Hematopoietic stem cell transplantation for systemic lupus erythematosus, the antiphospholipid syndrome and bullous skin diseases.

Systemic lupus erythematosus (SLE) is considered the paradigm of autoimmune diseases (AD), and the murine models are known to be curable by means of allogeneic hematopoietic stem cell transplantation (HSCT). However autologous transplantations were predominantly utilized in the clinic, starting from 1996, and by now well over 150 very severe patients have been transplanted worldwide. Transplant-related mortality (TRM) in 153 cases was 7%, with a wide center effect (from 0-2% to 13%). The disease arresting effect was dramatic even in patients on dialysis, although ASCT should not be considered a last resource, salvage therapy, but a disease- modifying intervention to be utilized in the early stages of patently aggressive disease. The autoimmune biological parameters are consistently modified, although some degree of ANA-positivity generally persists. Similar encouraging results have been obtained in the primary antiphospholipid syndrome (APS) and in bullous disorders of the skin.

Will hematopoietic stem cell transplantation cure human autoimmune diseases?

Hematopoietic stem cell transplantation is becoming an accepted therapy for severe autoimmune diseases, and over 1,000 patients have been transplanted worldwide. Diseases include neurological (multiple sclerosis, others), rheumatological (systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis), haematological (aplastic anemia, single line immune mediated cytopenias) and others. The aim of this article is not to review the copious specific literature, but to analyze whether the up to now existing evidence satisfies the requirements of cure. Prospective randomized trials have been launched by the European Group of Blood and Marrow Transplantation (EBMT). Autologous transplantation, by far the most widely utilized because of its safety, has been shown to possess a powerful disease-arresting effect, but whether the attendant immune reconstitution ("re-education") will finally lead to cure is not demonstrated. The experience with allogeneic transplantation is too limited to draw even tentative conclusions. A Graft-versus-Autoimmunity effect has been ascertained both experimentally and clinically, but cure of autoimmunity by this procedure has not been demonstrated. Unexpected relapses in spite of full donor chimerism have been published. Further experience and studies are necessary.

Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life.

Hematopoietic stem cell transplantation (HSCT) has been proposed for the treatment of severe multiple sclerosis (MS). In a phase 2 multicenter study we selected 19 non-primary progressive MS patients showing high disease activity on the basis of both brain magnetic resonance imaging (MRI) and sustained clinical deterioration despite conventional treatments. After stem cell mobilization with cyclophosphamide (CY) and filgrastim, patients were conditioned with BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea), cytosine arabinoside, etoposide, and melphalan (BEAM) followed by antithymocyte globulin (ATG). Unmanipulated peripheral blood stem cells (PBSCs) were then infused. No maintenance treatment was administered with a median follow-up of 36 months (range, 12 to 72 months). All patients showed clinical stabilization or improvement; 3 subsequently deteriorated, 1 beyond the baseline. No MRI active lesions were detected after the HSCT except in 1 patient who showed a new lesion at 4.5 years. Infections were limited and restricted to 3 months after HSCT. Health-related quality of life was assessed through the 54-item MS quality of life (MSQOL-54) questionnaire, showing a statistically significant improvement in both composite scores and in most of the individual domains. HSCT is able to induce a prolonged clinical stabilization in severe progressive MS patients, resulting in both sustained treatment-free periods and quality of life improvement.

Stem cell transplantation for autoimmune disorders. Coincidental autoimmune disease in patients transplanted for conventional indications.

The practice of stem cell transplantation for severe autoimmune diseases refractory to conventional therapy originated from two landmark discoveries: the excellent results of animal experiments, and serendipitous observations in human coincidental diseases. The latter include patients with an often long-standing autoimmune disease who have developed a haematological condition (aplasia, leukaemia, lymphoma) requiring stem cell transplantation (from marrow as well as from blood). Allogeneic and autologous transplants have been performed. The initial information deriving from both procedures is their feasibility, even more convincing since the patients were affected by two simultaneous severe diseases. The information derived from autologous transplants has, however, now been superseded by the considerable and increasing number of those transplants performed for primary autoimmune diseases. On the other hand, allogeneic stem cell transplantation for very severe autoimmune diseases is being cautiously explored in current protocols. Allogeneic transplants in coincidental disease have also suggested a graft-versus-autoimmunity effect, which may become relevant in conjunction with non-myeloablative, less toxic condition regimens.

Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure?

Hematopoietic stem cells (HSCs) are the earliest cells of the immune system, giving rise to B and T lymphocytes, monocytes, tissue macrophages, and dendritic cells. In animal models, adoptive transfer of HSCs, depending on circumstances, may cause, prevent, or cure autoimmune diseases. Clinical trials have reported early remission of otherwise refractory autoimmune disorders after either autologous or allogeneic hematopoietic stem cell transplantation (HSCT). By percentage of transplantations performed, autoimmune diseases are the most rapidly expanding indication for stem cell transplantation. Although numerous editorials or commentaries have been previously published, no prior review has focused on the immunology of transplantation tolerance or development of phase 3 autoimmune HSCT trials. Results from current trials suggest that mobilization of HSCs, conditioning regimen, eligibility and exclusion criteria, toxicity, outcome, source of stem cells, and posttransplantation follow-up need to be disease specific. HSCT-induced remission of an autoimmune disease allows for a prospective analysis of events involved in immune tolerance not available in cross-sectional studies.

Stem cell therapy for severe autoimmune diseases

A Imunossupressão intensa seguida do transplante de células precursoras hematopoiéticas (TCPH), alogênicas ou autogênicas é um procedimento relativamente recente e que foi utilizado pela primeira vez em casos dramáticos de lúpus eritematoso sistêmico. Atualmente três procedimentos agressivos são utilizados nas doenças autoimunes: Altas doses de quimioterapia sem o resgate de células precursoras, imunossupressão intensa com impulsão subsequente de células precursoras hematopoiéticas alogênicas combinadas ou não a seleção de células CD34+, e o transplante autogênico de células precursoras hematopoiéticas. A comprovação do efeito enxerto contra a leucemia observado e comprovado, define o TCPH como forma de imunoterapia, existindo evidencias também do efeito contra a imunidade o qual propiciaria a cura das doenças autoimunes nesta forma de terapia. O uso do TCPH autogênico teve seu avanço baseado na segurança do mesmo em relação aos TCPHs alogênicos. No relato são apresentados dados em esclerose múltipla e lúpus eritematoso sistêmico sendo nossa conclusão de que as TCPHs nas suas modalidades tem indicação a luz dos resultados na literatura.

Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure?

Hematopoietic stem cells (HSCs) are the earliest cells of the immune system, giving rise to B and T lymphocytes, monocytes, tissue macrophages, and dendritic cells. In animal models, adoptive transfer of HSCs, depending on circumstances, may cause, prevent, or cure autoimmune diseases. Clinical trials have reported early remission of otherwise refractory autoimmune disorders after either autologous or allogeneic hematopoietic stem cell transplantation (HSCT). By percentage of transplantations performed, autoimmune diseases are the most rapidly expanding indication for stem cell transplantation. Although numerous editorials or commentaries have been previously published, no prior review has focused on the immunology of transplantation tolerance or development of phase 3 autoimmune HSCT trials. Results from current trials suggest that mobilization of HSCs, conditioning regimen, eligibility and exclusion criteria, toxicity, outcome, source of stem cells, and posttransplantation follow-up need to be disease specific. HSCT-induced remission of an autoimmune disease allows for a prospective analysis of events involved in immune tolerance not available in cross-sectional studies.