STEM-CELL TRANSPLANTATION FOR SEVERE AUTOIMMUNE-DISEASES - PROGRESS AND PROBLEMS

Since Morton and Siegel's epochal experiments 30 years ago animal mode ls have been successfully utilized both for transfer and resolution of autoimmune diseases (AID). More recently human lymphocyte xenografts have reproduced clinical AID in SCID mice. Allogeneic stem cell transp lantation demonstrated therapeutic potential in fully developed autoim mune disease. Mixed allogeneic chimerism induced by a sublethal approa ch has also been shown to prevent and even reverse autoimmune insuliti s in nonobese diabetic (NOD) mice. More unexpectedly it was found that experimental adjuvant arthritis (AA) and experimental allergic enceph alomyelitis (EAE) could be cured by means of total body irradiation (T BI) followed by autologous hemolymphopoietic stem cell (HSC) transplan tation. It was postulated that the newly developing T cells might be t olerant to self antigens. The transfer of AID from affected donors to recipients of allogeneic HSC transplants has been reported for many or gan-specific AID, including diabetes (IDDM), thyroiditis, myasthenia g ravis and thrombocytopenic purpura (AITP); rheumatoid arthritis (RA) a nd systemic Lupus erythematosus (SLE) were not transferred. Conversely patients with the combination of AID and a severe blood disease (leuk emia, aplasia) were cured of both diseases following allogeneic BMT, w ith the notable exception of a relapse in a patient with RA despite fu ll donor engraftment. Allogeneic transplants are certainly more promis ing as far as concerns a resolution of AID, because they may also exer t a graft-versus-autoimmunity effect by gradually eradicating the reci pient's lymphopoiesis, but transplant related mortality (TRM) is consi dered still too high to employ this procedure consistently. New non-my eloablative conditioning regimens, designed to allow the donor's immun e system to take over, are already utilized for malignant and non-mali gnant hematologic diseases, and may become an attractive option for se vere, refractory AID. For the time being, however, autologous procedur es are still safer, and are being utilized in many projects worldwide. The EBMT/EULAR Registry has collected over 70 patient reports. The mo re numerous and favorable results have been obtained up to now in mult iple scleosis and in systemic lupus erythematosus,. the worst in refra ctory autoimmune thrombocytopenic purpura. No definite conclusions as to the efficacy of autologous HSC transplantation, from marrow or from blood, with or without T-cell depletion, may be drawn at this time, b ut the feeling is that real cures will be very difficult to obtain by this approach, and that corticosteroid-free remissions and a general l owering of the autoimmune potential will be more realistic goals. Accu rate comparisons with already existing aggressive immunosuppressive pr otocols will become necessary, if possible by means of prospective ran domized clinical studies. (C) 1998, Ferrata Storti Foundation.