Intense Immunosuppression and Stem-Cell Transplantation for Patients With Severe Rheumatic Autoimmune Disease: A Review

Jacob M. van Laar, MD, Alan Tyndall, MD


Cancer Control. 2003;10(1) 

In This Article


The concept of intensive immunosuppression is based on findings in animal models of autoimmune dis-ease, as well as results obtained in patients who under-went SCT for hematologic or oncologic diseases while coincidentally also having an autoimmune disease. Hematopoietic SCT as a treatment option in autoimmune diseases was first evaluated in lupus models in rodents after studies showed that transplantation of bone marrow from the hereditary or spontaneous lupus-like mouse strain New Zealand Black induced antinuclear antibodies and glomerulonephritis in lethally irradiated DBA/2 mice.[8,9] It was subsequently shown that infusion of bone marrow derived from nonsusceptible donors could prevent autoimmune disease after immunoablation of the host predisposed to develop autoimmune disease.[10,11] Following these observations, animals with induced forms of autoimmune diseases were treated with allogeneic or syngeneic bone marrow transplantation (ie, bone marrow from a healthy donor from the same strain) and pseudoautologous bone marrow transplantation (ie, bone marrow from affected animals of the same strain).[12] These models differ from the spontaneous forms as immunization with specific antigens is required.

In the case of adjuvant arthritis, heat-killed Mycobacterium tuberculosis is used for induction of disease. Adjuvant arthritis is T-cell mediated since adoptive transfer of T cells from affected animals causes disease in healthy animals. Adjuvant arthritis in Buffalo rats is a chronic, progressive type of polyarthritis with proliferating synovitis and pannus formation reminiscent of histopathologic findings in synovium of RA patients. In adjuvant arthritis in rats, a myeloablative regimen followed by allogeneic and also, unexpectedly, by autologous and syngeneic SCT not only prevented the disease but also induced remission.[13] Spontaneous relapses after syngeneic bone marrow transplantation were rare in adjuvant arthritis but did occur more frequently in experimental allergic encephalomyelitis, a model for multiple sclerosis (30% after syngeneic vs 5% after allogeneic transplantation).[14] Subsequent studies employing major histocompatibility complex (MHC)-matched allogeneic and pseudoautologous bone marrow transplantation strongly suggested that relapses in encephalomyelitis were due to residual host activated T lymphocytes and lymphocytes in the graft, respectively.[15,16] This was supported by studies in adjuvant arthritis demonstrating superiority of more intense conditioning.[17]

In summary, valuable lessons have been learned from the animal studies that may be relevant in the application of SCT in rheumatic autoimmune disease: (1) myeloablative therapy, followed by bone marrow transplantation, has curative potential, (2) allogeneic SCT may be more effective than autologous SCT if a graft-vs-autoimmunity effect exists and if intrinsic stem-cell defects play a role in the disease pathogenesis, and (3) in vivo T-cell depletion may be a prerequisite for a sustained response.

The results from experimental animal studies were paralleled by clinical observations in patients with autoimmune diseases who were treated with bone marrow transplantation because of a concomitant severe hematologic disorder. These involved RA patients who received allogeneic bone marrow transplantation because of aplastic anemia due to gold and/or D-penicillamine therapy.[18,19,20] Of the 8 reported RA cases, 3 patients who underwent bone marrow transplantation in the early days of this therapy died due to transplant-related complications after achieving a remission immediately following transplantation. The other patients were free of symptoms (1 patient reportedly relapsed) with a follow-up ranging from 2 to 8 years. However, 1 patient who received an allogeneic bone marrow transplantation for aplastic anemia RA relapsed after 2 years despite full donor engraftment.[21] Similar long-term remissions were observed in RA and SLE patients after autografting for a hematologic malignancy.[22,23] In contrast, 2 RA patients treated with autologous unmanipulated SCT for non-Hodgkin's lymphoma fared worse, with relapse of RA occurring 5 weeks and 20 months after autologous SCT.[24] This was ascribed to the presence of potentially autoreactive lymphocytes in the grafts.

These experimental studies and clinical observations paved the way for collaborative efforts to further explore the clinical potential of stem-cell grafting in human autoimmune disease. The lack of alternative treatment options for severe, uncontrolled autoimmune diseases prompted development of this treatment strategy. Until recently, mortality and morbidity of blood or marrow SCT were considered too high to justify the risk of such a procedure in patients with chronic autoimmune diseases where prevention of morbidity instead of mortality has long been the major goal. This pertains to allogeneic SCT in particular, with its attending transplant-related morbidity and mortality rates of 15% to 30% in hemato-oncologic diseases. Autologous SCT, however, carries a transplant-related mortality rate of less than 5% in malignancies such as myeloma, lymphoma, and breast cancer.[25,26,27] Therefore, for safety reasons, priority was given to autologous SCT. An international collaborative committee was established in 1995 under the auspices of the European Group for Blood and Marrow Transplantation (EBMT) and the European League Against Rheumatism (EULAR), which later included active groups in North America, that developed guidelines on entry criteria and transplant protocols for severe autoimmune diseases.[28] Furthermore, a database was created to collect clinical data that would enable monitoring of feasibility, toxicity, and efficacy of the different treatment protocols. Since its inception, the database has collected data from more than 400 transplants. Analysis of these pooled data has yielded relevant information on trends with regard to mortality, type of protocols used, and diseases targeted. These data are thus complementary to the primary data from the various phase I/II studies. Most transplants involved multiple sclerosis,[29] followed by the rheumatologic conditions of RA, JIA, SSc, and SLE.


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