Inhibition of BCL-2 for induction of mixed chimerism without myelosuppressive conditioning

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PROJECT SUMMARY / ABSTRACT Induction of specific immunologic tolerance is the ultimate goal of organ transplantation. Based on the conditioning regimen developed in our laboratory through decades-long research in nonhuman primates (NHP), successful renal allograft tolerance in HLA mismatched human kidney transplant recipients has now been achieved via the mixed chimerism approach. Nevertheless, widespread clinical application of this approach to tolerance induction has been hampered by the toxicity of myelosuppressive therapies (e.g., TBI or cyclophosphamide) included in the current conditioning regimen. It would therefore be desirable to develop a reliable nontoxic conditioning regimen that permits allogeneic hematopoietic stem cell (HSC) engraftment without nonselective myelosuppressive therapy. Although it has been extremely difficult to achieve engraftment of allogeneic HSC without myelosuppressive conditioning, Cippa et al. recently reported a novel approach to HSC engraftment using a B cell lymphoma-2 (Bcl-2) inhibitor, without myelosuppressive therapy. In that study, through induction of persistent mixed chimerism by a potent but selective Bcl-2 inhibitor, ABT-737, in combination with costimulatory blockade and cyclosporine, successful induction of skin allograft tolerance was achieved across a full MHC disparity. The major objective of the proposed exploratory R21 project is to translate this novel rodent bone marrow transplant study with ABT-263 (navitoclax), an orally available analog of ABT-737, to a non-human primate kidney transplant model and thereby develop a more clinically feasible protocol for inducing renal allograft tolerance using the mixed chimerism approach. Since our previous studies suggest that renal allograft tolerance achieved in NHP and human recipients after induction of chimerism is regulatory T cell (Tregs) dependent, understanding the effects of Bcl-2 inhibition on allo-reactive T cells and Tregs will enable us to determine the transplant outcome. Therefore, another important objective of this study is to evaluate the effect of ABT-263 on various T cell subsets to elucidate the mechanisms of tolerance after induction of mixed chimerism.