Treatment of severe autoimmune disease by stem-cell transplantation

Insight Review



NATURE|Vol 435|2 June 2005  |  doi:10.1038/nature03728

Megan Sykes1and Boris Nikolic2



Transplantation of haematopoietic stem cells — cells capable of self renewing and reconstituting all types of blood cell — can treat numerous lethal diseases, including leukaemias and lymphomas. It may now be applicable for the treatment of severe autoimmune diseases, such as therapy-resistant rheumatoid arthritis and multiple sclerosis. Studies in animal models show that the transfer of haematopoietic stem cells can reverse autoimmunity, and several mechanistic pathways may explain this phenomenon. The outcome of ongoing clinical trials, as well as of studies in patients and animal models, will help to determine the role that stem-cell transplantation can play in the treatment of autoimmune diseases.



The recent extension of the allo-HCT approach from rodents to humans for tolerance induction to alloantigens is highly encouraging. An understanding of the tolerization processes that apply to naive and memory T and B cells will ultimately lead to the development of less toxic, non-myeloablative conditioning regimens. The development of such conditioning regimens will lead to new hope for patients in need of organ transplants and possibly for those with autoimmune diseases. The ultimate role for allo-HCT in the treatment of autoimmune disease will be better defined by results of ongoing auto-HCT trials, and by an improved understanding of disease pathogenesis, the genetic defects underlying different forms of autoimmune disease, and the mechanisms by which HCT may tolerize memory T and B cells. In particular, the application of allo-HCT followed by transplantation of islets from the same donor has the potential to improve the therapy of patients with type 1 diabetes. Islet transplantation can normalize glucose levels and in theory could prevent some of the complications of diabetes. The immunosuppressive ‘Edmonton Protocol’ (which includes increased numbers of high-quality islet cells, omission of steroids and immunosuppression with tacrolimus, rapamycin and an anti-interleukin 2 receptor antibody) is a major step forward. Nonetheless, the overall outcome of clinical islet allotransplantation has been somewhat disappointing57. After 3–4 years, only 12–25% of transplanted patients were insulin independent57, possibly because of the allo- and autoimmune responses combined with complications of the drug therapy. In addition, the life-long immunosuppression needed to achieve allograft acceptance is hard to justify in young type 1 diabetic patients, making tolerance-inducing approaches particularly desirable. Tolerance would permit graft survival without the need for continuous immunosuppressive therapy. Successful tolerance protocols would overcome alloresponses to donor islet alloantigens and could prevent recurrent autoimmunity in the donor islets, as suggested by mixed-chimaerism studies in NOD mice with advanced diabetes39. Either combined HSC and islets from deceased donors or the combined transplantation of embryonic stem cell58or adult stem-cellderived islets and HSC could ultimately be used to achieve tolerance and cure of type 1 diabetes. In addition, promising approaches to xenotolerance induction, including HCT59, might ultimately allow the use of xenotransplants (grafts from donors of other species such as pigs) that could provide a solution to the shortage of allogeneic islets. In addition to tolerization of autoreactive and alloreactive cells, HCT might also allow regeneration of tissues that are destroyed by autoimmune disease. This could theoretically occur owing either to regeneration from endogenous stem cells once autoimmunity is reversed, or because of differentiation of HSCs or other cells in the HCT product into non-haematopoietic tissues. Endogenous islet


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