered the secondary progressive phase. Younger patients with low disability scores are more likely to benefit from this therapy. HSCT can be life-saving in desperate cases of very aggressive, rapidly progressing disease, which is refractory to any other therapy. HSCT is not curative, but it may offer prolonged periods of clinical disease stabilization or may change an aggressive disease course. It is not a therapy for the general population of MS patients, as the benefit does not justify the morbidity and mortality risks in cases of already stable disease, in primary progressive or long-standing secondary progressive MS, in cases without gadolinium-positive (inflammatory) lesions on MRI, and in wheelchair-bound patients (EDSS score ≥7) with low performance status and medical co-morbidities. In contrast, the best candidates, in whom the benefit of HSCT outweighs the risks, are young (below 40 years of age), who are still ambulatory, have active and rapidly progressing disease with inflammatory lesions in the CNS, and are in relapsing/remitting or recent secondary progressive phase without much disability. If such MS patients have no accompanying medical co-morbidities precluding transplantation, they may undergo HSCT with a practically zero mortality risk and a good outlook for clinical improvement and/or long disease stability.
It is well known that MS is a very difficult disease in which to show the efficacy of a therapy. Despite the very interesting outcomes of HSCT in treatment of MS, it is only in comparative trials that its superiority over other therapies can be demonstrated. Therefore, it is absolutely necessary to complete the running randomized studies comparing HSCT with mitoxantrone (ASTIMS) or other standard therapies. Unless such trials yield their final results, HSCT will never be approved as an established therapy for MS patients, who may therefore miss the opportunity of receiving an active, powerful immunosuppressive and immunomodulating treatment having a long-term beneficial impact on the course of the disease.
References
1. Abrahamsson SV, et al. Effects of immunosupressive conditioning regimens on immune reconstitution after haematopoietic stem cell transplantation in patients with MS. Mult Scler. 2007;P814.
2. Abrahamsson S. and Muraro PA. Immune re-education following autologous hematopoietic stem cell transplantation. Autoimmunity. 2008;41:577-584.
3. van Bekkum DW. Stem cell transplantation for autoimmuine disorders. Preclinical experiments. Best Pract Res Clin Haematol. 2004;17:201-222.
5. Burt RK, et al. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009;8:244-253.
6. Dubinsky AN, et al. T-cell clones persisting in the circulation after autologous hematopoietic SCT are undetectable in the peripheral CD34+ selected graft. Bone Marrow Transplant. 2009 June 22 [Epub ahead of print].
7. Fagius J, et al. Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation. Mult Scler. 2009;15:229-237.
9. Fassas A, et al. for the Autoimmune Disease Working Party of the EBMT (European Group for Blood and Marrow Transplantation): Hematopoietic stem cell transplantation for multiple sclerosis: a retrospective multicenter study. J Neurol. 2002;249:1088-1097.
10. Fassas A. and Nash R. Stem cell transplantation for autoimmune disorders. Multiple sclerosis. Best Pract Res Clin Haematol. 2004;17:247-262.
11. Fassas A. and Mancardi GL. Autologous hemopoietic stem cell transplantation for multiple sclerosis: is it worthwile? Autoimmunity. 2008;41:601-610.
13. Hamerschlak N, et al. Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG. Bone Marrow Transplant. 2009 Jul6. [Epub ahead of print].
14. Havrdova E. Aggressive multiple sclerosis - is there a role for stem cell transplantation? J Neurol. 2005;252[Suppl 3]:III/34-III37.
15. Kimiskidis V, et al. Treatment of a malignant form of multiple sclerosis with immune ablation and autologous stem cell transplantation. Mult Scler. 2008;14:278-283.
16. Mancardi GL, et al. and the Italian GITMO-NEURO Intergroup on Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis: Autologous hematopoietic stem cell transplantation suppresses Gd-enhanced MRI activity in MS. Neurology. 2001;57:62-68.
17. Mancardi GL, et al. Autologous stem cell transplantation as rescue therapy in malignant forms of multiple sclerosis. Mult Scler. 2005;11:367-371.
18. Mancardi G. and Saccardi R. Autologous haematopoetic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 2008;7:626-636.
21. Portaccio E, et al. Autologous hematopoietic stem cell transplantation for very active relapsing-remitting multiple sclerosis: report of two cases. Mult Scler. 2007;13:676-678.
23. Roccatagliata L, et al. Italian GITMO-NEURO Intergroup on Autologous Stem Cell Transplantation. The long-term effect of AHSCT on MRI measures of MS evolution: a five-year follow-up study. Mult Scler. 2007;13:1068-1070.
25. Saccardi R, et al. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler. 2006;12:814-823.
26. Saiz A, et al. Clinical and MRI outcome after autologous hemtopoietic stem cell transplantation in MS. Neurology. 2004;62:282-284.
27. Sun W, et al. Characteristics of T-cell receptor repertoire and myelin-reactive T cells reconstituted from autologous haematopoietic stem-cell grafts in multiple sclerosis. Brain. 2004;127:996-1008.
On the evolution of high-dose immunosuppressive therapy with autologous stem cell transplantation in multiple sclerosis
High-dose immunosuppressive therapy with hemopoietic stem cell transplantation (HSCT) was already introduced into the management of multiple sclerosis (MS) in 1995 [8]. The method was based on the concept of an immunological “renewal” after (near)-complete eradication of the aberrant immune system responsible for the development of the disease. Experimental hemopoietic transplants in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), performed in Israel and in the Netherlands, showed that the induction of profound and long-lasting immunosuppression followed by allogeneic or syngeneic or (pseudo)-autologous HSCT can actually have a beneficial impact on the course of EAE [3]. At that time, there was a need for new effective treatments for MS; in particular for the rapidly progressing, therapy-resistant cases, as the results of the existing standard therapies, namely interferon-beta and glatiramer acetate, were rather moderate to poor and their effect on the progression of disability was only marginal.
In order to eradicate the immune system and in view of the lack of a purely immunotoxic regimen, the proposal was for MS patients to be treated with high-dose chemotherapeutic agents (carmustin/ etoposide/ araC/ melphalan or busulfan/ cyclophosphamide) or total body irradiation (TBI), in the way patients with lymphoma or leukemia are conditioned for HSCT. To rescue the patient, autologous grafts were used, purged of T cells or CD34+ cell-selected. These were harvested from peripheral blood stem cells mobilized by cyclophosphamide plus G-CSF prior to HSCT. Intravenous anti-lymphocyte globulins (ALG, ATG) were also administered in the peri-transplant period in order to further eradicate any auto-reactive lymphocytes surviving the conditioning regimen or re-infused with the autologous graft. The “debulking” of autoreactive clones followed by reconstitution of the immune system in the presence of auto-antigens was speculated to bring about, apart from the abrogation of inflammation, qualitative changes as well, which might induce a degree of self-tolerance.
Since 1995, a number of centers in the European Union, Russia, Israel, China, USA, Canada, and Latin America have reported their experience in treating progressing, mainly advanced-stage and standard-therapy-resistant MS with high-dose immunosuppression and HSCT [9]. It is estimated that more than 400 patients have so far been treated worldwide, and favorable results have been reported with certain spectacular and long-lasting beneficial outcomes. However, after fourteen years of experience, the number of centers performing HSCT for MS still remains limited and few patients are referred for this kind treatment, which has not yet been accepted as an established therapy for aggressive MS because the neurological communities have constantly kept a skeptical attitude towards it. The reason lies mainly in the toxic complications of HSCT, especially in the risk of mortality associated with the procedure, which may be elevated in improperly selected patients [25]. This attitude has, unfortunately, prevented the accomplishment of comparative studies that were initiated in Europe (ASTIMS) and the USA (MIST, HALTMS) [11] some years ago and have not yet been finalized. In the meantime, other therapies emerged that were claimed to give good results in MS, e.g., mitoxantrone, alemtuzumab, rituximab, and natalizumab.
HSCT has been shown to be a most powerful immunosuppressive and anti-inflammatory treatment. Since 2000, all communications have consistently reported a dramatic, almost 100%, reduction in, or disappearance of, disease activity (inflammation) on magnetic resonance imaging (MRI) which is retained with time and has not been observed as an outcome of any other MS treatment [16, 26, 10, 23]. Also, brain atrophy, which seems to continue after HSCT as a result of edema resolution, slows down after the 2nd post-HSCT year [22, 12]. Consequently, patients with a lot of inflammation in the CNS experience substantial improvement of their disability status. On the other hand, patients with long-standing disease and those with primary progressive MS, i.e., cases in which the neurodegenerative component of the disease prevails, may not respond to HSCT [4]. This has been detected clinically and also in histopathological examinations of autopsy material, which show ongoing demyelination and axonal damage despite marked suppression of inflammation [19].
With regard to the clinical results of HSCT, it must first be noted that the great majority of the patient series treated worldwide had advanced disease with median EDSS scores of 6 to 6.5, while about 20% of the patients had primary progressive MS. All patients had evidence of disease progression over the twelve months preceding HSCT and/or gadolinium-enhancing lesions in MRI. After HSCT, improvement of disability scores by 1 to 4 steps was observed with a great reduction in the yearly relapse rate and a probability of disease progression-free survival (PFS) of 60–80% at three years [9, 25, 11, 10, 18]. At 10 years post-HSCT, PFS was around 65% for secondary and 40% for primary progressive MS (Fassas, unpublished data). Moreover, the patients’ quality of life and the physical and mental health have also been reported to improve [24]. The most dramatic effect, however, was seen in the so-called “malignant” cases of MS, which have a devastating course unresponsive to any standard therapy. In such cases, HSCT has been shown to be life-saving, with meaningful clinical improvement and long-standing disease stabilization [17, 14, 21, 15, 7].
From the immunological point of view, the effects of HSCT, especially the long-term ones on disease stabilization or on reduction in activity, do not seem to derive only from the immunosuppressive effect of the conditioning regimen, i.e., the “debulking” of auto-reactive clones, because MBP-recognizing T cells usually reappear within a year after HSCT [27, 6]. Immunological studies have shown that the speculated immunological remodulation can actually become a fact after HSCT. Expansion of naive CD4+ cells of thymic origin, decrease of memory T cells, reconstitution of broad clonal diversity, and renewal of clonal specificities have been described to occur after HSCT using high-intensity conditioning regimens (e.g. busulfan 16mg/kg.b.wt. or TBI) [20]. These changes may possibly create tolerance or tip the immunological balance towards suppression of autoimmunity and explain the long-standing beneficial effects of HSCT. Recently, there has been a tendency to use “light” conditioning regimens, e.g., cyclophosphamide 200mg/k.b.wt. plus alemtuzumab or ATG in order to diminish the procedure-related mortality risk. Low-intensity conditioning regimens are, too, capable of inducing immune changes, like the renewal of the balance between CD4+25+FoxP3 regulatory and other T cells or like the deviation of a proinflammatory phenotype of autoimmune cells to a tolerant one [2, 1]. There seems to be a difference in the kind of immune reconstitution brought about by the two types of conditioning, high and low, and we still do not know whether this difference might have the same or a different (better or worse) impact on the clinical outcome. It has been reported, however, that, although “light” conditioning regimens do have less toxicity, they are also associated with more autoimmune relapse after HSCT, compared to “strong” regimens [5, 13]. The regimen of cyclophosphamide plus ATG is less toxic than others but does not appear to have the same good impact on MRI compared to the intermediate-intensity BEAM (carmustine/ etoposide/ araC/ melphalan) [18]. The number of relapses after HSCT with cyclophosphamide plus alemtuzumab or ATG appears somewhat elevated [5], and it is still too early to conclude on the long-term effects on disease progression.
HSCT is a toxic treatment with a variety of complications depending on the intensity of the conditioning regimen [9, 25]. Although a patient may undergo HSCT without any problems, it not unusual for infections, organ damage, and transient neurological worsening to develop during the early post-transplant period. Secondary autoimmune phenomena may also appear late after HSCT. In the two EBMT reports of 2002 and 2006, the procedure-related mortality was 6% in 85 cases [9] and 5.3% in 185 cases [25], respectively. However, the mortality has dropped considerably from 7.3% in transplants before the year 2000 to 1.3% after the year 2000 [18]. This is the result of better patient selection, reserving HSCT for younger, ambulatory, not too-disabled patients, and avoiding the use of too “strong” and too intensive conditioning regimens, i.e., ex-vivo plus in-vivo, and lymphocyte depletion.
In summary, the analyses of the EBMT registry cases have shown that HSCT is active in the inflammatory phases of MS and is capable of slowing down the progression of the disease in relapsing/remitting cases and in patients that have recently entered the secondary progressive phase. Younger patients with low disability scores are more likely to benefit from this therapy. HSCT can be life-saving in desperate cases of very aggressive, rapidly progressing disease, which is refractory to any other therapy. HSCT is not curative, but it may offer prolonged periods of clinical disease stabilization or may change an aggressive disease course. It is not a therapy for the general population of MS patients, as the benefit does not justify the morbidity and mortality risks in cases of already stable disease, in primary progressive or long-standing secondary progressive MS, in cases without gadolinium-positive (inflammatory) lesions on MRI, and in wheelchair-bound patients (EDSS score ≥7) with low performance status and medical co-morbidities. In contrast, the best candidates, in whom the benefit of HSCT outweighs the risks, are young (below 40 years of age), who are still ambulatory, have active and rapidly progressing disease with inflammatory lesions in the CNS, and are in relapsing/remitting or recent secondary progressive phase without much disability. If such MS patients have no accompanying medical co-morbidities precluding transplantation, they may undergo HSCT with a practically zero mortality risk and a good outlook for clinical improvement and/or long disease stability.
It is well known that MS is a very difficult disease in which to show the efficacy of a therapy. Despite the very interesting outcomes of HSCT in treatment of MS, it is only in comparative trials that its superiority over other therapies can be demonstrated. Therefore, it is absolutely necessary to complete the running randomized studies comparing HSCT with mitoxantrone (ASTIMS) or other standard therapies. Unless such trials yield their final results, HSCT will never be approved as an established therapy for MS patients, who may therefore miss the opportunity of receiving an active, powerful immunosuppressive and immunomodulating treatment having a long-term beneficial impact on the course of the disease.
References
1. Abrahamsson SV, et al. Effects of immunosupressive conditioning regimens on immune reconstitution after haematopoietic stem cell transplantation in patients with MS. Mult Scler. 2007;P814.
2. Abrahamsson S. and Muraro PA. Immune re-education following autologous hematopoietic stem cell transplantation. Autoimmunity. 2008;41:577-584.
3. van Bekkum DW. Stem cell transplantation for autoimmuine disorders. Preclinical experiments. Best Pract Res Clin Haematol. 2004;17:201-222.
5. Burt RK, et al. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009;8:244-253.
6. Dubinsky AN, et al. T-cell clones persisting in the circulation after autologous hematopoietic SCT are undetectable in the peripheral CD34+ selected graft. Bone Marrow Transplant. 2009 June 22 [Epub ahead of print].
7. Fagius J, et al. Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation. Mult Scler. 2009;15:229-237.
9. Fassas A, et al. for the Autoimmune Disease Working Party of the EBMT (European Group for Blood and Marrow Transplantation): Hematopoietic stem cell transplantation for multiple sclerosis: a retrospective multicenter study. J Neurol. 2002;249:1088-1097.
10. Fassas A. and Nash R. Stem cell transplantation for autoimmune disorders. Multiple sclerosis. Best Pract Res Clin Haematol. 2004;17:247-262.
11. Fassas A. and Mancardi GL. Autologous hemopoietic stem cell transplantation for multiple sclerosis: is it worthwile? Autoimmunity. 2008;41:601-610.
13. Hamerschlak N, et al. Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG. Bone Marrow Transplant. 2009 Jul6. [Epub ahead of print].
14. Havrdova E. Aggressive multiple sclerosis - is there a role for stem cell transplantation? J Neurol. 2005;252[Suppl 3]:III/34-III37.
15. Kimiskidis V, et al. Treatment of a malignant form of multiple sclerosis with immune ablation and autologous stem cell transplantation. Mult Scler. 2008;14:278-283.
16. Mancardi GL, et al. and the Italian GITMO-NEURO Intergroup on Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis: Autologous hematopoietic stem cell transplantation suppresses Gd-enhanced MRI activity in MS. Neurology. 2001;57:62-68.
17. Mancardi GL, et al. Autologous stem cell transplantation as rescue therapy in malignant forms of multiple sclerosis. Mult Scler. 2005;11:367-371.
18. Mancardi G. and Saccardi R. Autologous haematopoetic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 2008;7:626-636.
21. Portaccio E, et al. Autologous hematopoietic stem cell transplantation for very active relapsing-remitting multiple sclerosis: report of two cases. Mult Scler. 2007;13:676-678.
23. Roccatagliata L, et al. Italian GITMO-NEURO Intergroup on Autologous Stem Cell Transplantation. The long-term effect of AHSCT on MRI measures of MS evolution: a five-year follow-up study. Mult Scler. 2007;13:1068-1070.
25. Saccardi R, et al. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler. 2006;12:814-823.
26. Saiz A, et al. Clinical and MRI outcome after autologous hemtopoietic stem cell transplantation in MS. Neurology. 2004;62:282-284.
27. Sun W, et al. Characteristics of T-cell receptor repertoire and myelin-reactive T cells reconstituted from autologous haematopoietic stem-cell grafts in multiple sclerosis. Brain. 2004;127:996-1008.
Атанасиос Фассас
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Во всех сообщениях, начиная с 2000 г., отмечается существенное (почти на 100%) снижение, или полное исчезновение признаков заболевания (воспаления), выявляемое с помощью метода ядерно-магнитного резонанса, и этот эффект сохраняется в течение длительного времени, в отличие от всех других методов лечения РС. Несмотря на весьма впечатляющие результаты применения HSCT для лечения РС, её преимущества были продемонстрированы только в сравнительных исследованиях. Поэтому представляется абсолютно необходимым завершить текущие рандомизированные исследования по сравнению HSCT с митоксантроном (ASTIMS) или с другими стандартными методами терапии. Пока не будут получены окончательные результаты этих исследований, HSCT не может быть принят как общепризнанный метод лечения больных с РС, которые могут быть лишены возможности получить действительно эффективную иммуносупрессивную и иммуномодулирующую терапию с длительным положительным воздействием на течение болезни.
Athanasios Fassas
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["VALUE"]=> array(2) { ["TEXT"]=> string(2394) "<p class="bodytext">Высокодозная иммуносупрессивная терапия и трансплантация аутологичных гемопоэтических стволовых клеток (HSCT) была введена в практику лечения больных рассеянным склерозом (РС) в 1995 г. Было показано, что HSCT является здесь наиболее эффективной иммуносупрессивной и противовоспалительной терапией. <br /><br />Во всех сообщениях, начиная с 2000 г., отмечается существенное (почти на 100%) снижение, или полное исчезновение признаков заболевания (воспаления), выявляемое с помощью метода ядерно-магнитного резонанса, и этот эффект сохраняется в течение длительного времени, в отличие от всех других методов лечения РС. Несмотря на весьма впечатляющие результаты применения HSCT для лечения РС, её преимущества были продемонстрированы только в сравнительных исследованиях. Поэтому представляется абсолютно необходимым завершить текущие рандомизированные исследования по сравнению HSCT с митоксантроном (ASTIMS) или с другими стандартными методами терапии. Пока не будут получены окончательные результаты этих исследований, HSCT не может быть принят как общепризнанный метод лечения больных с РС, которые могут быть лишены возможности получить действительно эффективную иммуносупрессивную и иммуномодулирующую терапию с длительным положительным воздействием на течение болезни. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2360) "Высокодозная иммуносупрессивная терапия и трансплантация аутологичных гемопоэтических стволовых клеток (HSCT) была введена в практику лечения больных рассеянным склерозом (РС) в 1995 г. Было показано, что HSCT является здесь наиболее эффективной иммуносупрессивной и противовоспалительной терапией.
Во всех сообщениях, начиная с 2000 г., отмечается существенное (почти на 100%) снижение, или полное исчезновение признаков заболевания (воспаления), выявляемое с помощью метода ядерно-магнитного резонанса, и этот эффект сохраняется в течение длительного времени, в отличие от всех других методов лечения РС. Несмотря на весьма впечатляющие результаты применения HSCT для лечения РС, её преимущества были продемонстрированы только в сравнительных исследованиях. Поэтому представляется абсолютно необходимым завершить текущие рандомизированные исследования по сравнению HSCT с митоксантроном (ASTIMS) или с другими стандартными методами терапии. Пока не будут получены окончательные результаты этих исследований, HSCT не может быть принят как общепризнанный метод лечения больных с РС, которые могут быть лишены возможности получить действительно эффективную иммуносупрессивную и иммуномодулирующую терапию с длительным положительным воздействием на течение болезни.
Высокодозная иммуносупрессивная терапия и трансплантация аутологичных гемопоэтических стволовых клеток (HSCT) была введена в практику лечения больных рассеянным склерозом (РС) в 1995 г. Было показано, что HSCT является здесь наиболее эффективной иммуносупрессивной и противовоспалительной терапией.
Во всех сообщениях, начиная с 2000 г., отмечается существенное (почти на 100%) снижение, или полное исчезновение признаков заболевания (воспаления), выявляемое с помощью метода ядерно-магнитного резонанса, и этот эффект сохраняется в течение длительного времени, в отличие от всех других методов лечения РС. Несмотря на весьма впечатляющие результаты применения HSCT для лечения РС, её преимущества были продемонстрированы только в сравнительных исследованиях. Поэтому представляется абсолютно необходимым завершить текущие рандомизированные исследования по сравнению HSCT с митоксантроном (ASTIMS) или с другими стандартными методами терапии. Пока не будут получены окончательные результаты этих исследований, HSCT не может быть принят как общепризнанный метод лечения больных с РС, которые могут быть лишены возможности получить действительно эффективную иммуносупрессивную и иммуномодулирующую терапию с длительным положительным воздействием на течение болезни.
Autologous versus allogeneic hematopoietic stem cell transplantation
Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) have some common and some clearly distinct goals. Both permit the application of high dose chemo-radiotherapy up to the dose limiting extramedullary toxicity; allogeneic HSCT in addition can replace a diseased host hematopoiesis, including the immune system, with a healthy donor hemopoiesis. In the case of an autoimmune disease, the necessary goal to be achieved still remains a matter of debate. High dose immunoablation can reset ontogenesis of the immune system in animal models of experimental encephalomyelitis as well as in clinical HSCT for multiple sclerosis in humans. In view of its significantly lower transplant-related mortality, autologous HSCT currently remains the preferred choice in clinical studies.
Hematopoietic stem cell transplantation (HSCT) has become the treatment of choice for many patients with severe congenital or acquired malignant or non-malignant disorders of the hematopoietic system, and for chemo-, radio-, or immuno-sensitive malignancies [1, 2]. Experimental animal studies, incidental reports from patients with HSCT for another indication but concomitant autoimmune disorders, and results from pilot studies have documented that complete remissions can be obtained in situations of severe treatment-refractory autoimmune disorders [3-6]. Animal data give clear indications that some forms of congenital autoimmune diseases can only be cured by allogeneic HSCT. Other forms of animal autoimmune diseases, considered as acquired immune disorders can just as clearly be cured by autologous HSCT alone [4, 5]. The situation is less clear in humans. Generally, autoimmune disorders in humans are considered to be induced by three independent components: a) inherited factors such as certain defined HLA-antigens, b) environmental factors such as smoking in rheumatoid arthritis and, c) chance phenomena [7].
These considerations make it clear that autologous HSCT cannot eradicate the congenital factor; it might, however, be sufficient to control the inflammatory component that was induced by chance through environmental factors in an individual patient. As such, the situation in autoimmune disorders is not so much different from the case of clonally aberrant lymphoid reactions in patients with lymphoid malignancies. In some of these high dose chemotherapy is sufficient for control of the disease; in others, an allogeneic healthy novel immune system might be required. These concepts were already well known more than ten years ago, when the European Group for Blood and Marrow Transplantation (EBMT) and the European League Against Rheumatism (EULAR) released a joint statement on the potential use of HSCT for treatment of patients with severe autoimmune disorders: the disease should be severe enough to justify the risk, the disease should not be so advanced not to permit clinical benefit for the patient, autologous HSCT should be the preferred choice, and standard techniques should be used [6, 9].
This view has not changed since. The experience from more than 200,000 HSCT procedures worldwide give some clear indications as to the potential benefits and risks of both allogeneic and autologous HSCT. Allogeneic HSCT is always linked with immunological complications, graft rejection (Host-versus-Graft reaction; HvG) and the reverse, rejection of the recipient by the immunocompetent transplanted immune system (Graft-versus-Host disease; GvHD). Furthermore, time to recovery of complete immuno-competence is considerably longer in allogeneic HSCT than in autologous HSCT. The reasons for this delayed immune recovery are probably manifold: donor-host interaction is required for competent immune response, and immunosuppression is needed to suppress both HvG reaction and GvHD. This combined and prolonged immuno-incompetence is associated with a prolonged higher risk for bacterial, fungal, viral, and parasitic infections in allogeneic, compared to autologous HSCT. For these reasons, allogeneic HSCT is associated with higher transplant related mortality (TRM) in the early as well as in the late post-transplantation period. As a benefit, allogeneic HSCT is devoid of malignant (in the case of HSCT for a malignant disease) or autoreactive (in the case of autoimmune disease) stem, precursor, or effector cells. The risk of relapse is significantly higher after autologous HSCT in all disease categories examined. The net balance of benefit and detrimental effects between autologous and allogeneic HSCT is not easy to assess. It can be very clear in some congenital or high-risk malignancies. In others, years may elapse until the beneficial effects of reduced relapse become higher than the early years of life lost after allogeneic HSCT. Overall, the best results are always obtained with syngeneic HSCT; if there is a syngeneic donor, HSCT is the preferred choice. This is true despite the fact that syngeneic twins possess an inherent risk of developing the same disease as their twin. This disease concordance for twins has clearly been shown in autoimmune disorders and in hematological malignancies [1, 10, 11].
The discordant effects of major histocompatibility antigens holds true as well for minor histocompatibility antigens (mHAg). This has been shown for the H-Y encoded mHAg. Male stem cells are more likely to be rejected by female recipients; female donors are more likely to induce more GvHD in male recipients. The detrimental effects of increased TRM in the female donor-male recipient situation never outweigh the benefits of a reduced relapse rate. Hence it is unlikely that beneficial allogeneic effects, whatever their mechanism, will outweigh the negative impact [12]. The situation in severe autoimmune disorders is even more complicated than after allogeneic HSCT for a malignancy. Some clinical features of chronic GvHD are indistinguishable from some autoimmune disorders [13]. Specifically, chronic GvHD was first described based on its resemblance with Sjögren’s syndrome, systemic sclerosis, or primary biliary cirrhosis [14]. Last but not least, late altered immunity has recently been described as a new late effect after allogeneic HSCT [15]. This syndrome includes some clinical and laboratory aspects of autoimmunity.
The introduction of reduced intensity conditioning transplants (RIC HSCT) has revolutionized clinical HSCT, expanded HSCT to patients with co-morbidities, and has abolished age limits [16]. It has also created big expectations that RIC HSCT might favor the clinical applicability of allogeneic HSCT for patients with severe autoimmune disorders. Indeed, RIC HSCT was recommended via a joint statement on allogeneic HSCT by an international panel [17]. However, experience over the last ten years with RIC HSCT for hematological malignancies does not support such expectations. Explanations are simple. The main reasons for death after an allogeneic HSCT are relapse, immunological complications (HvG and GvHD), infectious complications, and the toxicity of the conditioning regimen.
Conditioning regimens
The contribution to toxicity of the conditioning regimen is therefore just about one quarter of all toxicity. Earlier experience had clearly shown that increased conditioning intensity could reduce relapse risk, but only at the expense of higher TRM. The reverse is now the case. Reduced conditioning can reduce deaths from toxicity of the conditioning; it cannot reduce the risk of immunological complications. It does so at the expense of an increased relapse rate. The net benefit is in favor of the RIC HSCT early on, e.g., at day 100. It is lost at five-year follow up. RIC HSCT does not alter the inherent risk of the key pre-transplant patient factors as established by the EBMT risk score: age of the patient, disease stage, time interval from diagnosis to transplant, donor type, and donor recipient gender combination [11].
In summary, all current available information suggests that autologous HSCT should remain the standard approach to clinical HSCT for patients with severe autoimmune disorders including multiple sclerosis [18]. Syngeneic twin donors, if they exist, are preferred. Allogeneic HSCT can be discussed in rare patients with specific features that they are likely to benefit more, e.g., young patients with no co-morbidities and hematological autoimmune cytopenias [19].
References
1. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;27:1813-26. pmid: 16641398.
2. Gratwohl A, Baldomero H, Aljurf M, et al. Hematopoietic stem cell transplantation: a global perspective. JAMA. 2010;303:1617-24. pmid: 20424252.
5. Van Bekkum DW. Stem cell transplantation for autoimmune disorders. Preclinical experiments. Best Pract Res Clin Haematol. 2004;17:201-22. doi: 10.1016/j.beha.2004.04.003.
7. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med. 2001;345:340-50. pmid: 11484692.
8. Ringdén O, Karlsson H, Olsson R, Omazic B, Uhlin M. The allogeneic graft-versus-cancer effect. Br J Haematol. 2009;147:614-33. doi: 10.1111/j.1365-2141.2009.07886.x.
9. Marmont A, Tyndall A, Gratwohl A, Vischer T. Haemopoietic precursor-cell transplants for autoimmune diseases. Lancet. 1995;345:978.
10. Gratwohl A. Risk assessment in haematopoietic stem cell transplantation. Best Pract Res Clin Haematol. 2007;20:119-124. doi: 10.1016/j.beha.2006.10.011.
11. Gratwohl A, Stern M, Brand R et al. Risk score for outcome after alloge¬neic hematopoietic stem cell transplantation: a Retrospective Analysis. Cancer. 2009;115:4715-26. doi: 10.1002/cncr.24531.
13. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945-56.
14. Gratwohl AA, Moutsopoulos HM, Chused TM, Akizuki M, Wolf RO, Sweet JB, Deisseroth AB. Sjögren-type syndrome after allogeneic bone-marrow transplantation. Ann Intern Med. 1977;87:703-6. pmid: 22306.
16. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, Apperley J, Slavin S, Pasquini M, Sandmaier BM, Barrett J, Blaise D, Lowski R, Horowitz M. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15:1628-33. doi: 10.1016/j.bbmt.2009.07.004.
18. Farge D, Labopin M, Tyndall A, et al. Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on 12 years' experience from the European Group for Blood and Marrow Transplantation Working Party on Autoimmune Diseases. Haematologica. 2010;95:284-92.
19. Daikeler T, Hügle T, Farge D, et al. Allogeneic hematopoietic SCT for patients with autoimmune diseases. Bone Marrow Transplant. 2009;44:27-33. doi:10.1038/bmt.2008.424.
" ["~DETAIL_TEXT"]=> string(14158) "Autologous versus allogeneic hematopoietic stem cell transplantation
Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) have some common and some clearly distinct goals. Both permit the application of high dose chemo-radiotherapy up to the dose limiting extramedullary toxicity; allogeneic HSCT in addition can replace a diseased host hematopoiesis, including the immune system, with a healthy donor hemopoiesis. In the case of an autoimmune disease, the necessary goal to be achieved still remains a matter of debate. High dose immunoablation can reset ontogenesis of the immune system in animal models of experimental encephalomyelitis as well as in clinical HSCT for multiple sclerosis in humans. In view of its significantly lower transplant-related mortality, autologous HSCT currently remains the preferred choice in clinical studies.
Hematopoietic stem cell transplantation (HSCT) has become the treatment of choice for many patients with severe congenital or acquired malignant or non-malignant disorders of the hematopoietic system, and for chemo-, radio-, or immuno-sensitive malignancies [1, 2]. Experimental animal studies, incidental reports from patients with HSCT for another indication but concomitant autoimmune disorders, and results from pilot studies have documented that complete remissions can be obtained in situations of severe treatment-refractory autoimmune disorders [3-6]. Animal data give clear indications that some forms of congenital autoimmune diseases can only be cured by allogeneic HSCT. Other forms of animal autoimmune diseases, considered as acquired immune disorders can just as clearly be cured by autologous HSCT alone [4, 5]. The situation is less clear in humans. Generally, autoimmune disorders in humans are considered to be induced by three independent components: a) inherited factors such as certain defined HLA-antigens, b) environmental factors such as smoking in rheumatoid arthritis and, c) chance phenomena [7].
These considerations make it clear that autologous HSCT cannot eradicate the congenital factor; it might, however, be sufficient to control the inflammatory component that was induced by chance through environmental factors in an individual patient. As such, the situation in autoimmune disorders is not so much different from the case of clonally aberrant lymphoid reactions in patients with lymphoid malignancies. In some of these high dose chemotherapy is sufficient for control of the disease; in others, an allogeneic healthy novel immune system might be required. These concepts were already well known more than ten years ago, when the European Group for Blood and Marrow Transplantation (EBMT) and the European League Against Rheumatism (EULAR) released a joint statement on the potential use of HSCT for treatment of patients with severe autoimmune disorders: the disease should be severe enough to justify the risk, the disease should not be so advanced not to permit clinical benefit for the patient, autologous HSCT should be the preferred choice, and standard techniques should be used [6, 9].
This view has not changed since. The experience from more than 200,000 HSCT procedures worldwide give some clear indications as to the potential benefits and risks of both allogeneic and autologous HSCT. Allogeneic HSCT is always linked with immunological complications, graft rejection (Host-versus-Graft reaction; HvG) and the reverse, rejection of the recipient by the immunocompetent transplanted immune system (Graft-versus-Host disease; GvHD). Furthermore, time to recovery of complete immuno-competence is considerably longer in allogeneic HSCT than in autologous HSCT. The reasons for this delayed immune recovery are probably manifold: donor-host interaction is required for competent immune response, and immunosuppression is needed to suppress both HvG reaction and GvHD. This combined and prolonged immuno-incompetence is associated with a prolonged higher risk for bacterial, fungal, viral, and parasitic infections in allogeneic, compared to autologous HSCT. For these reasons, allogeneic HSCT is associated with higher transplant related mortality (TRM) in the early as well as in the late post-transplantation period. As a benefit, allogeneic HSCT is devoid of malignant (in the case of HSCT for a malignant disease) or autoreactive (in the case of autoimmune disease) stem, precursor, or effector cells. The risk of relapse is significantly higher after autologous HSCT in all disease categories examined. The net balance of benefit and detrimental effects between autologous and allogeneic HSCT is not easy to assess. It can be very clear in some congenital or high-risk malignancies. In others, years may elapse until the beneficial effects of reduced relapse become higher than the early years of life lost after allogeneic HSCT. Overall, the best results are always obtained with syngeneic HSCT; if there is a syngeneic donor, HSCT is the preferred choice. This is true despite the fact that syngeneic twins possess an inherent risk of developing the same disease as their twin. This disease concordance for twins has clearly been shown in autoimmune disorders and in hematological malignancies [1, 10, 11].
The discordant effects of major histocompatibility antigens holds true as well for minor histocompatibility antigens (mHAg). This has been shown for the H-Y encoded mHAg. Male stem cells are more likely to be rejected by female recipients; female donors are more likely to induce more GvHD in male recipients. The detrimental effects of increased TRM in the female donor-male recipient situation never outweigh the benefits of a reduced relapse rate. Hence it is unlikely that beneficial allogeneic effects, whatever their mechanism, will outweigh the negative impact [12]. The situation in severe autoimmune disorders is even more complicated than after allogeneic HSCT for a malignancy. Some clinical features of chronic GvHD are indistinguishable from some autoimmune disorders [13]. Specifically, chronic GvHD was first described based on its resemblance with Sjögren’s syndrome, systemic sclerosis, or primary biliary cirrhosis [14]. Last but not least, late altered immunity has recently been described as a new late effect after allogeneic HSCT [15]. This syndrome includes some clinical and laboratory aspects of autoimmunity.
The introduction of reduced intensity conditioning transplants (RIC HSCT) has revolutionized clinical HSCT, expanded HSCT to patients with co-morbidities, and has abolished age limits [16]. It has also created big expectations that RIC HSCT might favor the clinical applicability of allogeneic HSCT for patients with severe autoimmune disorders. Indeed, RIC HSCT was recommended via a joint statement on allogeneic HSCT by an international panel [17]. However, experience over the last ten years with RIC HSCT for hematological malignancies does not support such expectations. Explanations are simple. The main reasons for death after an allogeneic HSCT are relapse, immunological complications (HvG and GvHD), infectious complications, and the toxicity of the conditioning regimen.
Conditioning regimens
The contribution to toxicity of the conditioning regimen is therefore just about one quarter of all toxicity. Earlier experience had clearly shown that increased conditioning intensity could reduce relapse risk, but only at the expense of higher TRM. The reverse is now the case. Reduced conditioning can reduce deaths from toxicity of the conditioning; it cannot reduce the risk of immunological complications. It does so at the expense of an increased relapse rate. The net benefit is in favor of the RIC HSCT early on, e.g., at day 100. It is lost at five-year follow up. RIC HSCT does not alter the inherent risk of the key pre-transplant patient factors as established by the EBMT risk score: age of the patient, disease stage, time interval from diagnosis to transplant, donor type, and donor recipient gender combination [11].
In summary, all current available information suggests that autologous HSCT should remain the standard approach to clinical HSCT for patients with severe autoimmune disorders including multiple sclerosis [18]. Syngeneic twin donors, if they exist, are preferred. Allogeneic HSCT can be discussed in rare patients with specific features that they are likely to benefit more, e.g., young patients with no co-morbidities and hematological autoimmune cytopenias [19].
References
1. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;27:1813-26. pmid: 16641398.
2. Gratwohl A, Baldomero H, Aljurf M, et al. Hematopoietic stem cell transplantation: a global perspective. JAMA. 2010;303:1617-24. pmid: 20424252.
5. Van Bekkum DW. Stem cell transplantation for autoimmune disorders. Preclinical experiments. Best Pract Res Clin Haematol. 2004;17:201-22. doi: 10.1016/j.beha.2004.04.003.
7. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med. 2001;345:340-50. pmid: 11484692.
8. Ringdén O, Karlsson H, Olsson R, Omazic B, Uhlin M. The allogeneic graft-versus-cancer effect. Br J Haematol. 2009;147:614-33. doi: 10.1111/j.1365-2141.2009.07886.x.
9. Marmont A, Tyndall A, Gratwohl A, Vischer T. Haemopoietic precursor-cell transplants for autoimmune diseases. Lancet. 1995;345:978.
10. Gratwohl A. Risk assessment in haematopoietic stem cell transplantation. Best Pract Res Clin Haematol. 2007;20:119-124. doi: 10.1016/j.beha.2006.10.011.
11. Gratwohl A, Stern M, Brand R et al. Risk score for outcome after alloge¬neic hematopoietic stem cell transplantation: a Retrospective Analysis. Cancer. 2009;115:4715-26. doi: 10.1002/cncr.24531.
13. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945-56.
14. Gratwohl AA, Moutsopoulos HM, Chused TM, Akizuki M, Wolf RO, Sweet JB, Deisseroth AB. Sjögren-type syndrome after allogeneic bone-marrow transplantation. Ann Intern Med. 1977;87:703-6. pmid: 22306.
16. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, Apperley J, Slavin S, Pasquini M, Sandmaier BM, Barrett J, Blaise D, Lowski R, Horowitz M. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15:1628-33. doi: 10.1016/j.bbmt.2009.07.004.
18. Farge D, Labopin M, Tyndall A, et al. Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on 12 years' experience from the European Group for Blood and Marrow Transplantation Working Party on Autoimmune Diseases. Haematologica. 2010;95:284-92.
19. Daikeler T, Hügle T, Farge D, et al. Allogeneic hematopoietic SCT for patients with autoimmune diseases. Bone Marrow Transplant. 2009;44:27-33. doi:10.1038/bmt.2008.424.
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Вся имеющаяся в настоящее время информация предполагает, что аутологичные ТГСК должны оставаться стандартным подходом в клинической трансплантации для лечения больных с тяжелыми аутоиммунными заболеваниями, в том числе – при рассеянном склерозе. Выбор в пользу аллогенных ТГСК должен рассматриваться у немногих больных с особыми характеристиками, при которых, возможно, выгоднее использовать аллогенную ТГСК, например, для молодых пациентов без сопутствующих заболеваний и гематологических аутоиммунных цитопений. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1307) "Проведение аутологичных и аллогенных трансплантаций гемопоэтических стволовых клеток (ТГСК) имеет ряд общих целей, а также некоторые четкие различия по задачам их применения. Вся имеющаяся в настоящее время информация предполагает, что аутологичные ТГСК должны оставаться стандартным подходом в клинической трансплантации для лечения больных с тяжелыми аутоиммунными заболеваниями, в том числе – при рассеянном склерозе. Выбор в пользу аллогенных ТГСК должен рассматриваться у немногих больных с особыми характеристиками, при которых, возможно, выгоднее использовать аллогенную ТГСК, например, для молодых пациентов без сопутствующих заболеваний и гематологических аутоиммунных цитопений.
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High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (ASCT) is a promising approach to treatment of multiple sclerosis (MS) patients, since there are no effective treatment methods for this disease [4-7, 10]. HDCT+ASCT has been performed in more than 700 MS patients since 1995 all over the world. However, the patient selection criteria for HDIT +ASCT are still unclear and the proper selection of patients for transplantation remains the key issue [3, 9, 11]. In Russia more than 180 transplantations in MS patients were done within 10 years within a prospective Phase II multicenter trial coordinated by the Russian Cooperative Group for Cellular Therapy. The follow-up results of the patients who were enrolled in the Military Medical Academy (St. Petersburg) and Pirogov National Medical Surgical Center (Moscow) since 1999 are reported here. We focused on the efficacy of HDIT +ASCT in patients with different types and stages of MS. The patients underwent early, conventional, or salvage/late transplantation in accordance with the concept of HDIT +ASCT in MS [12, 13]. There are 3 strategies of HDIT +ASCT (Table 1). Early ASCT (in MS patients with EDSS 1.5–3.0) is performed soon after diagnosis in the case of primary refractory disease or poor prognosis. Conventional ASCT (EDSS 3.5–6.5) is performed in patients with secondary refractory disease. Salvage ASCT (EDSS 7.0–8.0) is an option in the case of high disease activity and rapid neurological deterioration in late stages of the disease.
Patients and Methods
132 MS patients were included in this study with a mean age of 33.0, and a male/female split of 58/74. The distribution according to the disease type was as follows: secondary progressive (SPMS): 57 patients, primary progressive (PPMS): 23, progressive-relapsing (PRMS): 9 and relapsing-remitting (RRMS): 43.
Criteria for patient selection were: age between 18 and 55 years, diagnosis of multiple sclerosis verified by clinical and laboratory findings, EDSS score 1.5–8.0, normal mental status, and absence of severe concomitant diseases.
The disease activity was determined either by magnetic resonance imaging scans displaying active lesions in the CNS (i.e., gadolinium-enhancing lesions, new or enlarging lesions on serial scans) or by clinical assessment showing rapid neurological deterioration, e.g., 0.5-point increase on the EDSS during the 6 months preceding enrollment.
Table 1. Classification of HDIT +ASCT in MS patients
|
Type of transplantation |
Pathogenetic goal |
Overall goal |
Timing |
|---|---|---|---|
|
Early transplantation |
To prevent the irreversible damage of the CNS by immunopathological process |
To stop the disease progression and |
In early stages of the disease in cases of poor prognosis |
|
Conventional transplantation |
|
To prevent the exacerbation of disability and to improve or stop the decline in patient’s QoL |
In cases of refractory disease |
|
|
|
To save a patient from complete disability and to improve severely declined patient QoL |
In late stages of the disease in cases of rapid progression of patient disability |
All three strategies of HDIT +ASCT were applied: 43 patients (32.7%) underwent early transplantation; 82 (62.0%), conventional transplantation; and 7 (5.3%) received salvage/late transplantation.
Neurological evaluation was performed at baseline, at discharge, at 3, 6, 9, and 12 months, and every 6 months thereafter; and MRI examinations at baseline, at 6, and 12 months, and at the end of follow-up.
According to the EBMT criteria of response, patients with steady EDSS scores representing halt of disease progression or with improved EDSS scores representing subsidence of inflammation in the CNS were regarded as responding to treatment. Clinical improvement was defined as a 0.5-point decrease in EDSS score as compared to the baseline. Progression was defined as an increase of at least 0.5 points. Both had to be confirmed after 6 months. Clinical relapse was defined as the appearance of new symptoms or worsening of old symptoms of at least 24-hour duration, in the absence of fever in a previously (4 weeks) stable patient.
A BEAM or BEAM-modified conditioning regimen was used.
Median EDSS at baseline was 4.5 (range 1.5-8.5). The mean follow-up duration was 21 months (range 6-120 months).
A separate group of patients was identified to whom consolidation therapy (Mitoxantrone) after HDIT +ASCT was administered. These were patients with a number of risk factors. 34 patients were enrolled in this group. The preliminary analysis of treatment outcomes in this group will be conducted by December 2009.
Results
Adverse events
No transplant-related deaths were reported; transplantation procedure was well tolerated by the patients. Mobilization was successful in all cases with a median number of 2.1 x106/kg (range 1.5-5.5 x106/kg) CD34+ cells collected; no major clinical adverse events were observed during this phase. Unmanipulated grafts were infused without complications. Engraftment was uneventful, and no signs of an engraftment syndrome were reported. Median days with PMN <0.5x109 and Plt <50x109 were 8 (range from 5 to 11) and 10 days (from 2 to 26), respectively.
Common adverse effects following the immunoablative regimen were thrombocytopenia (100%), neutropenia (100%), fatigue (100%), anemia (80%), alopecia (80%), neutropenic fever (51.6%), hepatic toxicity grade I and II (48.1%), transient neurological dysfunction (22.2%), and enteropathy (18.5%). Documented sepsis was registered in one patient.
Clinical outcomes
Eighty-seven patients with a follow-up period of at least 9 months or longer were included in the clinical outcome analysis. All patients responded to the treatment. At 6 months post-transplant the following distribution of patients according to clinical response was observed: 46 patients (52.8%) achieved an objective improvement of neurological symptoms (defined as a 0.5 point decrease in the EDSS score as compared to the baseline and confirmed over 3 months), and 41 patients (47.2 %) had disease stabilization (steady EDSS level as compared to the baseline and confirmed over 3 months). At long-term follow-up the clinical response in 40 patients (50.6%) was classified as improvement; 34 patients (43.1%) remained stable. Two patients deteriorated to a worse score after 18 months of stabilization (SPMS and PPMS; conventional auto-HSCT), and one patient after 6 months of stabilization (SPMS, conventional auto-HSCT); 2 others progressed after 12 and 30 months of improvement (RRMS, early auto-HSCT and SPMM, conventional auto-HSCT, respectively). No active, new, or enlarging lesions were registered in patients without disease progression.
The analysis of clinical outcomes at long-term follow-up was performed separately for the groups after early, conventional, and salvage transplantation. Out of 24 patients who underwent early ASCT 14 patients (58.3%) improved, 9 patients (37.5) stabilized, and one patient (4.2%) progressed (after improvement). Out of 48 patients who underwent conventional ASCT 24 patients (50%) improved, 20 patients (42%) stabilized, and 4 (8%) progressed (3 after stabilization, and 1 after improvement). In the group of patients who underwent salvage ASCT 2 patients (29%) improved and 5 (71%) were stable during the follow-up.
Remarkably, nine patients improved dramatically (1.5 points by EDSS). Patients with different types of MS were observed in this group. As an illustration, in an SPMS patient with the baseline EDSS value of 6.0 we observed a 2.0 point decrease on the EDSS scale at 1 month post-transplant, an additional 1.5 point decrease at 6 months and stabilization with EDSS score of 1.5 at 18 months post-transplant. In another case, an RRMS patient with a baseline EDSS score of 4.5 experienced a decrease in EDSS to 2.0 at 1 month post-transplant with a further decrease to 1.0 at 3 months. The latter EDSS level remained stable throughout the entire follow-up period of 1.5 years. The PRMS patient with a baseline EDSS value of 6.0 improved at 3 months to EDSS of 4.5 and then showed further improvement at 30 months post-transplant to the EDSS score of 4.0. The EDSS score at the end of follow-up (6.5 years post-transplant) was 3.5. Finally, the PPMS patient with severe disease (EDSS score of 7.5) had a 1.5 point EDSS decrease and maintained this score during 3.5 years of follow-up.
Conclusions
- The results of our study demonstrate the benefits of HDIT +ASCT in patients with various types of MS. The transplantation procedure was well tolerated by patients, with no transplant-related deaths at all. All the patients included in the efficacy analysis responded to treatment. At long-term follow-up clinical response in terms of improvement or stabilization was registered in more than 90% of patients.
- The advantage of our study is that we included patients with different types of MS. In spite of some evidence that PPMS patients are less responsive to HDIT +ASCT as compared to both SPMS and RRMS, the information about the outcomes of HSCT in patients with various types of MS is limited. The results of our study confirm that transplantation is effective not only in SPMS and RRMS patients but in PPMS as well. Thus, patients with different types of MS might benefit from HDIT +ASCT.
- Another advantage of our study is the performance of early, conventional, or salvage transplantation, while most patients in the previous studies had late stages of MS. Our data supports the idea that HDIT +ASCT is more effective in young patients with early stages of rapidly progressing disease. In these patients, autoreactive T cells play a pivotal role in MS pathogenesis. HDIT ablates the patient's immune system and eradicates autoimmune T cells. It is followed by HSCT to restore the immune system, which is expected to become tolerant to autoantigens. Such "resetting" of the immune system is only effective at early stages of MS, particularly in relapsing-remitting MS. Later in the clinical course of the disease, processes of axonal degeneration prevail and the damage to CNS tissue is too significant to expect a neurological recovery after HDIT +ASCT. Indeed, failure of HDIT +ASCT to prevent progression of the disease when performed in the late stages has been demonstrated in both animal models [1] and in clinical studies [8, 2].
- The data obtained points to the feasibility of early, conventional, and salvage HDIT +ASCT in MS patients. Further studies should be done to investigate the clinical and patient-reported outcomes in MS patients receiving early, conventional, and salvage transplantation to better define treatment success. The concept of HDIT +ASCT in MS opens a new window of opportunity for treatment of this patient population.
References
2. Burt RK, et al. Autologous haematopoietic stem cell transplantation in multiple sclerosis: importance of disease stage on outcome [abstract]. Neurology. 2003;40:A150.
3. Comi G, et al. Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and Marrow Transplantation and the European Charcot Foundation. J Neurol. 2000;247:376-382.
5. Fassas A, et al. Autologous stem cell transplantation in progressive multiple sclerosisdan interim analysis of efficacy. J Clin Immunol. 2000;20:24-30. doi: 10.1023/A:1006686426090.
6. Fassas A, et al. Haematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol. 2002;249:1088-1097. doi: 10.1007/s00415-002-0800-7.
7. Fassas A, Nash R. Multiple sclerosis. Best Pract Res Clin Hematol. 2004;17:247-262. doi: 10.1016/j.beha.2004.04.005.
10. Saccardi R, et al. Autoimmune Diseases Working Party of EBMT. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler. 2006;12:814-823.
12. Shevchenko Y, Novik A, et al. Three strategies of high dose chemotherapy (HDCT)+autologous stem cell transplantation (ASCT) in autoimmune diseases. Bone Marrow Transplantation. 2004;33(1):346.
13. Shevchenko Y. et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Experimental Hematology. 2008;36(8):922-928. doi: 10.1016/j.exphem.2008.03.001.
" ["~DETAIL_TEXT"]=> string(16652) "Introduction
High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (ASCT) is a promising approach to treatment of multiple sclerosis (MS) patients, since there are no effective treatment methods for this disease [4-7, 10]. HDCT+ASCT has been performed in more than 700 MS patients since 1995 all over the world. However, the patient selection criteria for HDIT +ASCT are still unclear and the proper selection of patients for transplantation remains the key issue [3, 9, 11]. In Russia more than 180 transplantations in MS patients were done within 10 years within a prospective Phase II multicenter trial coordinated by the Russian Cooperative Group for Cellular Therapy. The follow-up results of the patients who were enrolled in the Military Medical Academy (St. Petersburg) and Pirogov National Medical Surgical Center (Moscow) since 1999 are reported here. We focused on the efficacy of HDIT +ASCT in patients with different types and stages of MS. The patients underwent early, conventional, or salvage/late transplantation in accordance with the concept of HDIT +ASCT in MS [12, 13]. There are 3 strategies of HDIT +ASCT (Table 1). Early ASCT (in MS patients with EDSS 1.5–3.0) is performed soon after diagnosis in the case of primary refractory disease or poor prognosis. Conventional ASCT (EDSS 3.5–6.5) is performed in patients with secondary refractory disease. Salvage ASCT (EDSS 7.0–8.0) is an option in the case of high disease activity and rapid neurological deterioration in late stages of the disease.
Patients and Methods
132 MS patients were included in this study with a mean age of 33.0, and a male/female split of 58/74. The distribution according to the disease type was as follows: secondary progressive (SPMS): 57 patients, primary progressive (PPMS): 23, progressive-relapsing (PRMS): 9 and relapsing-remitting (RRMS): 43.
Criteria for patient selection were: age between 18 and 55 years, diagnosis of multiple sclerosis verified by clinical and laboratory findings, EDSS score 1.5–8.0, normal mental status, and absence of severe concomitant diseases.
The disease activity was determined either by magnetic resonance imaging scans displaying active lesions in the CNS (i.e., gadolinium-enhancing lesions, new or enlarging lesions on serial scans) or by clinical assessment showing rapid neurological deterioration, e.g., 0.5-point increase on the EDSS during the 6 months preceding enrollment.
Table 1. Classification of HDIT +ASCT in MS patients
|
Type of transplantation |
Pathogenetic goal |
Overall goal |
Timing |
|---|---|---|---|
|
Early transplantation |
To prevent the irreversible damage of the CNS by immunopathological process |
To stop the disease progression and |
In early stages of the disease in cases of poor prognosis |
|
Conventional transplantation |
|
To prevent the exacerbation of disability and to improve or stop the decline in patient’s QoL |
In cases of refractory disease |
|
|
|
To save a patient from complete disability and to improve severely declined patient QoL |
In late stages of the disease in cases of rapid progression of patient disability |
All three strategies of HDIT +ASCT were applied: 43 patients (32.7%) underwent early transplantation; 82 (62.0%), conventional transplantation; and 7 (5.3%) received salvage/late transplantation.
Neurological evaluation was performed at baseline, at discharge, at 3, 6, 9, and 12 months, and every 6 months thereafter; and MRI examinations at baseline, at 6, and 12 months, and at the end of follow-up.
According to the EBMT criteria of response, patients with steady EDSS scores representing halt of disease progression or with improved EDSS scores representing subsidence of inflammation in the CNS were regarded as responding to treatment. Clinical improvement was defined as a 0.5-point decrease in EDSS score as compared to the baseline. Progression was defined as an increase of at least 0.5 points. Both had to be confirmed after 6 months. Clinical relapse was defined as the appearance of new symptoms or worsening of old symptoms of at least 24-hour duration, in the absence of fever in a previously (4 weeks) stable patient.
A BEAM or BEAM-modified conditioning regimen was used.
Median EDSS at baseline was 4.5 (range 1.5-8.5). The mean follow-up duration was 21 months (range 6-120 months).
A separate group of patients was identified to whom consolidation therapy (Mitoxantrone) after HDIT +ASCT was administered. These were patients with a number of risk factors. 34 patients were enrolled in this group. The preliminary analysis of treatment outcomes in this group will be conducted by December 2009.
Results
Adverse events
No transplant-related deaths were reported; transplantation procedure was well tolerated by the patients. Mobilization was successful in all cases with a median number of 2.1 x106/kg (range 1.5-5.5 x106/kg) CD34+ cells collected; no major clinical adverse events were observed during this phase. Unmanipulated grafts were infused without complications. Engraftment was uneventful, and no signs of an engraftment syndrome were reported. Median days with PMN <0.5x109 and Plt <50x109 were 8 (range from 5 to 11) and 10 days (from 2 to 26), respectively.
Common adverse effects following the immunoablative regimen were thrombocytopenia (100%), neutropenia (100%), fatigue (100%), anemia (80%), alopecia (80%), neutropenic fever (51.6%), hepatic toxicity grade I and II (48.1%), transient neurological dysfunction (22.2%), and enteropathy (18.5%). Documented sepsis was registered in one patient.
Clinical outcomes
Eighty-seven patients with a follow-up period of at least 9 months or longer were included in the clinical outcome analysis. All patients responded to the treatment. At 6 months post-transplant the following distribution of patients according to clinical response was observed: 46 patients (52.8%) achieved an objective improvement of neurological symptoms (defined as a 0.5 point decrease in the EDSS score as compared to the baseline and confirmed over 3 months), and 41 patients (47.2 %) had disease stabilization (steady EDSS level as compared to the baseline and confirmed over 3 months). At long-term follow-up the clinical response in 40 patients (50.6%) was classified as improvement; 34 patients (43.1%) remained stable. Two patients deteriorated to a worse score after 18 months of stabilization (SPMS and PPMS; conventional auto-HSCT), and one patient after 6 months of stabilization (SPMS, conventional auto-HSCT); 2 others progressed after 12 and 30 months of improvement (RRMS, early auto-HSCT and SPMM, conventional auto-HSCT, respectively). No active, new, or enlarging lesions were registered in patients without disease progression.
The analysis of clinical outcomes at long-term follow-up was performed separately for the groups after early, conventional, and salvage transplantation. Out of 24 patients who underwent early ASCT 14 patients (58.3%) improved, 9 patients (37.5) stabilized, and one patient (4.2%) progressed (after improvement). Out of 48 patients who underwent conventional ASCT 24 patients (50%) improved, 20 patients (42%) stabilized, and 4 (8%) progressed (3 after stabilization, and 1 after improvement). In the group of patients who underwent salvage ASCT 2 patients (29%) improved and 5 (71%) were stable during the follow-up.
Remarkably, nine patients improved dramatically (1.5 points by EDSS). Patients with different types of MS were observed in this group. As an illustration, in an SPMS patient with the baseline EDSS value of 6.0 we observed a 2.0 point decrease on the EDSS scale at 1 month post-transplant, an additional 1.5 point decrease at 6 months and stabilization with EDSS score of 1.5 at 18 months post-transplant. In another case, an RRMS patient with a baseline EDSS score of 4.5 experienced a decrease in EDSS to 2.0 at 1 month post-transplant with a further decrease to 1.0 at 3 months. The latter EDSS level remained stable throughout the entire follow-up period of 1.5 years. The PRMS patient with a baseline EDSS value of 6.0 improved at 3 months to EDSS of 4.5 and then showed further improvement at 30 months post-transplant to the EDSS score of 4.0. The EDSS score at the end of follow-up (6.5 years post-transplant) was 3.5. Finally, the PPMS patient with severe disease (EDSS score of 7.5) had a 1.5 point EDSS decrease and maintained this score during 3.5 years of follow-up.
Conclusions
- The results of our study demonstrate the benefits of HDIT +ASCT in patients with various types of MS. The transplantation procedure was well tolerated by patients, with no transplant-related deaths at all. All the patients included in the efficacy analysis responded to treatment. At long-term follow-up clinical response in terms of improvement or stabilization was registered in more than 90% of patients.
- The advantage of our study is that we included patients with different types of MS. In spite of some evidence that PPMS patients are less responsive to HDIT +ASCT as compared to both SPMS and RRMS, the information about the outcomes of HSCT in patients with various types of MS is limited. The results of our study confirm that transplantation is effective not only in SPMS and RRMS patients but in PPMS as well. Thus, patients with different types of MS might benefit from HDIT +ASCT.
- Another advantage of our study is the performance of early, conventional, or salvage transplantation, while most patients in the previous studies had late stages of MS. Our data supports the idea that HDIT +ASCT is more effective in young patients with early stages of rapidly progressing disease. In these patients, autoreactive T cells play a pivotal role in MS pathogenesis. HDIT ablates the patient's immune system and eradicates autoimmune T cells. It is followed by HSCT to restore the immune system, which is expected to become tolerant to autoantigens. Such "resetting" of the immune system is only effective at early stages of MS, particularly in relapsing-remitting MS. Later in the clinical course of the disease, processes of axonal degeneration prevail and the damage to CNS tissue is too significant to expect a neurological recovery after HDIT +ASCT. Indeed, failure of HDIT +ASCT to prevent progression of the disease when performed in the late stages has been demonstrated in both animal models [1] and in clinical studies [8, 2].
- The data obtained points to the feasibility of early, conventional, and salvage HDIT +ASCT in MS patients. Further studies should be done to investigate the clinical and patient-reported outcomes in MS patients receiving early, conventional, and salvage transplantation to better define treatment success. The concept of HDIT +ASCT in MS opens a new window of opportunity for treatment of this patient population.
References
2. Burt RK, et al. Autologous haematopoietic stem cell transplantation in multiple sclerosis: importance of disease stage on outcome [abstract]. Neurology. 2003;40:A150.
3. Comi G, et al. Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and Marrow Transplantation and the European Charcot Foundation. J Neurol. 2000;247:376-382.
5. Fassas A, et al. Autologous stem cell transplantation in progressive multiple sclerosisdan interim analysis of efficacy. J Clin Immunol. 2000;20:24-30. doi: 10.1023/A:1006686426090.
6. Fassas A, et al. Haematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol. 2002;249:1088-1097. doi: 10.1007/s00415-002-0800-7.
7. Fassas A, Nash R. Multiple sclerosis. Best Pract Res Clin Hematol. 2004;17:247-262. doi: 10.1016/j.beha.2004.04.005.
10. Saccardi R, et al. Autoimmune Diseases Working Party of EBMT. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler. 2006;12:814-823.
12. Shevchenko Y, Novik A, et al. Three strategies of high dose chemotherapy (HDCT)+autologous stem cell transplantation (ASCT) in autoimmune diseases. Bone Marrow Transplantation. 2004;33(1):346.
13. Shevchenko Y. et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Experimental Hematology. 2008;36(8):922-928. doi: 10.1016/j.exphem.2008.03.001.
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Новик<sup>1</sup>, Алексей Н. Кузнецов<sup>1,2</sup>, Владимир Я. Мельниченко<sup>1</sup>, Денис А. Федоренко<sup>1</sup>, Tатьяна И. Ионова<sup>3</sup>, Кира А. Курбатова<sup>3</sup></span> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(316) "Aндрей A. Новик1, Алексей Н. Кузнецов1,2, Владимир Я. Мельниченко1, Денис А. Федоренко1, Tатьяна И. Ионова3, Кира А. Курбатова3
" ["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"]=> string(5) "18307" ["VALUE"]=> array(2) { ["TEXT"]=> string(1287) "<p class="bodytext"><sup>1</sup>Национальный медико-хирургический центр им. Н.И. Пирогова, Москва, Россия; <sup>2</sup>Институт усовершенствования врачей Национального медико-хирургического центра им. Н.И.Пирогова, Москва, Россия; <sup>3</sup>Межнациональный центр исследования качества жизни, Санкт-Петербург, Россия<br /><br /><b>Контакт</b><br> А. А. Новик, Национальный медико-хирургический центр им.Н.И. Пирогова, ул. Нижняя Первомайская 70, Москва, 105203, Россия<br> E-mail: <a href="javascript:linkTo_UnCryptMailto('qempxs.rgvxg48Dqemp2vy');">ncrtc04@<span style="display:none;">spam is bad</span>mail.ru</a>, <a href="javascript:linkTo_UnCryptMailto('qempxs.ruspgDcerhib2vy');">nqolc@<span style="display:none;">spam is bad</span>yandex.ru</a> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1105) "1Национальный медико-хирургический центр им. Н.И. Пирогова, Москва, Россия; 2Институт усовершенствования врачей Национального медико-хирургического центра им. Н.И.Пирогова, Москва, Россия; 3Межнациональный центр исследования качества жизни, Санкт-Петербург, Россия
Контакт
А. А. Новик, Национальный медико-хирургический центр им.Н.И. Пирогова, ул. Нижняя Первомайская 70, Москва, 105203, Россия
E-mail: ncrtc04@mail.ru, nqolc@yandex.ru
Одним из новых перспективных подходов к лечению РС является высокодозная иммуносупрессивная терапия с трансплантацией кроветворных стволовых клеток (ВИСТ+ТКСК). ВИСТ+ТКСК является эффективным методом лечения больных с различными формами РС. Целесообразно выделение следующих стратегий ВИСТ+ТКСК: ранняя трансплантация, этапная трансплантация и трансплантация спасения. Концепция ВИСТ+ТКСК открывает большие возможности для интеграции специалистов, занимающихся разработкой новых методов лечения РС, определяя основные направления дальнейших клинических исследований в данной области.
Ключевые слова
рассеянный склероз, аутологичная трансплантация стволовых кроветворных клеток, отдаленные результаты лечения, ранняя трансплантация, этапная трансплантация, трансплантация спасения
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Correspondence
Professor Tatyana I. Ionova, Multinational Center for Quality of Life Research, 1 Artilleriiskaya str., 191014 St. Petersburg, Russia
E-mail: tion16@mail.ru
High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (ASCT) is a promising approach to the treatment of multiple sclerosis (MS) patients. The data obtained points to the feasibility of early, conventional, and salvage HDIT +ASCT in MS patients. Further studies should be done to investigate clinical and patient-reported outcomes in MS patients receiving early, conventional, and salvage transplantation to better define treatment success. The concept of HDIT +ASCT in MS opens a new window of opportunity for treatment of this patient population.
Keywords
multiple sclerosis, autologous stem cell transplantation, long-term clinical outcomes, early ASCT, conventional ASCT, salvage ASCT
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Одним из новых перспективных подходов к лечению РС является высокодозная иммуносупрессивная терапия с трансплантацией кроветворных стволовых клеток (ВИСТ+ТКСК). В настоящее время в мире выполнено более 700 трансплантаций больным с различными формами РС. Безопасность и эффективность метода изучена в международных многоцентровых исследованиях. К нерешенным вопросам ВИСТ+ТСКК относятся следующие: показания, методы трансплантации, режимы кондиционирования, деплеция Т-лимфоцитов, фармакоэкономическое обоснование и др. [3, 9, 11].<br> <br> Разработана концепция ВИСТ+ТКСК при РС, включающая следующие положения: содержание метода, основные показания, методика проведения трансплантации, общий алгоритм, направления дальнейших исследований. Основные положения концепции подтверждены результатами проспективного многоцентрового исследования Российской кооперативной группы клеточной терапии изучения эффективности ВИСТ+ТКСК у больных различными формами РС. <br> <br> В рамках концепции выделено две принципиальные цели лечения больных РС. Первая из них патогенетическая – остановить прогрессирование заболевания и предотвратить появление новых очагов демиелинизации в ЦНС за счет воздействия на иммунопатологический процесс на различных уровнях. Вторая цель, основная или конечная, состоит в сохранении и, по возможности, в улучшении качества жизни больных. Данные положения основаны на теории принятия решений в клинической медицине, согласно которой в формализованном виде существует три возможных цели лечения больного: <br> <br> I – излечение с учетом качества жизни больного после выздоровления, <br> II – увеличение продолжительности жизни больного с учетом ее качества<br> III – улучшение качества жизни больного. <br> <br> При РС, хроническом неизлечимом заболевании, в большинстве случаев не снижающем продолжительность жизни больного, максимально возможное восстановление и сохранение параметров качества жизни является приоритетной целью лечения. Вследствие этого, наряду с традиционными лабораторными и инструментальными тестами, описывающими изменения в течении патологического процесса на фоне терапии, к ключевым критериям эффективности лечения РС следует отнести и показатели качества жизни больного, отражающие сложный комплекс физических, психологических и социальных детерминант, свойственных конкретному индивидууму. <br> <br> Учитывая вышесказанное, в рамках концепции выделены 3 вида трансплантации, отличающиеся по целям и времени проведения операции [12, 13]<br> <br> <b>Ранняя трансплантация</b><br> 1. Патогенетическая цель – предупредить развитие необратимых изменений в ЦНС в результате иммунопатологического процесса.<br> 2. Основная цель – сохранить качество жизни больного, предотвратить формирование инвалидизации. <br> 3. Время проведения – в дебюте заболевания.<br> <br> <b>Этапная трансплантация</b><br> 4. Патогенетическая цель – остановить прогрессирование заболевания на фоне самоподдерживающегося иммунопатологического процесса, имеющихся очагов необратимых изменений и частично утраченных функций, предупредить появление новых очагов поражения.<br> 5. Основная цель – улучшить качество жизни больного и сохранить его на максимально возможном уровне, предупредить углубление инвалидизации пациента.<br> 6. Время проведения – на различных этапах прогрессирования РС при выходе заболевания из-под контроля традиционных методов лечения.<br> <br> <b>Трансплантация спасения<br> </b>7. Патогенетическая цель – остановить прогрессирование заболевания на фоне большого количества очагов необратимых изменений и существенно нарушенных функций, предупредить появление новых очагов поражения.<br> 8. Основная цель – сохранить качество жизни больного на максимально возможном уровне, предотвратить наступление критической инвалидизации.<br> 9. Время проведения – в далеко зашедшей стадии заболевания при высокой активности иммунопатологического процесса, быстром прогрессировании инвалидизации больного. </p> <p class="bodytext"> В данном докладе представлены результаты исследования безопасности и эффективности ВИСТ+ТКСК у 132 больных РС, которым ВИСТ+ТКСК проведена в Военно-медицинской академии (Санкт-Петербург) и Национальном медико-хирургическом центре им. Н.И. Пирогова (Москва), начиная с 1999 года. В исследование включено 58 мужчин и 74 женщины; средний возраст – 33 года. У 57 пациентов была диагностирована вторично-прогрессирующая форма заболевания, у 23 – первично-прогрессирующая, у 9 – прогрессирующе-рецидивирующая и у 43 – рецидивирующая ремитирующая. Выделены три группы пациентов в зависимости от вида трансплантации: ранняя трансплантация проводилась при EDSS от 1,5 до 3,0; этапная трансплантация - при EDSS от 3,5 до 6,5; трансплантация спасения - при EDSS от 7,0 до 8,5. 83 пациентам была проведена этапная ВИСТ+ТКСК; 43 – ранняя трансплантация; 7 – трансплантация спасения. Для кондиционирования использовали режимы BEAM или mini-BEAM. Эффект ВИСТ+ТКСК оценивали по изменению степени инвалидизации больного и активности заболевания.<br> <br> Отдельно была выделена группа больных, которым проводили консолидирующую терапию (митоксантрон) после ВИСТ+ТКСК. В эту группу вошли пациенты, имеющие факторы риска. В настоящее время данная группа включает 34 пациента; анализ результатов лечения в этой группе будет проведен в декабре 2009г.<br> <br> При проведении ВИСТ+ТКСК не было летальных исходов, связанных с трансплантацией, а также тяжелых непрогнозируемых осложнений. У всех больных зарегистрирован ответ на лечение: у половины больных было зарегистрировано клиническое улучшение; у остальных – стабилизация состояния. По данным МРТ у всех больных имелось либо улучшение, либо стабилизация процесса. В отдаленные сроки после ВИСТ+ТКСК (2 года и более) у подавляющего большинства больных (более 90%) наблюдали клиническое улучшение или стабилизацию заболевания. По данным магнитно-резонансной томографии отсутствие активности заболевания зарегистрировано у всех больных с клиническим улучшением или стабилизацией. Особого внимания заслуживает группа больных, которым проведена ранняя ВИСТ+ТКСК, и группа больных, у которых трансплантацию проводили с применением немиелоаблативных режимов кондиционирования. <br> <br> ВИСТ+ТКСК является эффективным методом лечения больных с различными формами РС. Целесообразно выделение следующих стратегий ВИСТ+ТКСК: ранняя трансплантация, этапная трансплантация и трансплантация спасения. Концепция ВИСТ+ТКСК открывает большие возможности для интеграции специалистов, занимающихся разработкой новых методов лечения РС, определяя основные направления дальнейших клинических исследований в данной области. </p> <h3>Литература</h3> <p class="bodytext"> 1. <a href="http://bloodjournal.hematologylibrary.org/cgi/reprint/91/7/2609" title="Opens external link in new window" target="_blank" class="external-link-new-window"><u>Burt RK, et al. Effect of disease stage on clinical outcome after syngeneic bone marrow transplantation for relapsing experimental autoimmune encephalomyelitis. Blood. 1998;91:2609–2616</u></a><u>.</u> </p> <p class="bodytext"> 2. Burt RK, et al. Autologous haematopoietic stem cell transplantation in multiple sclerosis: importance of disease stage on outcome [abstract]. Neurology. 2003;40:A150. </p> <p class="bodytext"> 3. Comi G, et al. Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and Marrow Transplantation and the European Charcot Foundation. J Neurol. 2000;247:376-382. </p> <p class="bodytext"> 4. <a href="http://www.nature.com/bmt/journal/v20/n8/pdf/1700944a.pdf" title="Opens external link in new window" target="_blank" class="external-link-new-window"><u>Fassas A, et al. Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study. Bone Marrow Transplant. 1997;20:631-638</u></a><u>.</u> </p> <p class="bodytext"> 5. Fassas A, et al. Autologous stem cell transplantation in progressive multiple sclerosisdan interim analysis of efficacy. J Clin Immunol. 2000;20:24-30. doi: 10.1023/A:1006686426090. </p> <p class="bodytext"> 6. Fassas A, et al. Haematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol. 2002;249:1088-1097. doi: 10.1007/s00415-002-0800-7. </p> <p class="bodytext"> 7. Fassas A, Nash R. Multiple sclerosis. Best Pract Res Clin Hematol. 2004;17:247-262. doi: 10.1016/j.beha.2004.04.005. </p> <p class="bodytext"> 8. <a href="http://bloodjournal.hematologylibrary.org/cgi/content/full/102/7/2364" title="Opens external link in new window" target="_blank" class="external-link-new-window"><u>Nash RA, et al. High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood. 2003;102:2364-2372. doi: 10.1182/blood-2002-12-3908</u></a><u>.</u> </p> <p class="bodytext"> 9. <a href="http://bloodjournal.hematologylibrary.org/cgi/content/full/105/6/2601" title="Opens external link in new window" target="_blank" class="external-link-new-window"><u>Saccardi R, et al. Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life. Blood. 2005;105:2601-2607. doi: 10.1182/blood-2004-08-3205</u></a><u>.</u> </p> <p class="bodytext"> 10. Saccardi R, et al. Autoimmune Diseases Working Party of EBMT. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler. 2006;12:814-823. </p> <p class="bodytext"> 11. <a href="typo3/1-2-shevchenko-et-al-2008dec3.html" title="Opens external link in new window" class="external-link-new-window"><u>Shevchenko Y, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis. Cellular Therapy and Transplantation (CTT). 2008;1:2. doi: 10.3205/ctt-2008-en-000025.01</u></a>. </p> <p class="bodytext"> 12. Shevchenko Y, Novik A, et al. Three strategies of high dose chemotherapy (HDCT)+autologous stem cell transplantation (ASCT) in autoimmune diseases. Bone Marrow Transplantation. 2004;33(1):346. </p> <p class="bodytext"> 13. Shevchenko Y. et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Experimental Hematology. 2008;36(8):922-928. doi: 10.1016/j.exphem.2008.03.001. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(16499) "
Традиционные методы иммуномодулирующей и иммуносупрессивной терапии рассеянного склероза (РС) не позволяют достичь выраженного и длительного терапевтического эффекта [4-7, 10]. Одним из новых перспективных подходов к лечению РС является высокодозная иммуносупрессивная терапия с трансплантацией кроветворных стволовых клеток (ВИСТ+ТКСК). В настоящее время в мире выполнено более 700 трансплантаций больным с различными формами РС. Безопасность и эффективность метода изучена в международных многоцентровых исследованиях. К нерешенным вопросам ВИСТ+ТСКК относятся следующие: показания, методы трансплантации, режимы кондиционирования, деплеция Т-лимфоцитов, фармакоэкономическое обоснование и др. [3, 9, 11].
Разработана концепция ВИСТ+ТКСК при РС, включающая следующие положения: содержание метода, основные показания, методика проведения трансплантации, общий алгоритм, направления дальнейших исследований. Основные положения концепции подтверждены результатами проспективного многоцентрового исследования Российской кооперативной группы клеточной терапии изучения эффективности ВИСТ+ТКСК у больных различными формами РС.
В рамках концепции выделено две принципиальные цели лечения больных РС. Первая из них патогенетическая – остановить прогрессирование заболевания и предотвратить появление новых очагов демиелинизации в ЦНС за счет воздействия на иммунопатологический процесс на различных уровнях. Вторая цель, основная или конечная, состоит в сохранении и, по возможности, в улучшении качества жизни больных. Данные положения основаны на теории принятия решений в клинической медицине, согласно которой в формализованном виде существует три возможных цели лечения больного:
I – излечение с учетом качества жизни больного после выздоровления,
II – увеличение продолжительности жизни больного с учетом ее качества
III – улучшение качества жизни больного.
При РС, хроническом неизлечимом заболевании, в большинстве случаев не снижающем продолжительность жизни больного, максимально возможное восстановление и сохранение параметров качества жизни является приоритетной целью лечения. Вследствие этого, наряду с традиционными лабораторными и инструментальными тестами, описывающими изменения в течении патологического процесса на фоне терапии, к ключевым критериям эффективности лечения РС следует отнести и показатели качества жизни больного, отражающие сложный комплекс физических, психологических и социальных детерминант, свойственных конкретному индивидууму.
Учитывая вышесказанное, в рамках концепции выделены 3 вида трансплантации, отличающиеся по целям и времени проведения операции [12, 13]
Ранняя трансплантация
1. Патогенетическая цель – предупредить развитие необратимых изменений в ЦНС в результате иммунопатологического процесса.
2. Основная цель – сохранить качество жизни больного, предотвратить формирование инвалидизации.
3. Время проведения – в дебюте заболевания.
Этапная трансплантация
4. Патогенетическая цель – остановить прогрессирование заболевания на фоне самоподдерживающегося иммунопатологического процесса, имеющихся очагов необратимых изменений и частично утраченных функций, предупредить появление новых очагов поражения.
5. Основная цель – улучшить качество жизни больного и сохранить его на максимально возможном уровне, предупредить углубление инвалидизации пациента.
6. Время проведения – на различных этапах прогрессирования РС при выходе заболевания из-под контроля традиционных методов лечения.
Трансплантация спасения
7. Патогенетическая цель – остановить прогрессирование заболевания на фоне большого количества очагов необратимых изменений и существенно нарушенных функций, предупредить появление новых очагов поражения.
8. Основная цель – сохранить качество жизни больного на максимально возможном уровне, предотвратить наступление критической инвалидизации.
9. Время проведения – в далеко зашедшей стадии заболевания при высокой активности иммунопатологического процесса, быстром прогрессировании инвалидизации больного.
В данном докладе представлены результаты исследования безопасности и эффективности ВИСТ+ТКСК у 132 больных РС, которым ВИСТ+ТКСК проведена в Военно-медицинской академии (Санкт-Петербург) и Национальном медико-хирургическом центре им. Н.И. Пирогова (Москва), начиная с 1999 года. В исследование включено 58 мужчин и 74 женщины; средний возраст – 33 года. У 57 пациентов была диагностирована вторично-прогрессирующая форма заболевания, у 23 – первично-прогрессирующая, у 9 – прогрессирующе-рецидивирующая и у 43 – рецидивирующая ремитирующая. Выделены три группы пациентов в зависимости от вида трансплантации: ранняя трансплантация проводилась при EDSS от 1,5 до 3,0; этапная трансплантация - при EDSS от 3,5 до 6,5; трансплантация спасения - при EDSS от 7,0 до 8,5. 83 пациентам была проведена этапная ВИСТ+ТКСК; 43 – ранняя трансплантация; 7 – трансплантация спасения. Для кондиционирования использовали режимы BEAM или mini-BEAM. Эффект ВИСТ+ТКСК оценивали по изменению степени инвалидизации больного и активности заболевания.
Отдельно была выделена группа больных, которым проводили консолидирующую терапию (митоксантрон) после ВИСТ+ТКСК. В эту группу вошли пациенты, имеющие факторы риска. В настоящее время данная группа включает 34 пациента; анализ результатов лечения в этой группе будет проведен в декабре 2009г.
При проведении ВИСТ+ТКСК не было летальных исходов, связанных с трансплантацией, а также тяжелых непрогнозируемых осложнений. У всех больных зарегистрирован ответ на лечение: у половины больных было зарегистрировано клиническое улучшение; у остальных – стабилизация состояния. По данным МРТ у всех больных имелось либо улучшение, либо стабилизация процесса. В отдаленные сроки после ВИСТ+ТКСК (2 года и более) у подавляющего большинства больных (более 90%) наблюдали клиническое улучшение или стабилизацию заболевания. По данным магнитно-резонансной томографии отсутствие активности заболевания зарегистрировано у всех больных с клиническим улучшением или стабилизацией. Особого внимания заслуживает группа больных, которым проведена ранняя ВИСТ+ТКСК, и группа больных, у которых трансплантацию проводили с применением немиелоаблативных режимов кондиционирования.
ВИСТ+ТКСК является эффективным методом лечения больных с различными формами РС. Целесообразно выделение следующих стратегий ВИСТ+ТКСК: ранняя трансплантация, этапная трансплантация и трансплантация спасения. Концепция ВИСТ+ТКСК открывает большие возможности для интеграции специалистов, занимающихся разработкой новых методов лечения РС, определяя основные направления дальнейших клинических исследований в данной области.
Литература
2. Burt RK, et al. Autologous haematopoietic stem cell transplantation in multiple sclerosis: importance of disease stage on outcome [abstract]. Neurology. 2003;40:A150.
3. Comi G, et al. Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and Marrow Transplantation and the European Charcot Foundation. J Neurol. 2000;247:376-382.
5. Fassas A, et al. Autologous stem cell transplantation in progressive multiple sclerosisdan interim analysis of efficacy. J Clin Immunol. 2000;20:24-30. doi: 10.1023/A:1006686426090.
6. Fassas A, et al. Haematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol. 2002;249:1088-1097. doi: 10.1007/s00415-002-0800-7.
7. Fassas A, Nash R. Multiple sclerosis. Best Pract Res Clin Hematol. 2004;17:247-262. doi: 10.1016/j.beha.2004.04.005.
10. Saccardi R, et al. Autoimmune Diseases Working Party of EBMT. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler. 2006;12:814-823.
12. Shevchenko Y, Novik A, et al. Three strategies of high dose chemotherapy (HDCT)+autologous stem cell transplantation (ASCT) in autoimmune diseases. Bone Marrow Transplantation. 2004;33(1):346.
13. Shevchenko Y. et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Experimental Hematology. 2008;36(8):922-928. doi: 10.1016/j.exphem.2008.03.001.
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Novik<sup>1</sup>, Aleksey N. Kuznetsov<sup>1</sup>, Vladimir Y. Melnichenko<sup>1</sup>, Denis A. Fedorenko<sup>1</sup>, Tatyana I. Ionova<sup>2</sup>, Kira A. Kurbatova<sup>2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(199) "Andrei A. Novik1, Aleksey N. Kuznetsov1, Vladimir Y. Melnichenko1, Denis A. Fedorenko1, Tatyana I. Ionova2, Kira A. Kurbatova2
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Keywords
multiple sclerosis, autologous stem cell transplantation, long-term clinical outcomes, early ASCT, conventional ASCT, salvage ASCT
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(775) "High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (ASCT) is a promising approach to the treatment of multiple sclerosis (MS) patients. The data obtained points to the feasibility of early, conventional, and salvage HDIT +ASCT in MS patients. Further studies should be done to investigate clinical and patient-reported outcomes in MS patients receiving early, conventional, and salvage transplantation to better define treatment success. The concept of HDIT +ASCT in MS opens a new window of opportunity for treatment of this patient population.
Keywords
multiple sclerosis, autologous stem cell transplantation, long-term clinical outcomes, early ASCT, conventional ASCT, salvage ASCT
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Correspondence
Professor Tatyana I. Ionova, Multinational Center for Quality of Life Research, 1 Artilleriiskaya str., 191014 St. Petersburg, Russia
E-mail: tion16@mail.ru
1Pirogov National Medical Surgical Center, Moscow, Russia; 2Multinational Center for Quality of Life Research, Saint Petersburg, Russia
Correspondence
Professor Tatyana I. Ionova, Multinational Center for Quality of Life Research, 1 Artilleriiskaya str., 191014 St. Petersburg, Russia
E-mail: tion16@mail.ru
Aндрей A. Новик1, Алексей Н. Кузнецов1,2, Владимир Я. Мельниченко1, Денис А. Федоренко1, Tатьяна И. Ионова3, Кира А. Курбатова3
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ВИСТ+ТКСК является эффективным методом лечения больных с различными формами РС. Целесообразно выделение следующих стратегий ВИСТ+ТКСК: ранняя трансплантация, этапная трансплантация и трансплантация спасения. Концепция ВИСТ+ТКСК открывает большие возможности для интеграции специалистов, занимающихся разработкой новых методов лечения РС, определяя основные направления дальнейших клинических исследований в данной области.<br /><br /><h3>Ключевые слова</h3> <p>рассеянный склероз, аутологичная трансплантация стволовых кроветворных клеток, отдаленные результаты лечения, ранняя трансплантация, этапная трансплантация, трансплантация спасения </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1515) "Одним из новых перспективных подходов к лечению РС является высокодозная иммуносупрессивная терапия с трансплантацией кроветворных стволовых клеток (ВИСТ+ТКСК). ВИСТ+ТКСК является эффективным методом лечения больных с различными формами РС. Целесообразно выделение следующих стратегий ВИСТ+ТКСК: ранняя трансплантация, этапная трансплантация и трансплантация спасения. Концепция ВИСТ+ТКСК открывает большие возможности для интеграции специалистов, занимающихся разработкой новых методов лечения РС, определяя основные направления дальнейших клинических исследований в данной области.
Ключевые слова
рассеянный склероз, аутологичная трансплантация стволовых кроветворных клеток, отдаленные результаты лечения, ранняя трансплантация, этапная трансплантация, трансплантация спасения
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1515) "Одним из новых перспективных подходов к лечению РС является высокодозная иммуносупрессивная терапия с трансплантацией кроветворных стволовых клеток (ВИСТ+ТКСК). ВИСТ+ТКСК является эффективным методом лечения больных с различными формами РС. Целесообразно выделение следующих стратегий ВИСТ+ТКСК: ранняя трансплантация, этапная трансплантация и трансплантация спасения. Концепция ВИСТ+ТКСК открывает большие возможности для интеграции специалистов, занимающихся разработкой новых методов лечения РС, определяя основные направления дальнейших клинических исследований в данной области.
Ключевые слова
рассеянный склероз, аутологичная трансплантация стволовых кроветворных клеток, отдаленные результаты лечения, ранняя трансплантация, этапная трансплантация, трансплантация спасения
" } ["ORGANIZATION_RU"]=> array(37) { ["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"]=> string(5) "18307" ["VALUE"]=> array(2) { ["TEXT"]=> string(1287) "<p class="bodytext"><sup>1</sup>Национальный медико-хирургический центр им. Н.И. Пирогова, Москва, Россия; <sup>2</sup>Институт усовершенствования врачей Национального медико-хирургического центра им. Н.И.Пирогова, Москва, Россия; <sup>3</sup>Межнациональный центр исследования качества жизни, Санкт-Петербург, Россия<br /><br /><b>Контакт</b><br> А. А. Новик, Национальный медико-хирургический центр им.Н.И. Пирогова, ул. Нижняя Первомайская 70, Москва, 105203, Россия<br> E-mail: <a href="javascript:linkTo_UnCryptMailto('qempxs.rgvxg48Dqemp2vy');">ncrtc04@<span style="display:none;">spam is bad</span>mail.ru</a>, <a href="javascript:linkTo_UnCryptMailto('qempxs.ruspgDcerhib2vy');">nqolc@<span style="display:none;">spam is bad</span>yandex.ru</a> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1105) "1Национальный медико-хирургический центр им. Н.И. Пирогова, Москва, Россия; 2Институт усовершенствования врачей Национального медико-хирургического центра им. Н.И.Пирогова, Москва, Россия; 3Межнациональный центр исследования качества жизни, Санкт-Петербург, Россия
Контакт
А. А. Новик, Национальный медико-хирургический центр им.Н.И. Пирогова, ул. Нижняя Первомайская 70, Москва, 105203, Россия
E-mail: ncrtc04@mail.ru, nqolc@yandex.ru
1Национальный медико-хирургический центр им. Н.И. Пирогова, Москва, Россия; 2Институт усовершенствования врачей Национального медико-хирургического центра им. Н.И.Пирогова, Москва, Россия; 3Межнациональный центр исследования качества жизни, Санкт-Петербург, Россия
Контакт
А. А. Новик, Национальный медико-хирургический центр им.Н.И. Пирогова, ул. Нижняя Первомайская 70, Москва, 105203, Россия
E-mail: ncrtc04@mail.ru, nqolc@yandex.ru
Традиционные методы иммуномодулирующей и иммуносупрессивной терапии рассеянного склероза (РС) не позволяют достичь выраженного и длительного терапевтического эффекта [4-7, 10]. Одним из новых перспективных подходов к лечению РС является высокодозная иммуносупрессивная терапия с трансплантацией кроветворных стволовых клеток (ВИСТ+ТКСК). В настоящее время в мире выполнено более 700 трансплантаций больным с различными формами РС. Безопасность и эффективность метода изучена в международных многоцентровых исследованиях. К нерешенным вопросам ВИСТ+ТСКК относятся следующие: показания, методы трансплантации, режимы кондиционирования, деплеция Т-лимфоцитов, фармакоэкономическое обоснование и др. [3, 9, 11].
Разработана концепция ВИСТ+ТКСК при РС, включающая следующие положения: содержание метода, основные показания, методика проведения трансплантации, общий алгоритм, направления дальнейших исследований. Основные положения концепции подтверждены результатами проспективного многоцентрового исследования Российской кооперативной группы клеточной терапии изучения эффективности ВИСТ+ТКСК у больных различными формами РС.
В рамках концепции выделено две принципиальные цели лечения больных РС. Первая из них патогенетическая – остановить прогрессирование заболевания и предотвратить появление новых очагов демиелинизации в ЦНС за счет воздействия на иммунопатологический процесс на различных уровнях. Вторая цель, основная или конечная, состоит в сохранении и, по возможности, в улучшении качества жизни больных. Данные положения основаны на теории принятия решений в клинической медицине, согласно которой в формализованном виде существует три возможных цели лечения больного:
I – излечение с учетом качества жизни больного после выздоровления,
II – увеличение продолжительности жизни больного с учетом ее качества
III – улучшение качества жизни больного.
При РС, хроническом неизлечимом заболевании, в большинстве случаев не снижающем продолжительность жизни больного, максимально возможное восстановление и сохранение параметров качества жизни является приоритетной целью лечения. Вследствие этого, наряду с традиционными лабораторными и инструментальными тестами, описывающими изменения в течении патологического процесса на фоне терапии, к ключевым критериям эффективности лечения РС следует отнести и показатели качества жизни больного, отражающие сложный комплекс физических, психологических и социальных детерминант, свойственных конкретному индивидууму.
Учитывая вышесказанное, в рамках концепции выделены 3 вида трансплантации, отличающиеся по целям и времени проведения операции [12, 13]
Ранняя трансплантация
1. Патогенетическая цель – предупредить развитие необратимых изменений в ЦНС в результате иммунопатологического процесса.
2. Основная цель – сохранить качество жизни больного, предотвратить формирование инвалидизации.
3. Время проведения – в дебюте заболевания.
Этапная трансплантация
4. Патогенетическая цель – остановить прогрессирование заболевания на фоне самоподдерживающегося иммунопатологического процесса, имеющихся очагов необратимых изменений и частично утраченных функций, предупредить появление новых очагов поражения.
5. Основная цель – улучшить качество жизни больного и сохранить его на максимально возможном уровне, предупредить углубление инвалидизации пациента.
6. Время проведения – на различных этапах прогрессирования РС при выходе заболевания из-под контроля традиционных методов лечения.
Трансплантация спасения
7. Патогенетическая цель – остановить прогрессирование заболевания на фоне большого количества очагов необратимых изменений и существенно нарушенных функций, предупредить появление новых очагов поражения.
8. Основная цель – сохранить качество жизни больного на максимально возможном уровне, предотвратить наступление критической инвалидизации.
9. Время проведения – в далеко зашедшей стадии заболевания при высокой активности иммунопатологического процесса, быстром прогрессировании инвалидизации больного.
В данном докладе представлены результаты исследования безопасности и эффективности ВИСТ+ТКСК у 132 больных РС, которым ВИСТ+ТКСК проведена в Военно-медицинской академии (Санкт-Петербург) и Национальном медико-хирургическом центре им. Н.И. Пирогова (Москва), начиная с 1999 года. В исследование включено 58 мужчин и 74 женщины; средний возраст – 33 года. У 57 пациентов была диагностирована вторично-прогрессирующая форма заболевания, у 23 – первично-прогрессирующая, у 9 – прогрессирующе-рецидивирующая и у 43 – рецидивирующая ремитирующая. Выделены три группы пациентов в зависимости от вида трансплантации: ранняя трансплантация проводилась при EDSS от 1,5 до 3,0; этапная трансплантация - при EDSS от 3,5 до 6,5; трансплантация спасения - при EDSS от 7,0 до 8,5. 83 пациентам была проведена этапная ВИСТ+ТКСК; 43 – ранняя трансплантация; 7 – трансплантация спасения. Для кондиционирования использовали режимы BEAM или mini-BEAM. Эффект ВИСТ+ТКСК оценивали по изменению степени инвалидизации больного и активности заболевания.
Отдельно была выделена группа больных, которым проводили консолидирующую терапию (митоксантрон) после ВИСТ+ТКСК. В эту группу вошли пациенты, имеющие факторы риска. В настоящее время данная группа включает 34 пациента; анализ результатов лечения в этой группе будет проведен в декабре 2009г.
При проведении ВИСТ+ТКСК не было летальных исходов, связанных с трансплантацией, а также тяжелых непрогнозируемых осложнений. У всех больных зарегистрирован ответ на лечение: у половины больных было зарегистрировано клиническое улучшение; у остальных – стабилизация состояния. По данным МРТ у всех больных имелось либо улучшение, либо стабилизация процесса. В отдаленные сроки после ВИСТ+ТКСК (2 года и более) у подавляющего большинства больных (более 90%) наблюдали клиническое улучшение или стабилизацию заболевания. По данным магнитно-резонансной томографии отсутствие активности заболевания зарегистрировано у всех больных с клиническим улучшением или стабилизацией. Особого внимания заслуживает группа больных, которым проведена ранняя ВИСТ+ТКСК, и группа больных, у которых трансплантацию проводили с применением немиелоаблативных режимов кондиционирования.
ВИСТ+ТКСК является эффективным методом лечения больных с различными формами РС. Целесообразно выделение следующих стратегий ВИСТ+ТКСК: ранняя трансплантация, этапная трансплантация и трансплантация спасения. Концепция ВИСТ+ТКСК открывает большие возможности для интеграции специалистов, занимающихся разработкой новых методов лечения РС, определяя основные направления дальнейших клинических исследований в данной области.
Литература
2. Burt RK, et al. Autologous haematopoietic stem cell transplantation in multiple sclerosis: importance of disease stage on outcome [abstract]. Neurology. 2003;40:A150.
3. Comi G, et al. Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and Marrow Transplantation and the European Charcot Foundation. J Neurol. 2000;247:376-382.
5. Fassas A, et al. Autologous stem cell transplantation in progressive multiple sclerosisdan interim analysis of efficacy. J Clin Immunol. 2000;20:24-30. doi: 10.1023/A:1006686426090.
6. Fassas A, et al. Haematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol. 2002;249:1088-1097. doi: 10.1007/s00415-002-0800-7.
7. Fassas A, Nash R. Multiple sclerosis. Best Pract Res Clin Hematol. 2004;17:247-262. doi: 10.1016/j.beha.2004.04.005.
10. Saccardi R, et al. Autoimmune Diseases Working Party of EBMT. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler. 2006;12:814-823.
12. Shevchenko Y, Novik A, et al. Three strategies of high dose chemotherapy (HDCT)+autologous stem cell transplantation (ASCT) in autoimmune diseases. Bone Marrow Transplantation. 2004;33(1):346.
13. Shevchenko Y. et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Experimental Hematology. 2008;36(8):922-928. doi: 10.1016/j.exphem.2008.03.001.
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Традиционные методы иммуномодулирующей и иммуносупрессивной терапии рассеянного склероза (РС) не позволяют достичь выраженного и длительного терапевтического эффекта [4-7, 10]. Одним из новых перспективных подходов к лечению РС является высокодозная иммуносупрессивная терапия с трансплантацией кроветворных стволовых клеток (ВИСТ+ТКСК). В настоящее время в мире выполнено более 700 трансплантаций больным с различными формами РС. Безопасность и эффективность метода изучена в международных многоцентровых исследованиях. К нерешенным вопросам ВИСТ+ТСКК относятся следующие: показания, методы трансплантации, режимы кондиционирования, деплеция Т-лимфоцитов, фармакоэкономическое обоснование и др. [3, 9, 11].
Разработана концепция ВИСТ+ТКСК при РС, включающая следующие положения: содержание метода, основные показания, методика проведения трансплантации, общий алгоритм, направления дальнейших исследований. Основные положения концепции подтверждены результатами проспективного многоцентрового исследования Российской кооперативной группы клеточной терапии изучения эффективности ВИСТ+ТКСК у больных различными формами РС.
В рамках концепции выделено две принципиальные цели лечения больных РС. Первая из них патогенетическая – остановить прогрессирование заболевания и предотвратить появление новых очагов демиелинизации в ЦНС за счет воздействия на иммунопатологический процесс на различных уровнях. Вторая цель, основная или конечная, состоит в сохранении и, по возможности, в улучшении качества жизни больных. Данные положения основаны на теории принятия решений в клинической медицине, согласно которой в формализованном виде существует три возможных цели лечения больного:
I – излечение с учетом качества жизни больного после выздоровления,
II – увеличение продолжительности жизни больного с учетом ее качества
III – улучшение качества жизни больного.
При РС, хроническом неизлечимом заболевании, в большинстве случаев не снижающем продолжительность жизни больного, максимально возможное восстановление и сохранение параметров качества жизни является приоритетной целью лечения. Вследствие этого, наряду с традиционными лабораторными и инструментальными тестами, описывающими изменения в течении патологического процесса на фоне терапии, к ключевым критериям эффективности лечения РС следует отнести и показатели качества жизни больного, отражающие сложный комплекс физических, психологических и социальных детерминант, свойственных конкретному индивидууму.
Учитывая вышесказанное, в рамках концепции выделены 3 вида трансплантации, отличающиеся по целям и времени проведения операции [12, 13]
Ранняя трансплантация
1. Патогенетическая цель – предупредить развитие необратимых изменений в ЦНС в результате иммунопатологического процесса.
2. Основная цель – сохранить качество жизни больного, предотвратить формирование инвалидизации.
3. Время проведения – в дебюте заболевания.
Этапная трансплантация
4. Патогенетическая цель – остановить прогрессирование заболевания на фоне самоподдерживающегося иммунопатологического процесса, имеющихся очагов необратимых изменений и частично утраченных функций, предупредить появление новых очагов поражения.
5. Основная цель – улучшить качество жизни больного и сохранить его на максимально возможном уровне, предупредить углубление инвалидизации пациента.
6. Время проведения – на различных этапах прогрессирования РС при выходе заболевания из-под контроля традиционных методов лечения.
Трансплантация спасения
7. Патогенетическая цель – остановить прогрессирование заболевания на фоне большого количества очагов необратимых изменений и существенно нарушенных функций, предупредить появление новых очагов поражения.
8. Основная цель – сохранить качество жизни больного на максимально возможном уровне, предотвратить наступление критической инвалидизации.
9. Время проведения – в далеко зашедшей стадии заболевания при высокой активности иммунопатологического процесса, быстром прогрессировании инвалидизации больного.
В данном докладе представлены результаты исследования безопасности и эффективности ВИСТ+ТКСК у 132 больных РС, которым ВИСТ+ТКСК проведена в Военно-медицинской академии (Санкт-Петербург) и Национальном медико-хирургическом центре им. Н.И. Пирогова (Москва), начиная с 1999 года. В исследование включено 58 мужчин и 74 женщины; средний возраст – 33 года. У 57 пациентов была диагностирована вторично-прогрессирующая форма заболевания, у 23 – первично-прогрессирующая, у 9 – прогрессирующе-рецидивирующая и у 43 – рецидивирующая ремитирующая. Выделены три группы пациентов в зависимости от вида трансплантации: ранняя трансплантация проводилась при EDSS от 1,5 до 3,0; этапная трансплантация - при EDSS от 3,5 до 6,5; трансплантация спасения - при EDSS от 7,0 до 8,5. 83 пациентам была проведена этапная ВИСТ+ТКСК; 43 – ранняя трансплантация; 7 – трансплантация спасения. Для кондиционирования использовали режимы BEAM или mini-BEAM. Эффект ВИСТ+ТКСК оценивали по изменению степени инвалидизации больного и активности заболевания.
Отдельно была выделена группа больных, которым проводили консолидирующую терапию (митоксантрон) после ВИСТ+ТКСК. В эту группу вошли пациенты, имеющие факторы риска. В настоящее время данная группа включает 34 пациента; анализ результатов лечения в этой группе будет проведен в декабре 2009г.
При проведении ВИСТ+ТКСК не было летальных исходов, связанных с трансплантацией, а также тяжелых непрогнозируемых осложнений. У всех больных зарегистрирован ответ на лечение: у половины больных было зарегистрировано клиническое улучшение; у остальных – стабилизация состояния. По данным МРТ у всех больных имелось либо улучшение, либо стабилизация процесса. В отдаленные сроки после ВИСТ+ТКСК (2 года и более) у подавляющего большинства больных (более 90%) наблюдали клиническое улучшение или стабилизацию заболевания. По данным магнитно-резонансной томографии отсутствие активности заболевания зарегистрировано у всех больных с клиническим улучшением или стабилизацией. Особого внимания заслуживает группа больных, которым проведена ранняя ВИСТ+ТКСК, и группа больных, у которых трансплантацию проводили с применением немиелоаблативных режимов кондиционирования.
ВИСТ+ТКСК является эффективным методом лечения больных с различными формами РС. Целесообразно выделение следующих стратегий ВИСТ+ТКСК: ранняя трансплантация, этапная трансплантация и трансплантация спасения. Концепция ВИСТ+ТКСК открывает большие возможности для интеграции специалистов, занимающихся разработкой новых методов лечения РС, определяя основные направления дальнейших клинических исследований в данной области.
Литература
2. Burt RK, et al. Autologous haematopoietic stem cell transplantation in multiple sclerosis: importance of disease stage on outcome [abstract]. Neurology. 2003;40:A150.
3. Comi G, et al. Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and Marrow Transplantation and the European Charcot Foundation. J Neurol. 2000;247:376-382.
5. Fassas A, et al. Autologous stem cell transplantation in progressive multiple sclerosisdan interim analysis of efficacy. J Clin Immunol. 2000;20:24-30. doi: 10.1023/A:1006686426090.
6. Fassas A, et al. Haematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol. 2002;249:1088-1097. doi: 10.1007/s00415-002-0800-7.
7. Fassas A, Nash R. Multiple sclerosis. Best Pract Res Clin Hematol. 2004;17:247-262. doi: 10.1016/j.beha.2004.04.005.
10. Saccardi R, et al. Autoimmune Diseases Working Party of EBMT. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler. 2006;12:814-823.
12. Shevchenko Y, Novik A, et al. Three strategies of high dose chemotherapy (HDCT)+autologous stem cell transplantation (ASCT) in autoimmune diseases. Bone Marrow Transplantation. 2004;33(1):346.
13. Shevchenko Y. et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Experimental Hematology. 2008;36(8):922-928. doi: 10.1016/j.exphem.2008.03.001.
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