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Stem-cell transplantation for autoimmune diseases
ISC0.y
Society for Cellular Therap~
i!aylor&Francis • health sciences
Cytotherapy (2003) Vo\. 5, No. 3, 243 - 251
Stem-cell transplantation for autoimmune diseases P Scheinberg Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda MD, USA
Summary
advanced and debilitating cases of rheumatoid arthritis, scleroderma,
The use of intensive immunosuppressive treatment coupled with BM
systemic lupus erythematosis and multiple sclerosis. In this review the
stem-cell transplantation (SeT) to treat human autoimmune diseases
etiology of AID and the experimental basis of seT is presented,
(AID) follows anecdotal observations of responses of AID to allogeneic
together with recent clinical results of seT for AID. While much has
SeT and an extensive background ofexperience with SeT in animals
been learned about the risks and benefits of seT in AID, the
with AID. In the last decade, numerous clinical trials have been
underlying mechanisms regulating remission and relapse ofAID after
initiated to explore a potential benefit of (mainly autologous) SeT in
treatment remain largely unknown.
Introduction
AID and discusses the mechanisms of action of SCT and limitations to successful eradication of AID.
Autologous and allogeneic stem-cell transplantation (SCT) is being increasingly used to treat patients with autoimmune diseases (AID) following encouraging experimental data and serendipitous observations of ptolonged
Experimental background
remissions of patients with malignancies with concomitant
A relationship between the hematopoietic system and AID was first appreciated by Denman et al. who demonstrated in 1969 that transplantation of spleen or BM cells (BMC) from SLE-prone New Zealand Black (NZB) mice to immunosuppressed BALBjC mice, induced autoimmune disease in the recipient [2]. This observation was later confirmed by Morton and Siegel in 1974 when they transferred SLE by transplanting whole BM, neonatal spleen or fetal liver cells to lethally-irradiated mice of non-autoimmune strains [3]. This led to the hypothesis that the underlying defect in AID resided in the hematopoietic stem cell. While the initial experiments used unmanipulated marrow, Akizuki et al. showed that Tcell depleted BM from (NZB-NZW) Fl (BjWF1) mice also induced autoimmunity in lethally-irradiated BALBjc recipients, indicating that the disease originated in nonlymphoid cells [4]. The adoptive transfer of other autoimmune diseases, such as insulin-dependent diabetes mellitus, antiphospholipid syndrome, experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA) was also demonstrated [5]. In a recapitulation of Koch's postulates, it was found that the same autoimmune diseases that were transmitted by SCT to normal
AID undergoing hematopoietic SCT. There is now a wealth of clinical experience with SCT in a variety of common AID. Interest in SCT for AID stimulated the formation of a joint committee of the European Group for Blood and Marrow Transplantation (EBMT) and the European League Against Rheumatism (EULAR) to evaluate the potential of high-dose immunosuppressive therapy (HDIT) and autologous SCT to treat severe autoimmune diseases [1] . This group was joined by several North American and Australian centers and is referred to as the International Autoimmune Disease Stem Cell Project. Data has now accrued on over 500 patients, ymainly with multiple sclerosis (MS), systemic sclerosis (SS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). While there is now considerable clinical experience with SCT regimens and disease monitoring, it is fair to state that the immunologic mechanisms underlying the therapeutic benefit of SCT in AID remain largely unclear and unproven. This review outlines the experimental basis for using SCT in AID, describes recent clinical results of SCT for
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Correspondence to: PhiIlip Scheinberg, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda MD 2089, USA.
© 2003 [SCT
001: 10.1080/ 14653240310001505
P Scheinberg
244
reCIpIents, could also be cured or prevented with trans-
ftiology of AID and its relationship with transplant outcome
plants from healthy recipients (Figure 1). In 1985 Ikehara et at. demonstrated that allogeneic SCT
This experience in animal models indicated that AID can
could treat established autoimmune diseases in autoim-
be either primarily the result of a genetic predisposition or
mune-prone mice (NZB-NZW Fl:B/WF1, MRL/lpr,
acquired as the result of environmental influence. The
BXSB). When 6 month or older BXSB and B/WFl mice
etiological relationship between the hematopoietic stem
with lupus nephritis and lymphadenopathy were lethally
cell and AID is illustrated in Figure 2. While there is
irradiated and then reconstituted with allogeneic BMC or
overlap between the two etiologies, when designing
T-cell depleted BMC of young BALB/c mice, lymphade-
curative strategies with SCT, it is important to consider
nopathy disappeared and autoimmune disease was either
whether the AID is primarily genetic (with abnormalities
prevented or ameliorated with reduced glomerular damage
at the stem cell level), or primarily acquired (with normal
and titers of anti-DNA and anti-smooth muscle Abs [6] . An animal model for Type 1 diabetes, the nonobese
stem cells). In the hereditary forms of AID in experimental animals,
diabetic mouse (NOD) features a striking infiltration of T cells in pancreatic islets. When < 6 month old NOD mice
(e.g., SLE, type 1 diabetes in mice, and the arthritis/ colitis/ dermatitis syndrome in HLA-B27 transgenic rats)
were lethally irradiated and reconstituted with T-cell
symptoms develop with age and the genetic factors
depleted BALBj c BMC, there was no lymphocytic
B islets
predominate. In the acquired/ induced form, immunization
cells were intact and overt
with specific tissues in susceptible animals is required for
diabetes was prevented [7]. However, mice with overt
the development of AID (e.g., brain in experimental
infiltration observed,
diabetes did not benefit, presumably because the
B islet
cells were already destroyed. Predictably, when NOD mice
allergic encephalomyelitis bacterial antigens -
a model for MS -
M. tuberculosis or streptococcus -
and in
with overt diabetes were transplanted with BM and
adjuvant arthritis). Numerous studies indicate that allo-
pancreatic tissue from fetal or newborn BALB/c mice
geneic BMT is curative in animal models with both
they developed normal glucose tolerance and ·normal
hereditary and inducible forms of AID [9-14]. In this approach, myelo- and Iympho-ablation sets
blood levels of insulin [8].
the scene for complete allogeneic chimerism, with a Hematopoietic stem cell in BM
A
I '\ Bursa equivalent " \ (A )
PostthymicT cells
Mature B cells
------- ~
~
Help
t
§:O(Q)OeQ Tissue damage
Figure 2. Relationship between AID the hematopoietic stem cell and its progeny. Tissue damage in autoimmune disease is mediated by Figure 1. Models of autoimmune disease transftr and cure by hematopoietic stem cell transplantation. (A) AID induction in healthy mice by adoptive stem cell transftr. (B) AID eradication in sick mice by transplantation from a healthy donor.
mature T cells and B cells recognizing autoantigens. In acquired forms, HSC is normal and the autoimmune process develops in developing T and B cells (B) while inherited forms of AID involve a genetic abnormality in the HSC (A) predisposing to generation ofautoimmune clones.
Stem-cell transplantation for auroimmune diseases
concomitant elimination of autoreactive lymphocytes. The possibility that similar responses in AID might also be
245
Furthermore, the mechanisms underlying successful resetting of the immune system following the massive insult of
achieved with non-allogeneic stem cells came from observations that animals with AA recovered following
immunoablation are poorly understood and not control-
syngeneic BMT. This in turn led to experiments with autologous transplantation in inducible forms of AID,
from an autologous SCT in most human AID remains
mainly AA and EAE [IS] . In both diseases, high dose TBI of9-10 cGy induced responses in all animals. In AA spontaneous relapses or exacerbations were rare and it was difficult to induce relapses. In EAE, there was a rapid regression of symptoms following auto-BMT, but spontaneous relapses occurred in 30%. Interestingly, there was no difference in relapse rates between autologous or syngeneic BM rescue, indicating that relapses were initiated by T cells surviving the conditioning regimen. Although T-cell depletion was not shown to diminish
lable at present. Thus, the likelihood of a therapeutic effect debatable. While the allograft approach would be more reliably curative, its application is limited by toxicity, usually unacceptable in an experimental therapeutic setting.
Remissions of AID following allogeneic SCT for malignant diseases That the promise which results from animal experiments using SCT to treat AID could be translated into clinical successes was supported by reports that patients obtained prolonged remission of their underlying AID (including RA, SLE, Crohn's disease and autoimmune cytopenias)
spontaneous relapse, the addition of autologous spleen cells to the BM graft resulted in relapses in > 90 %. The fact that relapses were less common in allogeneic trans-
following high-dose intensive therapy and autologous or
plantation (5 %) suggests the existence of a graft versus autoimmunity effect by immune elimination of residual recipient lymphocytes. In both models, the best results
from Seattle, 11 of 917 patients transplanted for aplastic anemia or hematological malignancy were identified as
were seen with the intensive lympho-myeloablative regimens using highest tolerated TBI doses (9- 10 G y) when compared with less intense regimens using CY or Bu alone. The ability to achieve complete responses and few relapses with autologous-BMT in AA mice is surprising. The reinfusion of auto-reactive T cells through the graft would seem to nullify the benefits of initial lympho-
allogeneic SCT for malignancies [16 - 24]. In a review
having a concomitant autoimmune disorder. The diagnoses included one RA, one discoid lupus, one systemic lupuslike, three type-l diabetes, four hyperthyroidism and one dermatitis herpetiformis [25] . DFS was 7- 20 years. However, patients with permanent organ failure did not benefit: patients with type-l diabetes remained insulin dependent, and patients previously treated for autoim-
myeloablation. The most likely hypothesis is that the reconstitution of autologous hematopoietic stem cells represents a recapitulation of ontogeny with the acquisition of self-tolerance. Therefore, if the primary defect of
mune thyroid disease continued to require thyroid
an autoimmune disease is an aberrant reaction to an acquired or self-Ag (e.g., drug-induced, infections), tolerance may be acquired in the newly reconstituted immune system following a 'resetting' by the auto-SCT. However, if
Rationale of allogeneic SCT to treat human AID
the primary defect resides in the stem cells, cure could only be achieved through stem-cell replacement by allogeneic SCT.
AID and seT in man While these studies have been illuminating in terms of defining therapeutic strategies for AID, they do not equate fully to the complex situation of human AID. Pathogenesis of AID in humans is multifactorial, and includes genetic, infectious, hormonal and environmental factors.
replacement.
The clinical transplantation data raises some important aspects of AID. Both severiry and natural evolution of AID are highly variable, spanning a spectrum from mild selflimited episodes (e.g., Still's disease, pauciarticular juvenile RA), to continuous, with or without fluctuations (e.g., SLE, RA), progressive or incapacitating life-threatening disease (e.g., scleroderma). Furthermore, some AID cause permanent organ failure. In determining a rationale for using allogeneic SCT as a treatment for AID many questions are raised:
--
• How best to measure response_ .ofifi~eases that have an intermittent relapsing course and may be in remission at the time of transplant?
246
P Scheinberg
• Is there a risk that GvHD or its treatment could exacerbate the autoimmune process and increase damage to the target tissues and organs of the AID? Chronic GvHD has clinical and pathogenic characteristics similar to AID (e.g., scleroderma, Sjogren's syndrome) and thymic insufficiency post-transplant should favor autoreactivity because of decreased autoregulatory T lymphocytes [26]. Furthermore, autoimmune diseases such as hypothyroidism, myasthenia gravis and immune cytopenias occur with increased frequency in the post BMT setting [26]. • What is the etiology of the autoimmune disease specifically, what is the evidence that transplantation of a new donor immune system can prevent disease occurrence/ progression/ recurrence? Direct evidence of autoimmunity is found only in a minority of diseases and mostly we rely on indirect criteria to establish an autoimmuneetiology of human disease [27]. Such criteria are important since pathological autoreactivity has to be distinguished from the occurrence in normal individuals of self-reactive lymphocytes and autoantibodies. The induction of an AID by antibody or lymphocyte transfer provides direct proof of an autoimmune etiology of a disease. In a classic experiment, Harrington injected himself with plasma from a patient with idiopathic thrombocytpenic purpura (ITP), causing thrombocytopenia and severe bleeding [28]. Such instances, however, are rare. Other examples are the transplacental transmission of IgG autoantibody from an affiicted mother to the fetus, as occurs in neonatal myasthenia gravis and Grave's disease. Evidence for adoptive transfer of cellular autoimmunity with allogeneic SCT has been reported with celiac disease, type 1 diabetes and autoimmune thyroiditis [29- 31] . However, the failure to confer AID in some cases indicates that transfer of AID is not always inevitable - for example, an allogeneic BM recipient from a donor with severe RA did not show any evidence of the disease after 4 years, despite full donor chimerism [32]. ...-- . More frequently, the evidence for autoimmunity IS indirect, for example, the isolation of auto antibodies or autoreactive T cells - as occurs in MS. Less reliably, the association of a disease with autoimmunity is circumstantial. Here the suspicion of an autoimmune process is raised by clinical findings, such as an association with other autoimmune diseases, lymphocytic infiltration of target organs, or a favorable response to immunosuppression.
Autologous SeT for AID Conceptually, cure of AID with an autologous SCT should occur if high-dose immunoablative treatment eliminates autoreactive lymphocytes and replaces them with a new repertoire of CD34-derived immune cells emerging from the thymus. The approach should be curative if the original trigger for the AID is no longer present and/ or the predisposition to AID does not reside primarily in the stem cell. This is the presumption that has been followed in experimental trials of autologous SCT for AID.
RA Preliminary experience revealed that AID patients could react during mobilization with disease exacerbation severe enough to cause fatalities ('disease flaring'), a complication unique to AID patients. Approximately half the patients with refractory RA were mobilized with G-CSF and CV, and half received G-CSF alone. Conditioning regimens varied among centers, the commonest regimen being CY 200 mg/ kg. Disease flares following stem-cell mobilization were exacerbated by concurrent administration of CV, but patients also showed increased toxicity from standard conditioning regimens, indicating that careful patient selection and choice of regimens were critical for safe application of the transplant procedure [33]. Of 39 evaluable patients, 13 (30%) were reported as being 'better', 18 (42%) initially improved but later relapsed, and seven (16%) were 'worse'. Of the patients who relapsed, the majority had an adequate response to the reintroduction of disease-modifying antirheumatic agents (DMARD) (e.g., MTX and CYA). Transplant-related mortality was 7.5%. A prospective randomized trial is currently open [auto-SCT for RA (ASTIRA)], in which patients will be mobilized with CY 4 mg/ m2 , then randomized to CY 200 mg/kg and SCT, or continued best available treatment with DMARDs. The study will include patients 2- 15 years from onset of disease who have failed two conventional DMARDs, including MTX; failed anti-tumor necrosis factor treatment for > 3 months; have no major organ failure; have progressive erosive disease; and a potential functional status to ensure an adequate quality-of-life if inflammation is controlled.
Scleroderma Although the autoimmune pathogenesis of SS has not been clearly established, considerable data supports its intimate association with an autoimmune mechanism [34]. With a
Stem-cell transplantation for autoimmune diseases
5-year mortality in diffuse scleroderma of 30% and no effective treatment available, the disease is a good
247
inflammatory lesions around axons with axonal loss. It affects mainly young adults, and leads in the majority of cases to physical and psychological impairment. Therapies
candidate for investigating HDIT and SCT. In a Phase 1/ If EBMT study, patients with scleroderma for > 3 years, with a rapid progressive disease course and no severe
are usually efficacious in early disease (relapsing/ remitting) and consist of anti-inflammatory agents (corticoster-
irreversible internal organ damage, were enrolled for HDIT and auto-SCT [35] . Patients with limited scleroderma with life-threatening pulmonary fibrosis or hy-
oids), immunosuppressive agents (CYA, CV) and immunomodulating agents IFN-~. With the exception of IFN-~, other therapies are of little or no benefit in the
pertension were also enrolled. A variety of mobilization and condition regimens were used.
chronic progressive course (secondary progressive) MS. Data from the EBMT registry on 85 patients have been
Of 41 patients evaluated, 69% had an improved skin score of > 25% from baseline, with stabilization of lung
reported [37]. Nearly all patients had progressive disease (22% primary, 55% secondary), with a median time-
function . A total of 11 / 41 (27%) patients died after start of treatment, four after mobilization (all received CV), four related to the transplant and three of disease progression. The overall transplant-related mortality (TRM) was 27%
interval from diagnosis of 7.5 years and a median expanded disability status scale (EDSS, ranging from 0 = no disability to 10 = dead from disease) of 6.5 (4.5 - 8.5). Patients
(17% TRM and 10% disease progression). In an attempt to decrease TRM, recommendations for further enrollment of patients with scleroderma for HDIT and autoSCT were to exclude patients with a pulmonary artery pressure > 50 mmHg, cardiac ejection fraction < 50%, uncontrolled arrhythmias, established lung disease with DLCO < 45% of predicted, or gastrointestinal involvement requiring total parenteral nutrition. CY was avoided during mobilization, and TBI was performed with lung shielding. Since 2001, 58 patients with scleroderma were registered and underwent SCT. TRM was around 10% and > 50% of patients improved [34]. The American experience of 19 patients with poor prognosis SS was reported by McSweeney et al. [36]. PBSC were mobilized with G-CSF alone and conditioned with CY TBI and anti-thymocyte globulin. Self-limiting disease flares were seen during G-CSF mobilization, with no fatal toxicities. Three patients died of treatment-related complications, and one of disease progression. At a median follow-up of 15 months, the Kaplan - Meier estimated 2year survival for 15 of 19 patients was 79%. The median decrease in the modified Rodman skin scores from baseline was 21 % at 3 months (P = 0.002) and 39% at 12 months
had previously failed a variety of conventional therapies and were considered to have active disease, based on deteriorating disability of 2 1 on the EDSS in the 12 months preceding SCT. Following SCT the 3-year progression free survival was 74% (78% in the non-primary progressive group). Improvement of more than one EDSS post-transplant was seen in 18 (21 %), with later progression in six. Five patients (6%) died from transplant-related causes and death occurred from progressive disease in two (2 %). Disease flares associated with G-CSF mobilization were observed with one fatality. Twenty-two patients (27%) showed neurological deterioration during transplantation, possibly related to infection. Although the TRM did not differ significantly from that seen after auto-SCT for lymphomas (6%), it remains to be determined if this risk is acceptable in a disease that is rarely life-threatening. A prospective randomized study is currently ongoing (ASTIMS) where patients with severe MS will either receive HDIT [BEAM/ (carmustine etoposide, cytarabine, melphalan) + ATG] and SCT or mitoxantrone.
SLE
(P = 0.0005). A multicenter, prospective randomized trial (ASTIS) is currently accruing patients with scleroderma progressing over a minimum of 4 years, who are randomized to HDIT and SCT versus monthly CY 750 mg/ m2.
The results of the combined international experience of 34 patients with SLE who had undergone SCT have been reported [38]. The mobilization and conditioning regimens again varied among patients. Overall, there was a 13% TRM, with a 61 % initial response rate and 21.7%
MS
relapse rate. The largest series from Chi~o used CY and G-CSF for mobilization, followed:bJ' conditioning with CV, methylprednisolone and eq~ine antithymocyte globu-
MS IS an incurable demyelinating immune-mediated disease of the central nervous system, characterized by
lin [39] . Nine patients with progressive SLE refractory to 6
248
P Scheinberg
months of i.v. CY were enrolled. There were two deaths after mobilization, one from infection and the other from progressive disease. The remaining seven patients underwent auto-SCT and, at a median follow-up of 25 months, all were free of from signs of active lupus. As with other AID, patient selection for auto-SCT in SLE remains unclear. Consensus statements addressing inclusion criteria for SCT in SLE have been proposed [34].
Immune reconstitution after SCT The main determinants of immune reconstitution following HDIT and SCT are age, source of hematopoietic stem cells, mobilization protocol, conditioning regimen, graft manipulation, and post-transplant treatment [40] . A decrease in the number of CD4 + cells often persists for years after SCT [41,42]. In contrast, CDS+ T-cell repopulation is more rapid, causing an inverted CD4j CDS ratio in the months following auto-SCT. Even when Iymphocyte counts normalize, functional recovery of T- and B-cell immunity occurs only gradually. An inverse correlation between the size of the thymus and level of circulating CD4 + cells after high-dose chemotherapy supports the notion that CD4 + development depends on residual thymic function [43]. In contrast, the faster recovery of COS + appears to be independent of age-related thymic involution, suggesting that regeneration of the COS repertoire is derived largely from expansion of post-thymic T cells [44]. Consistent with this, the first months post-transplant are characterized by predominance ofCD45RO memory cells, followed 3-6 months later by the reappearance of CD45RA naIve cells. These observations indicate that thymic function is significantly impaired by the transplant conditioning, further exaggerating the thymic involution of adulthood, which is largely complete by the age of 20. Thus, the ability of the transplanted stem cell to regenerate a new peripheral T-cell repertoire is likely to be delayed, and possibly permanently limited in adults. Instead, immune function is largely maintained by the transplanted or residual post-thymic T cells. fh~ failure to reconstitute a new immune repertoire has implications for the success or failure of SCT in AID. On one hand, thymic failure may protect the individual from recapitulation of the disease from residual or transplanted HSC. On the other hand, the risk of reinitiation of the disease from persisting or transfused peripheral T cells is greater.
Mechanisms of action and reasons for failure ofSCT Understanding the diverse pathophysiology of autoimmune diseases can improve the selection of appropriate AID for transplant. If the AID arises from the stem cells, allogeneic SCT would be more likely to cure the disease than autologous SCT, whereas if the primary defect is an aberrant immune reaction to an acquired or self Ag, tolerance may be acquired after auto-SCT if the triggering event is no longer present. Although the results of auto-SCT in AID are encouraging, so far the majority of responses have been remissions rather than cures. Identifying the mechanism of relapse should also help determine the optimal transplant design. There are several possible causes of treatment failure, illustrated in Figure 3. After auto-SCT, cells conferring autoimmunity may reconstitute from three sources: I.
2. 3.
Residual T cells that survived conditioning (3B) T cells or B cells reinfused with the graft (3C) Transplanted or residual recipients stem cells that recapitulate the autoimmune process (3D). If residual stem cells contribute to disease relapse, more
intensive myeloablative conditioning regimens would be favorable to eliminate auto reactive clones, whereas more immunoablative regimens would be required to eliminate residual T and B cells. IfT cells or stem cells from the graft are the culprits, graft manipulation with T-cell depletion, or the absence of the stem-cell rescue altogether would be preferable. Encouraging results using high-dose immunosuppression without stem-cell rescue support this possibility [45] .
Future perspectives Prospective randomized trials, currently underway, should help resolve which patients with AID should receive auto or allogeneic SCT, and what are the best-tolerated mobilization and conditioning regimens. However, many fundamental questions pertaining to the mechanism of the therapeutic benefit remain unresolved: • Is the therapeutic benefit from high-dose immunosuppression or from 'rebooting' the immune system with a transplant? • Should the transplant be manipulated to remove T cells or not used at all?
Stem-cell transplantation for autoimmune diseases
Transplanted hematopoietic stem cell
249
Transplanted hematopoietic stem cell
A
Tissue repair
B
AID
c
Transplanted hematopoietic stem cell
Transplanted hematopoietic stem cell
D
seT
AID
AID
Figure 3. Mechanism of cure and treatment failure after seT (A) Successful cure ofAID follows the eradication of autoimmune T- and B-cell clones and the substitution of a new, hematopoietic system. (8) Failure of
seT occurring because residual autoimmune clones escape
immunoablation. (e) Failure of seT because autoimmune clones were reinfused with transplanted HSC. (D) Failure of seT because autoimmune disease is recapitulated in transplanted cells.
One anecdotal case history suggests that transplantation does play a role in the response of AID to high-dose
without transplant, suggests that there future for SCT in AID.
IS
an important
immunosuppression [46]. A 13-year-old girl with SS with Raynaud's phenomenon, myopathy and polyarthritis since the age of four developed diffuse skin thickening, gastro-
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Ishida T, Inaba M, Hisha H et al. Requirement of donor derived marrow transplantation. Complete prevention of recurrence of
Nelson JL, Torrez R, Louie FM. Pre-existing autoimmune disease in patients with long term survival after allogeneic bone
autoimmune prone mice treated for autoimmune disease by
11
Schachna L, Ryan PF, Schwarer AP. Malignancy-associated
transplantation. Proc Natl Acad Sci USA 1985;82:7743 - 7.
of allogeneic bone marrow and pancreatic tissue. Proc Natl Acad 9
Meloni G, Capria S, Vignetti M et al. Blast crisis of chronic
Acad Sci USA 1985;82:2483 - 7. diabetes in nonobese diabetic mice by allogeneic bone marrow 8
21
multicenter study. 38
J
Neurol 2002;249:1088 - 97.
Tyndall A, Passweg J, Gratwohl A. Haematopoietic stem cell
transplantation for hematologic malignancy. Arthn"tis Rheum
transplantation in the treatment of severe autoiqtmune disease
1997;40:1712 - 5.
2000. Ann Rheum Dis 2001;60:702 - 7.
Stem-cell transplantation for autoimmune diseases
39
Traynor AE, Schroeder J, Rosa RM et al. Treatment of severe
chemotherapy with autologous bone marrow support. Trans-
systemic lupus erythematosus with high dose chemotherapy and
plantation 1988;46:57.
hematopoietic stem cell transplantation: a phase I study. Lancet 40
43
2000;356:701-7. Van Laar JM. Immune ablation and stem cell therapy in autoimmune disease immunological reconstitution after high
44
dose immunosuppression and hematopoietic stem cell transplantation. Arth Res 2000;2:270- 5. 41
Sugita K, Soiffer RJ, Murray C et al. The phenotype and reconstitution of immunoregulatory T cell subsets after T cell
45
depleted allogeneic and autologous bone marrow transplanta42
251
tion. Transplantation 1994;57: 1465. Olsen GA, Gockerman JP, Bast RC et al. Altered immunologic reconstitution after standard dose chemotherapy or high dose
46
Mackall CL, Fleisher TA, Brown MR et al. Age, thymopoiesis, and CD4 + T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995;332:143. Mackall CL, Fleisher TA, Brown MR et al. Distinctions between CD8 + and CD4 + T cell regenerative pathways result in prolonged T cell subset imbalance after intensive chemotherapy. Blood 1997;89:3 700. Brodsky RA, Petri M, Smith BD et al. lmmunoablative high dose cyclophosphamide without stem cell rescue for refractory, severe autoimmune disease. Ann Intern Med 1998;129:1031-5. Martini A, Maccario R, Ravelli A et al. Marked and sustained improvement two years after autologous stem cell transplantation in a girl with systemic sclerosis. Arth Rheum 1999;42:807-11.
Society for Cellular Therap~
i!aylor&Francis • health sciences
Cytotherapy (2003) Vo\. 5, No. 3, 243 - 251
Stem-cell transplantation for autoimmune diseases P Scheinberg Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda MD, USA
Summary
advanced and debilitating cases of rheumatoid arthritis, scleroderma,
The use of intensive immunosuppressive treatment coupled with BM
systemic lupus erythematosis and multiple sclerosis. In this review the
stem-cell transplantation (SeT) to treat human autoimmune diseases
etiology of AID and the experimental basis of seT is presented,
(AID) follows anecdotal observations of responses of AID to allogeneic
together with recent clinical results of seT for AID. While much has
SeT and an extensive background ofexperience with SeT in animals
been learned about the risks and benefits of seT in AID, the
with AID. In the last decade, numerous clinical trials have been
underlying mechanisms regulating remission and relapse ofAID after
initiated to explore a potential benefit of (mainly autologous) SeT in
treatment remain largely unknown.
Introduction
AID and discusses the mechanisms of action of SCT and limitations to successful eradication of AID.
Autologous and allogeneic stem-cell transplantation (SCT) is being increasingly used to treat patients with autoimmune diseases (AID) following encouraging experimental data and serendipitous observations of ptolonged
Experimental background
remissions of patients with malignancies with concomitant
A relationship between the hematopoietic system and AID was first appreciated by Denman et al. who demonstrated in 1969 that transplantation of spleen or BM cells (BMC) from SLE-prone New Zealand Black (NZB) mice to immunosuppressed BALBjC mice, induced autoimmune disease in the recipient [2]. This observation was later confirmed by Morton and Siegel in 1974 when they transferred SLE by transplanting whole BM, neonatal spleen or fetal liver cells to lethally-irradiated mice of non-autoimmune strains [3]. This led to the hypothesis that the underlying defect in AID resided in the hematopoietic stem cell. While the initial experiments used unmanipulated marrow, Akizuki et al. showed that Tcell depleted BM from (NZB-NZW) Fl (BjWF1) mice also induced autoimmunity in lethally-irradiated BALBjc recipients, indicating that the disease originated in nonlymphoid cells [4]. The adoptive transfer of other autoimmune diseases, such as insulin-dependent diabetes mellitus, antiphospholipid syndrome, experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA) was also demonstrated [5]. In a recapitulation of Koch's postulates, it was found that the same autoimmune diseases that were transmitted by SCT to normal
AID undergoing hematopoietic SCT. There is now a wealth of clinical experience with SCT in a variety of common AID. Interest in SCT for AID stimulated the formation of a joint committee of the European Group for Blood and Marrow Transplantation (EBMT) and the European League Against Rheumatism (EULAR) to evaluate the potential of high-dose immunosuppressive therapy (HDIT) and autologous SCT to treat severe autoimmune diseases [1] . This group was joined by several North American and Australian centers and is referred to as the International Autoimmune Disease Stem Cell Project. Data has now accrued on over 500 patients, ymainly with multiple sclerosis (MS), systemic sclerosis (SS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). While there is now considerable clinical experience with SCT regimens and disease monitoring, it is fair to state that the immunologic mechanisms underlying the therapeutic benefit of SCT in AID remain largely unclear and unproven. This review outlines the experimental basis for using SCT in AID, describes recent clinical results of SCT for
;.:--'
.
....-
Correspondence to: PhiIlip Scheinberg, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda MD 2089, USA.
© 2003 [SCT
001: 10.1080/ 14653240310001505
P Scheinberg
244
reCIpIents, could also be cured or prevented with trans-
ftiology of AID and its relationship with transplant outcome
plants from healthy recipients (Figure 1). In 1985 Ikehara et at. demonstrated that allogeneic SCT
This experience in animal models indicated that AID can
could treat established autoimmune diseases in autoim-
be either primarily the result of a genetic predisposition or
mune-prone mice (NZB-NZW Fl:B/WF1, MRL/lpr,
acquired as the result of environmental influence. The
BXSB). When 6 month or older BXSB and B/WFl mice
etiological relationship between the hematopoietic stem
with lupus nephritis and lymphadenopathy were lethally
cell and AID is illustrated in Figure 2. While there is
irradiated and then reconstituted with allogeneic BMC or
overlap between the two etiologies, when designing
T-cell depleted BMC of young BALB/c mice, lymphade-
curative strategies with SCT, it is important to consider
nopathy disappeared and autoimmune disease was either
whether the AID is primarily genetic (with abnormalities
prevented or ameliorated with reduced glomerular damage
at the stem cell level), or primarily acquired (with normal
and titers of anti-DNA and anti-smooth muscle Abs [6] . An animal model for Type 1 diabetes, the nonobese
stem cells). In the hereditary forms of AID in experimental animals,
diabetic mouse (NOD) features a striking infiltration of T cells in pancreatic islets. When < 6 month old NOD mice
(e.g., SLE, type 1 diabetes in mice, and the arthritis/ colitis/ dermatitis syndrome in HLA-B27 transgenic rats)
were lethally irradiated and reconstituted with T-cell
symptoms develop with age and the genetic factors
depleted BALBj c BMC, there was no lymphocytic
B islets
predominate. In the acquired/ induced form, immunization
cells were intact and overt
with specific tissues in susceptible animals is required for
diabetes was prevented [7]. However, mice with overt
the development of AID (e.g., brain in experimental
infiltration observed,
diabetes did not benefit, presumably because the
B islet
cells were already destroyed. Predictably, when NOD mice
allergic encephalomyelitis bacterial antigens -
a model for MS -
M. tuberculosis or streptococcus -
and in
with overt diabetes were transplanted with BM and
adjuvant arthritis). Numerous studies indicate that allo-
pancreatic tissue from fetal or newborn BALB/c mice
geneic BMT is curative in animal models with both
they developed normal glucose tolerance and ·normal
hereditary and inducible forms of AID [9-14]. In this approach, myelo- and Iympho-ablation sets
blood levels of insulin [8].
the scene for complete allogeneic chimerism, with a Hematopoietic stem cell in BM
A
I '\ Bursa equivalent " \ (A )
PostthymicT cells
Mature B cells
------- ~
~
Help
t
§:O(Q)OeQ Tissue damage
Figure 2. Relationship between AID the hematopoietic stem cell and its progeny. Tissue damage in autoimmune disease is mediated by Figure 1. Models of autoimmune disease transftr and cure by hematopoietic stem cell transplantation. (A) AID induction in healthy mice by adoptive stem cell transftr. (B) AID eradication in sick mice by transplantation from a healthy donor.
mature T cells and B cells recognizing autoantigens. In acquired forms, HSC is normal and the autoimmune process develops in developing T and B cells (B) while inherited forms of AID involve a genetic abnormality in the HSC (A) predisposing to generation ofautoimmune clones.
Stem-cell transplantation for auroimmune diseases
concomitant elimination of autoreactive lymphocytes. The possibility that similar responses in AID might also be
245
Furthermore, the mechanisms underlying successful resetting of the immune system following the massive insult of
achieved with non-allogeneic stem cells came from observations that animals with AA recovered following
immunoablation are poorly understood and not control-
syngeneic BMT. This in turn led to experiments with autologous transplantation in inducible forms of AID,
from an autologous SCT in most human AID remains
mainly AA and EAE [IS] . In both diseases, high dose TBI of9-10 cGy induced responses in all animals. In AA spontaneous relapses or exacerbations were rare and it was difficult to induce relapses. In EAE, there was a rapid regression of symptoms following auto-BMT, but spontaneous relapses occurred in 30%. Interestingly, there was no difference in relapse rates between autologous or syngeneic BM rescue, indicating that relapses were initiated by T cells surviving the conditioning regimen. Although T-cell depletion was not shown to diminish
lable at present. Thus, the likelihood of a therapeutic effect debatable. While the allograft approach would be more reliably curative, its application is limited by toxicity, usually unacceptable in an experimental therapeutic setting.
Remissions of AID following allogeneic SCT for malignant diseases That the promise which results from animal experiments using SCT to treat AID could be translated into clinical successes was supported by reports that patients obtained prolonged remission of their underlying AID (including RA, SLE, Crohn's disease and autoimmune cytopenias)
spontaneous relapse, the addition of autologous spleen cells to the BM graft resulted in relapses in > 90 %. The fact that relapses were less common in allogeneic trans-
following high-dose intensive therapy and autologous or
plantation (5 %) suggests the existence of a graft versus autoimmunity effect by immune elimination of residual recipient lymphocytes. In both models, the best results
from Seattle, 11 of 917 patients transplanted for aplastic anemia or hematological malignancy were identified as
were seen with the intensive lympho-myeloablative regimens using highest tolerated TBI doses (9- 10 G y) when compared with less intense regimens using CY or Bu alone. The ability to achieve complete responses and few relapses with autologous-BMT in AA mice is surprising. The reinfusion of auto-reactive T cells through the graft would seem to nullify the benefits of initial lympho-
allogeneic SCT for malignancies [16 - 24]. In a review
having a concomitant autoimmune disorder. The diagnoses included one RA, one discoid lupus, one systemic lupuslike, three type-l diabetes, four hyperthyroidism and one dermatitis herpetiformis [25] . DFS was 7- 20 years. However, patients with permanent organ failure did not benefit: patients with type-l diabetes remained insulin dependent, and patients previously treated for autoim-
myeloablation. The most likely hypothesis is that the reconstitution of autologous hematopoietic stem cells represents a recapitulation of ontogeny with the acquisition of self-tolerance. Therefore, if the primary defect of
mune thyroid disease continued to require thyroid
an autoimmune disease is an aberrant reaction to an acquired or self-Ag (e.g., drug-induced, infections), tolerance may be acquired in the newly reconstituted immune system following a 'resetting' by the auto-SCT. However, if
Rationale of allogeneic SCT to treat human AID
the primary defect resides in the stem cells, cure could only be achieved through stem-cell replacement by allogeneic SCT.
AID and seT in man While these studies have been illuminating in terms of defining therapeutic strategies for AID, they do not equate fully to the complex situation of human AID. Pathogenesis of AID in humans is multifactorial, and includes genetic, infectious, hormonal and environmental factors.
replacement.
The clinical transplantation data raises some important aspects of AID. Both severiry and natural evolution of AID are highly variable, spanning a spectrum from mild selflimited episodes (e.g., Still's disease, pauciarticular juvenile RA), to continuous, with or without fluctuations (e.g., SLE, RA), progressive or incapacitating life-threatening disease (e.g., scleroderma). Furthermore, some AID cause permanent organ failure. In determining a rationale for using allogeneic SCT as a treatment for AID many questions are raised:
--
• How best to measure response_ .ofifi~eases that have an intermittent relapsing course and may be in remission at the time of transplant?
246
P Scheinberg
• Is there a risk that GvHD or its treatment could exacerbate the autoimmune process and increase damage to the target tissues and organs of the AID? Chronic GvHD has clinical and pathogenic characteristics similar to AID (e.g., scleroderma, Sjogren's syndrome) and thymic insufficiency post-transplant should favor autoreactivity because of decreased autoregulatory T lymphocytes [26]. Furthermore, autoimmune diseases such as hypothyroidism, myasthenia gravis and immune cytopenias occur with increased frequency in the post BMT setting [26]. • What is the etiology of the autoimmune disease specifically, what is the evidence that transplantation of a new donor immune system can prevent disease occurrence/ progression/ recurrence? Direct evidence of autoimmunity is found only in a minority of diseases and mostly we rely on indirect criteria to establish an autoimmuneetiology of human disease [27]. Such criteria are important since pathological autoreactivity has to be distinguished from the occurrence in normal individuals of self-reactive lymphocytes and autoantibodies. The induction of an AID by antibody or lymphocyte transfer provides direct proof of an autoimmune etiology of a disease. In a classic experiment, Harrington injected himself with plasma from a patient with idiopathic thrombocytpenic purpura (ITP), causing thrombocytopenia and severe bleeding [28]. Such instances, however, are rare. Other examples are the transplacental transmission of IgG autoantibody from an affiicted mother to the fetus, as occurs in neonatal myasthenia gravis and Grave's disease. Evidence for adoptive transfer of cellular autoimmunity with allogeneic SCT has been reported with celiac disease, type 1 diabetes and autoimmune thyroiditis [29- 31] . However, the failure to confer AID in some cases indicates that transfer of AID is not always inevitable - for example, an allogeneic BM recipient from a donor with severe RA did not show any evidence of the disease after 4 years, despite full donor chimerism [32]. ...-- . More frequently, the evidence for autoimmunity IS indirect, for example, the isolation of auto antibodies or autoreactive T cells - as occurs in MS. Less reliably, the association of a disease with autoimmunity is circumstantial. Here the suspicion of an autoimmune process is raised by clinical findings, such as an association with other autoimmune diseases, lymphocytic infiltration of target organs, or a favorable response to immunosuppression.
Autologous SeT for AID Conceptually, cure of AID with an autologous SCT should occur if high-dose immunoablative treatment eliminates autoreactive lymphocytes and replaces them with a new repertoire of CD34-derived immune cells emerging from the thymus. The approach should be curative if the original trigger for the AID is no longer present and/ or the predisposition to AID does not reside primarily in the stem cell. This is the presumption that has been followed in experimental trials of autologous SCT for AID.
RA Preliminary experience revealed that AID patients could react during mobilization with disease exacerbation severe enough to cause fatalities ('disease flaring'), a complication unique to AID patients. Approximately half the patients with refractory RA were mobilized with G-CSF and CV, and half received G-CSF alone. Conditioning regimens varied among centers, the commonest regimen being CY 200 mg/ kg. Disease flares following stem-cell mobilization were exacerbated by concurrent administration of CV, but patients also showed increased toxicity from standard conditioning regimens, indicating that careful patient selection and choice of regimens were critical for safe application of the transplant procedure [33]. Of 39 evaluable patients, 13 (30%) were reported as being 'better', 18 (42%) initially improved but later relapsed, and seven (16%) were 'worse'. Of the patients who relapsed, the majority had an adequate response to the reintroduction of disease-modifying antirheumatic agents (DMARD) (e.g., MTX and CYA). Transplant-related mortality was 7.5%. A prospective randomized trial is currently open [auto-SCT for RA (ASTIRA)], in which patients will be mobilized with CY 4 mg/ m2 , then randomized to CY 200 mg/kg and SCT, or continued best available treatment with DMARDs. The study will include patients 2- 15 years from onset of disease who have failed two conventional DMARDs, including MTX; failed anti-tumor necrosis factor treatment for > 3 months; have no major organ failure; have progressive erosive disease; and a potential functional status to ensure an adequate quality-of-life if inflammation is controlled.
Scleroderma Although the autoimmune pathogenesis of SS has not been clearly established, considerable data supports its intimate association with an autoimmune mechanism [34]. With a
Stem-cell transplantation for autoimmune diseases
5-year mortality in diffuse scleroderma of 30% and no effective treatment available, the disease is a good
247
inflammatory lesions around axons with axonal loss. It affects mainly young adults, and leads in the majority of cases to physical and psychological impairment. Therapies
candidate for investigating HDIT and SCT. In a Phase 1/ If EBMT study, patients with scleroderma for > 3 years, with a rapid progressive disease course and no severe
are usually efficacious in early disease (relapsing/ remitting) and consist of anti-inflammatory agents (corticoster-
irreversible internal organ damage, were enrolled for HDIT and auto-SCT [35] . Patients with limited scleroderma with life-threatening pulmonary fibrosis or hy-
oids), immunosuppressive agents (CYA, CV) and immunomodulating agents IFN-~. With the exception of IFN-~, other therapies are of little or no benefit in the
pertension were also enrolled. A variety of mobilization and condition regimens were used.
chronic progressive course (secondary progressive) MS. Data from the EBMT registry on 85 patients have been
Of 41 patients evaluated, 69% had an improved skin score of > 25% from baseline, with stabilization of lung
reported [37]. Nearly all patients had progressive disease (22% primary, 55% secondary), with a median time-
function . A total of 11 / 41 (27%) patients died after start of treatment, four after mobilization (all received CV), four related to the transplant and three of disease progression. The overall transplant-related mortality (TRM) was 27%
interval from diagnosis of 7.5 years and a median expanded disability status scale (EDSS, ranging from 0 = no disability to 10 = dead from disease) of 6.5 (4.5 - 8.5). Patients
(17% TRM and 10% disease progression). In an attempt to decrease TRM, recommendations for further enrollment of patients with scleroderma for HDIT and autoSCT were to exclude patients with a pulmonary artery pressure > 50 mmHg, cardiac ejection fraction < 50%, uncontrolled arrhythmias, established lung disease with DLCO < 45% of predicted, or gastrointestinal involvement requiring total parenteral nutrition. CY was avoided during mobilization, and TBI was performed with lung shielding. Since 2001, 58 patients with scleroderma were registered and underwent SCT. TRM was around 10% and > 50% of patients improved [34]. The American experience of 19 patients with poor prognosis SS was reported by McSweeney et al. [36]. PBSC were mobilized with G-CSF alone and conditioned with CY TBI and anti-thymocyte globulin. Self-limiting disease flares were seen during G-CSF mobilization, with no fatal toxicities. Three patients died of treatment-related complications, and one of disease progression. At a median follow-up of 15 months, the Kaplan - Meier estimated 2year survival for 15 of 19 patients was 79%. The median decrease in the modified Rodman skin scores from baseline was 21 % at 3 months (P = 0.002) and 39% at 12 months
had previously failed a variety of conventional therapies and were considered to have active disease, based on deteriorating disability of 2 1 on the EDSS in the 12 months preceding SCT. Following SCT the 3-year progression free survival was 74% (78% in the non-primary progressive group). Improvement of more than one EDSS post-transplant was seen in 18 (21 %), with later progression in six. Five patients (6%) died from transplant-related causes and death occurred from progressive disease in two (2 %). Disease flares associated with G-CSF mobilization were observed with one fatality. Twenty-two patients (27%) showed neurological deterioration during transplantation, possibly related to infection. Although the TRM did not differ significantly from that seen after auto-SCT for lymphomas (6%), it remains to be determined if this risk is acceptable in a disease that is rarely life-threatening. A prospective randomized study is currently ongoing (ASTIMS) where patients with severe MS will either receive HDIT [BEAM/ (carmustine etoposide, cytarabine, melphalan) + ATG] and SCT or mitoxantrone.
SLE
(P = 0.0005). A multicenter, prospective randomized trial (ASTIS) is currently accruing patients with scleroderma progressing over a minimum of 4 years, who are randomized to HDIT and SCT versus monthly CY 750 mg/ m2.
The results of the combined international experience of 34 patients with SLE who had undergone SCT have been reported [38]. The mobilization and conditioning regimens again varied among patients. Overall, there was a 13% TRM, with a 61 % initial response rate and 21.7%
MS
relapse rate. The largest series from Chi~o used CY and G-CSF for mobilization, followed:bJ' conditioning with CV, methylprednisolone and eq~ine antithymocyte globu-
MS IS an incurable demyelinating immune-mediated disease of the central nervous system, characterized by
lin [39] . Nine patients with progressive SLE refractory to 6
248
P Scheinberg
months of i.v. CY were enrolled. There were two deaths after mobilization, one from infection and the other from progressive disease. The remaining seven patients underwent auto-SCT and, at a median follow-up of 25 months, all were free of from signs of active lupus. As with other AID, patient selection for auto-SCT in SLE remains unclear. Consensus statements addressing inclusion criteria for SCT in SLE have been proposed [34].
Immune reconstitution after SCT The main determinants of immune reconstitution following HDIT and SCT are age, source of hematopoietic stem cells, mobilization protocol, conditioning regimen, graft manipulation, and post-transplant treatment [40] . A decrease in the number of CD4 + cells often persists for years after SCT [41,42]. In contrast, CDS+ T-cell repopulation is more rapid, causing an inverted CD4j CDS ratio in the months following auto-SCT. Even when Iymphocyte counts normalize, functional recovery of T- and B-cell immunity occurs only gradually. An inverse correlation between the size of the thymus and level of circulating CD4 + cells after high-dose chemotherapy supports the notion that CD4 + development depends on residual thymic function [43]. In contrast, the faster recovery of COS + appears to be independent of age-related thymic involution, suggesting that regeneration of the COS repertoire is derived largely from expansion of post-thymic T cells [44]. Consistent with this, the first months post-transplant are characterized by predominance ofCD45RO memory cells, followed 3-6 months later by the reappearance of CD45RA naIve cells. These observations indicate that thymic function is significantly impaired by the transplant conditioning, further exaggerating the thymic involution of adulthood, which is largely complete by the age of 20. Thus, the ability of the transplanted stem cell to regenerate a new peripheral T-cell repertoire is likely to be delayed, and possibly permanently limited in adults. Instead, immune function is largely maintained by the transplanted or residual post-thymic T cells. fh~ failure to reconstitute a new immune repertoire has implications for the success or failure of SCT in AID. On one hand, thymic failure may protect the individual from recapitulation of the disease from residual or transplanted HSC. On the other hand, the risk of reinitiation of the disease from persisting or transfused peripheral T cells is greater.
Mechanisms of action and reasons for failure ofSCT Understanding the diverse pathophysiology of autoimmune diseases can improve the selection of appropriate AID for transplant. If the AID arises from the stem cells, allogeneic SCT would be more likely to cure the disease than autologous SCT, whereas if the primary defect is an aberrant immune reaction to an acquired or self Ag, tolerance may be acquired after auto-SCT if the triggering event is no longer present. Although the results of auto-SCT in AID are encouraging, so far the majority of responses have been remissions rather than cures. Identifying the mechanism of relapse should also help determine the optimal transplant design. There are several possible causes of treatment failure, illustrated in Figure 3. After auto-SCT, cells conferring autoimmunity may reconstitute from three sources: I.
2. 3.
Residual T cells that survived conditioning (3B) T cells or B cells reinfused with the graft (3C) Transplanted or residual recipients stem cells that recapitulate the autoimmune process (3D). If residual stem cells contribute to disease relapse, more
intensive myeloablative conditioning regimens would be favorable to eliminate auto reactive clones, whereas more immunoablative regimens would be required to eliminate residual T and B cells. IfT cells or stem cells from the graft are the culprits, graft manipulation with T-cell depletion, or the absence of the stem-cell rescue altogether would be preferable. Encouraging results using high-dose immunosuppression without stem-cell rescue support this possibility [45] .
Future perspectives Prospective randomized trials, currently underway, should help resolve which patients with AID should receive auto or allogeneic SCT, and what are the best-tolerated mobilization and conditioning regimens. However, many fundamental questions pertaining to the mechanism of the therapeutic benefit remain unresolved: • Is the therapeutic benefit from high-dose immunosuppression or from 'rebooting' the immune system with a transplant? • Should the transplant be manipulated to remove T cells or not used at all?
Stem-cell transplantation for autoimmune diseases
Transplanted hematopoietic stem cell
249
Transplanted hematopoietic stem cell
A
Tissue repair
B
AID
c
Transplanted hematopoietic stem cell
Transplanted hematopoietic stem cell
D
seT
AID
AID
Figure 3. Mechanism of cure and treatment failure after seT (A) Successful cure ofAID follows the eradication of autoimmune T- and B-cell clones and the substitution of a new, hematopoietic system. (8) Failure of
seT occurring because residual autoimmune clones escape
immunoablation. (e) Failure of seT because autoimmune clones were reinfused with transplanted HSC. (D) Failure of seT because autoimmune disease is recapitulated in transplanted cells.
One anecdotal case history suggests that transplantation does play a role in the response of AID to high-dose
without transplant, suggests that there future for SCT in AID.
IS
an important
immunosuppression [46]. A 13-year-old girl with SS with Raynaud's phenomenon, myopathy and polyarthritis since the age of four developed diffuse skin thickening, gastro-
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