Conclusions And Future Directions

The use of alloBMT and autoBMT for the treatment of otherwise resistant hematologic malignancies and and certain chemotherapy sensitive solid tumors, respectively, is well established. Our recent observations suggest that GVL and possibly GVT effects may be amplified with alloCT mediated by donor alloreactive lymphocytes which could be further activated with rIL-2. Furthermore, we suggest that equally effective GVL and possibly GVT effects may be induced with a safer alloBMT procedure following nonmye-loablative conditioning, which could open new and safer therapeutic options for patients in need of alloBMT at all age groups. Furthermore, we suggest that many of the benefits that can be accomplished with autoBMT and alloBMT may be applicable for patients with life-threatening autoimmune disorders. Experiments carried out in animal models of human autoimmune disorders suggests that disease manifestations and immunological processes leading to the development of autoimmunity may be reversed by cytoreductive therapy followed by either syngeneic, autologous or preferably allogeneic stem-cell transplantation. Whereas following experimental induction of autoimmunity in animals without pre-existing genetic susceptibility, complete cure and resistance against re-establishment of the autoimmune process can be accomplished following syngeneic stem-cell transplantation, animals with genetic susceptibility and spontaneous autoimmunity may best benefit from alloBMT. The available data suggest that some patients may benefit from autoBMT, preferably T-cell-depleted to prevent reinfusion of autoreactive cells, others may require alloBMT for complete eradication of disease manifestation and especially for complete prevention of recurrence of the basic autoimmune process. Clearly, following autoBMT, it seems rational to maximize T-cell-depletion in vivo as well as use purified uncommitted stem cells to prevent disease recurrence from autoreactive lymphocytes introduced with the stem cells.

In considering alloBMT for the treatment of autoimmunity, cumulative data from a cohort of patients treated successfully with alloNST suggests that a lower intensity of nonmyeloablative yet sufficiently immunosuppressive conditioning may be sufficient to provide a window of opportunity for induction of host vs graft transplantation tolerance as a platform for subsequent elimination of residual host hematopoietic cells by alloreactive donor lymphocytes in the course of alloNST or later on an outpatient basis as part of an alloCT program with graded increments of DLI while controlling for GVHD. Future developments using protocols with reduced toxicity and improved efficacy, particularly preventing GVHD by T-cell-depletion and/or stem cell (CD34+) purification, combined with future procedures for better host tolerization to the T-cell-depleted allograft, or alternatively gradual tolerization of donor T cells to the host by using graded increments of donor lymphocytes for continuous eradication of host derived immune cells over a longer period of time, similarly to prevention of relapse in patients with hematologic malignancies, are likely to increase the indication and success rate in utilizing stem-cell transplantation for the treatment of autoimmune diseases which at the present time must be restricted only for patients with severe and life-threatening clinical condition in patients resistant to all available modalities.

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