The Rationale For The Use Of alloBmt For The Treatment Of Autoimmune Disorders

Stem-cell transplantation may help accomplish the reinduction of unresponsiveness to self-antigens since the conditioning prior to the transplantation procedure normally involves myeloablative treatment that results in elimination of host-type immunohematopoi-etic cells, T cells included, followed by stem-cell rescue which results in regeneration of new T cells tolerant to self-antigens. Hence, if the autograft is T-cell-depleted, newly regenerating T cells are likely to become tolerant to self-antigens since self-reactive T cells, certainly high affinity self-reactive T cells, are likely to undergo apoptosis in status nascendi in the thymus [25], Similarly, following the use of T-cell-depleted stem-cell allograft, which can also be used for rescue of the myeloablated recipient, it seems very reasonable that both antiself as well as antihost reactivity will be abolished by the aforementioned procedure. Based on the above it can be anticipated that de novo development of the T-cell repertoire from uncommitted progenitor cells in the presence of the autoantigen against which self-reactive T cells are reactive is the best recipe for the reinduction of self-tolerance, similarly to the normal ontogeny of the immune system during induction of self-tolerance during fetal stage.

Allogeneic bone marrow transplantation which normally follows myeloablative conditioning can also eliminate spontaneous autoimmunity, as has been shown in (NZBxNZW)Fl, BxSB, (NZBxNZW)Fl females and MRL/lpr mice [13], and more recently in clinical practice [19-22], most likely by a combination of elimination of self-reactive lymphocytes of hostorigin and replacement of genetically susceptible stem cells with normal stem cells of donor origin.

Successful elimination of manifestations of autoimmune disease were documented in patients with RA, SLE, hyperthyroidism, dermatitis, vasculitis and Crohn's disease [13-22]. Successful treatment of MS was also reported in a patient with chronic myeloid leukemia following alloBMT, with subjective improvement in symptoms and objective improvement of neurological manifestations of disease and stabilization of MRI [14]. We have also treated one patient with CML with severe psoriasis accompanied by severe psoriatic arthritis and another patient with acute myeloid leukemia and thyroiditis, both successfully treated with alloBMT with complete elimination of signs and symptoms of the underlying autoimmune diseases (> 1 year) in parallel with eradication of the primary malignant disease (Slavin et al., in preparation). Resolution of pre-existing autoimmune diseases following alloBMT was recently reviewed by Marmont [21],

As indicated above, in addition to replacement of host stem cells which may be genetically susceptible to develop a particular autoimmune disorder, alloBMT may provide additional potential benefits against self-reactive lymphocytes that may escape chemoradio-therapy. Immunotherapy of autoimmunity by allore-active donor lymphocytes is mediated by recognition of minor histocompatibility antigens on the cell surface of host lymphocytes by immunocompetent donor T cells. Immunotherapy mediated by donor lymphocyte infusion (DLI) is the most important therapeutic component in the course of alloBMT, also due to elimination of residual host cells by donor alloreactive T cells [26, 27]. It is therefore important to understand the principles of immunotherapy in leukemia, also mediated by DLI, including elimination of normal and malignant lymphocytes by donor T cells, as a model for documenting the feasibility of ablation of host immune cells by alloreactive donor T cells through a process of graft vs leukemia (GVL) like effects [26, 27].

We have previously established the feasibility of reversing relapse following alloBMT in patients conditioned with myeloablative chemoradiotherapy by DLI [26, 27]. Out data suggests that the major therapeutic component of alloBMT can be attributed to immunocompetent donor T lymphocytes recognizing and eliminating tumor cells of host origin. We have recently demonstrated that similar graft vs host hematopoietic cells, lymphocytes included, may be observed also in patients with nonmalignant disorders, such as genetic diseases (beta thalassemia major) and enzyme deficiency disorders (Gaucher's disease, Hurler's syndrome, etc.) [28, 29]. Therefore, in addition to effective eradication of host-derived hematopoietic cells, we suggest that allogeneic cellmediated immunotherapy (alloCT) inducible with DLI, may also be used to eliminate host-type lymphocytes and genetically susceptible stem cells, autoreactive immune cells included. Hence, the use of alloBMT may be eventually recommended for more effective treatment of severe autoimmune disorders due to combination of the following principles:

(1) Elimination of self-reactive lymphocytes with myeloablative chemoradiotherapy;

(2) Elimination of genetically susceptible host stem cells and replacement with genetically more resistant stem cells;

(3) Re-induction of self-tolerance from uncommitted stem cells, provided that a T-cell-deleted allograft was used or GVHD otherwise controlled; and

(4) Elimination of residual self-reactive cells of host origin may be accomplished in patients with no GVHD following transplantation of CD34 enriched stem cells or T-cell-depletion by DLI. Graft vs autoimmunity may be accomplished with no additional DLI in patients receiving a non-T-cell-depleted allograft, since there are sufficient T cells in the graft, especially when mobilized stem cells are used, similarly to the procedures used for prevention/treatment relapse [26, 27, 30], Unfortunately, alloBMT is still considered a risky procedure that may not be yet justified as a routine procedure for patients with autoimmune diseases, especially due to the risks of acute and chronic GVHD, which as of todate can be neither safely prevented nor adequately treated. It so happens that T-cell-depletion, which appears to be the only method for effective prevention of GVHD, is frequently associated with increased incidence of graft rejection, which further requires intensification of chemoradiotherapy required for prevention of graft rejection as well as using larger stem-cell inocula, to compensate for lack of donor T cells that are known to facilitate graft acceptance [31, 32],

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