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NDT Advance Access originally published online on January 23, 2006
Nephrology Dialysis Transplantation 2006 21(5):1154-1157; doi:10.1093/ndt/gfk077
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Editorial Comment

Haematopoietic stem cell transplantation for severe autoimmune diseases: new perspectives

Michel Toungouz Névessignsky1 and Alina Ferster2

1 Hôpital Erasme and 2 Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Université Libre de Bruxelles, Brussels, Belgium

Correspondence and offprint requests to: M. Toungouz Névessignsky, Department of Immunology-Hematology-Transfusion, Erasme Hospital, 808, route de Lennik, B-1070, Brussels, Belgium. Email: toungouz{at}ulb.ac.be

Keywords: autoimmune disease; autoimmunity; haematopoietic stem cell transplantation; immune reconstitution; non-myeloablative conditioning



   Introduction
Top
 Introduction
Clinical experience
 New perspectives
 Conclusion
 References
 
Autoimmune diseases affect ~5% of the population. Autoimmunity, inflammation and tissue damage feature in this heterogeneous group of disorders. The potential of haematopoietic stem cell transplantation (HSCT) for the treatment of autoimmune diseases was originally supported by animal experiments (reviewed in van Bekkum [1]) together with occasional remission of autoimmune diseases in patients undergoing HSCT for haematological disorders. Improved safety of both autologous and allogeneic HSCT has allowed the use of such procedures as an experimental treatment for severe autoimmune disease resistant to conventional treatments. One of the first challenges in this context was to bring together haematologists and specialists in many other fields including nephrology, rheumatology, paediatrics, internal medicine and neurology. From now on, data on almost 800 procedures are collated in international databases [2]. Although phase III trials are in progress, the main conclusion that can be drawn from this experience is that HSCT is certainly not effective in all patients whatever the type of autoimmune disease, and has so far not been proved to be of long-term benefit at the population level. In this comment, we will discuss the potential explanations for such a limitation and suggest some innovations that might improve clinical outcome.



   Clinical experience
Top
 Introduction
 Clinical experience
New perspectives
 Conclusion
 References
 
The first proposal considering HSCT in autoimmune diseases was published in 1995 [3]. The year after saw the first international meeting devoted to stem cell therapy in autoimmune diseases held in Basel under the auspices of the European Group for Bone Marrow Transplantation (EBMT) and the European League against Rheumatism (EULAR). Consensus guidelines were published and the International Autoimmune Stem Cell Project Database was established. Although allogeneic transplantation was considered, autologous HSCT was mostly preferred for obvious safety reasons. Various autoimmune diseases were transplanted, but, rapidly, multiple sclerosis (MS) and rheumatoid arthritis (RA) emerged as the most frequent indications.

Very soon, it emerged that the management of these patients was more difficult and problematic than that of conventional autologous transplant patients. Indeed, the mortality reported by the first studies was higher than previously reported for autologous HSCT performed in haematological malignancies. Today, toxicity, including renal complications [4], remains an issue.

In a recent series including 85 MS patients from 20 centres, autologous HSCT was associated with significant toxicity although ~20% of patients improved by an expanded disability severity score (EDSS) score of ≥1 [5]. The principal aims of stem cell therapy for autoimmune diseases are to stop disease evolution and prevent disease recurrence. In MS, this means stopping neurological deterioration and preventing disability. The worldwide experience to date suggests that autologous HSCT has a substantial anti-inflammatory effect with improvement in magnetic resonance imaging (MRI) lesions and an apparent early stabilization of the disease. However, subsequent progression occurs in a proportion of patients.

In severely ill juvenile idiopathic arthritis (JIA) patients, HSCT induced a prolonged drug-free remission in >50% of the patients and a profound increase in general well-being in a substantial part of them. However, toxicity was also important, making it necessary to carefully weigh morbidity and mortality risks of the prolonged immunosuppression of conventional treatment against those of the short but intense immunosuppression of HSCT [6]. As for MS, subsequent progression is a concern in JIA and RA: clinical responses can be transient. This has led some investigators to explore allogeneic HSCT with the hope that rheumatoid diseases might be cured by a single hit treatment [7].

HSCT has also been used in several other autoimmune diseases including systemic lupus erythematosus, immune cytopenias, systemic sclerosis, Crohn's disease and other inflammatory conditions with controversial results, although a long-lasting response is sometimes achieved in previously refractory or relapsing patients [8].

HSCT thus remains an experimental treatment for severe autoimmune disease, and the relative efficacy and toxicity compared with more conventional approaches must be evaluated now in the context of prospective, randomized trials. The main issue in conducting such trials is that of recruitment, especially for RA and JIA. Most of the early studies in autologous HSCT for RA were performed prior to the availability of biological therapies. In recent years, such therapies, particularly blockers of tumour necrosis factor-{alpha} (TNF-{alpha}), have become established as safe and highly effective treatment for resistant RA and JIA [9]. However, there remains a significant proportion (25%) of treatment failures, and the potential use of HSCT is now limited to these rather rare patients. In other autoimmune diseases for which biological therapies are not yet available, the main challenge is to identify early on, among patients who are refractory to conventional treatments, those who will benefit from HSCT before tissue destruction is irreversible.



   New perspectives
Top
 Introduction
 Clinical experience
 New perspectives
Conclusion
 References
 
Many pivotal questions are still open and should be answered to optimize HSCT in autoimmune diseases. At the forefront are the mechanisms of action of stem cells, both for modulation of immunity and for tissue repair. These effects are related to the conditioning regimen and to the graft manipulation which in turn are crucial for post-transplant immune reconstitution. Finally, the source of stem cells must be reconsidered. Although experimental animal models usually required allogeneic HSCs for curing autoimmune diseases, autologous HSCT has been the first choice because of safety concerns. The recent development of non-myeloablative conditioning regimens opens up new perspectives for the use of allogeneic stem cells in autoimmune diseases.

Modulation of immunity
There has been a lot of speculation regarding the nature of the mechanism involved in the clinical response elicited by HSCT in autoimmune diseases. The first effect is probably the result of the eradication of autoreactive T cells related to the direct lymphoablation induced by the conditioning regimen. This is a non-specific and transient effect. In order to reduce the risk of disease recurrence, some teams have initially tried to deplete the graft further from T cells in order to avoid reinfusion of autoreactive T cells [10]. This has been mainly performed through positive selection of CD34+ cells resulting in a near 2 log depletion of T cells in the stem cell graft. This labour-intensive and money-consuming approach has not proven a definitive advantage over the transplantation of non-T-cell-depleted stem cells probably because the number of remaining T cells in the patient, even after conditioning, is far higher than that of graft-contaminating T cells. New insights into the immunomodulatory effects of HSCT in autoimmune diseases will probably come from a more careful study of the role of regulatory T cells (T reg cells). Indeed, the network of T reg cells can modulate or downregulate immunological responses. The population of T reg cells is heterogeneous, but naturally occurring T reg cells identified by the expression of CD25 and transcription factor FoxP3 [11] seem to be extremely important for the control of autoimmunity [12]. Studies on CD4+ CD25+ T cells in human disease are still limited and their antigen specificity is still debated, but there is no doubt that they will be of major importance for the optimization of treatment aimed at curing autoimmune diseases. In disease where the autoantigen is clearly identified, this would open the door to the ex vivo generation of autoantigen-specific inhibitory T cells that could be used for adoptive immunotherapy.

Conditioning regimen and source of haematopoietic stem cells
As previously discussed in the context of autologous HSCT, the conditioning regimen is essential for the eradication of autoreactive T cells but is also a major cause of toxicity. In trying to reduce transplant-related mortality and morbidity of allogeneic HSCT in haematological patients at high risk of toxicity, conventional myeloablative regimens have now been replaced by non-myeloablative but more immunosuppressive conditioning. These non-myeloablative regimens initially combined anti-lymphocyte globulins and cyclophosphamide or low dose TBI plus fludarabine. More recently, Campath-1H (alemtuzimab) has been introduced. Because of its long half-life, administration of this anti-lymphocyte antibody reduces recipient T cell numbers and lyses infused donor T cells, reducing the risk of graft vs host disease. In murine models, non-myeloablative conditioning followed by allogeneic transplantation has been shown to treat some autoimmune diseases effectively [13]. This non-myeloablative approach minimizes the therapy-related toxicity, induces allograft tolerance and results in mixed chimerism, which is of interest for the eradication of autoreactive T cells. Until now, only a few case reports confirmed the feasibility of this approach in humans [14]. Feasibility must also take into account the availability of a histocompatible donor which has been mostly a matched sibling donor. This type of donor is only available for about one-third of patients. The opportunity to perform allogeneic stem cell transplantation using alternative sources of stem cells such as cord blood has now to be questioned for the remaining two-thirds. Indeed, the possibility of using partially matched cord blood and of performing pooled or sequential cord blood transplantation will have to be considered in the near future because they greatly enhance the chance to find a suitable graft and to dispose of a sufficient amount of stem cells to transplant an adult [15].

Immune reconstitution
Rapid and non-skewed immune reconstitution is essential for post-transplant survival. Major parameters influencing recovery of immune cells include CD34+ and T cell content of the graft. T cell reconstitution is primarily dependent on mature T cells that are present in the graft. Post-transplant, most of the CD4+ T cells are expanded from the peripheral pool which includes a vast proportion of memory CD45 RO cells. Transplantation of T cell-depleted HSCs has been associated with delayed immune reconstitution particularly with respect to CD4+ T cells, although the diversity of the repertoire seemed to be globally recovered [10], probably because of slow but gradual thymopoiesis. In order to limit the infectious complications related to impaired cellular immunity, immune reconstitution has to be accelerated. There are two main avenues in that direction. The first is at least technically easy to implement. This is the infusion of higher numbers of CD34+ cells. The second is quite experimental and is related to the use of lymphocytic growth factors susceptible to speed up thymopoiesis such as interleukin (IL)-7 which is currently being tested in phase I/II trials [16].

Regenerative properties of stem cells
HSCs but also non-haematopoietic stem cells such as mesenchymal stem cells (MSCs) present in the bone marrow could also contribute to the cure of autoimmune diseases by repairing the damaged tissue. This concept comes from recent works showing that marrow-derived cells can be incorporated into, for example, heart, liver, joints and brain. The extent to which these cells could replace damaged neurons in MS or contribute to joint repair in RA and JIA is an exciting prospect [17,18]. In that context, MSCs are of special interest because they are also endowed with immunosuppressive properties that could help to abrogate not only deleterious allogeneic reactions such as graft vs host disease but also autoimmune manifestations [19].



   Conclusion
Top
 Introduction
 Clinical experience
 New perspectives
 Conclusion
References
 
Despite occasional impressive clinical improvements, a definitive proof of sustained efficacy of HSCT in autoimmune diseases is still lacking. However, new insights into the control of the immune response as well as into the biology of stem cells open up new avenues for innovative cellular therapies. Conducting large-scale randomized trials taking advantage of these recent achievements will be the challenge for the coming years.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Clinical experience
 New perspectives
 Conclusion
 References
 

  1. van Bekkum DW. New opportunities for the treatment of severe autoimmune diseases: bone marrow transplantation. J Clin Immunol 2000; 20: 10–16[CrossRef][ISI][Medline]
  2. Hough RE, Snowden JA, Wulfraat NM. Haematopoietic stem cell transplantation in autoimmune diseases: a European perspective. Br J Haematol 2004; 128: 423–459
  3. Marmont AM, Tyndall A, Gratwohl A, Vischer T. Haematopoietic precursors cell transplants for autoimmune diseases. Lancet 1995; 345: 978[Medline]
  4. Parikh CR, Sandmaier BM, Storb RF et al. Acute renal failure after nonmyeloablative hematopoietic cell transplantation. J Am Soc Nephrol 2004; 15: 1868–1876[Abstract/Free Full Text]
  5. Fassas A, Passweg JR, Anagnastopoulos A et al. Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol 2002; 249: 1088–1097[CrossRef][ISI][Medline]
  6. De Kleer IM, Brinkman DM, Ferster A et al. Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical effects, mortality and transplant related morbidity. Ann Rheum Dis 2004; 63: 1318–1326[Abstract/Free Full Text]
  7. Mc Coll G, Kohsaka H, Szer J, Wicks I. High dose chemotherapy and syngeneic hematopoietic stem-cell transplantation for severe, seronegative rheumatoid arthritis. Ann Intern Med 1999; 131: 507–509[Abstract/Free Full Text]
  8. Jayne D, Passweg J, Marmont A et al. Autologous stem cell transplantation for systemic lupus erythematosus. Lupus 2004; 13: 168–176[Abstract/Free Full Text]
  9. Lovell DJ, Giannini EH, Reiff A et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Eng J Med 2000; 342: 763–769[Abstract/Free Full Text]
  10. Durez P, Toungouz M, Schandené L, Lambermont M, Goldman M. Remission and immune reconstitution after T-cell depleted stem cell transplantation for rheumatoid arthritis. Lancet 1998; 352: 881[Medline]
  11. Shevach EM, Piccirillo CA, Thornton AM, Mc Hughs RS. Control of T cell activation by CD4+CD25+ suppressor T cells. Novartis Found Symp 2003; 252: 24–36[Medline]
  12. Verginis P, Li HS and Carayanniotis G. Tolerogenic semi-mature dendritic cells suppress experimental autoimmune thyroiditis by activation of thyroglobulin-specific CD4+CD25+ T cells. J Immunol 2005; 174: 7433–7439[Abstract/Free Full Text]
  13. Nikolic B, Takeuchi Y, Leykin I, Fudaba Y, Smith RN, Sykes M. Mixed hematopoietic chimerism allows cure of autoimmune diabetes through allogeneic tolerance and reversal of autoimmunity. Diabetes 2004; 53: 376–393[Abstract/Free Full Text]
  14. Jones OY, Good RA, Cahill RA. Nonmyeloablative allogeneic bone marrow transplantation for treatment of childhood overlap syndrome and small vessel vasculitis. Bone Marrow Transplant 2004; 33: 1061–1063[CrossRef][Medline]
  15. Ballen KK. New trends in umbilical cord blood transplantation. Blood 2005; 105: 3786–3792[Abstract/Free Full Text]
  16. Wils EJ, Cornelissen JJ. Thymopoiesis following allogeneic stem cell transplantation: new possibilities for improvement. Blood Rev 2005; 19: 89–98[CrossRef][Medline]
  17. Mezey E, Chandross KJ, Harta G, Maki RA, Mc Kercher SR. Turning blood into brain: cells bearing neuronal antigens generated from bone marrow. Science 2000; 290: 1779–1782[Abstract/Free Full Text]
  18. Gangji V, Toungouz M, Hauzeur JP. Stem cell therapy for osteonecrosis of the femoral head. Expert Opin Biol Ther 2005; 5: 437–442[CrossRef][Medline]
  19. Le Blanc K, Ringden O. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 321–334[CrossRef][Medline]
Received for publication: 2. 7.05
Accepted in revised form: 22.12.05


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