ABSTRACT
Memory T cells (Tm) represent a major barrier for immunosuppression and tolerance induction after solid organ transplantation. Taking into consideration the critical role of the intrinsic apoptosis pathway in the generation and maintenance of Tm, we developed a new concept to deplete alloreactive Tm by targeting Bcl-2 proteins. The small-molecule Bcl-2/Bcl-XL inhibitor ABT-737 efficiently induced apoptosis in alloreactive Tm in vitro and in vivo and prolonged skin graft survival in sensitized recipients. A short course of ABT-737 induction therapy prevented Tm-mediated resistance in a donor-specific transfusion model and allowed mixed chimerism induction across Tm barriers. Since Bcl-2 inhibitors yielded encouraging safety results in cancer trials, this novel approach might represent a substantial advance to prevent allograft rejection and induce tolerance in sensitized recipients.
Subject(s)
Bone Marrow Transplantation , Graft Survival/immunology , Immunologic Memory/immunology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Skin Transplantation , T-Lymphocytes/immunology , bcl-X Protein/antagonists & inhibitors , Animals , Apoptosis/drug effects , Apoptosis/immunology , Biphenyl Compounds/pharmacology , Blotting, Western , Cells, Cultured , Flow Cytometry , Graft Survival/drug effects , Immune Tolerance/drug effects , Immune Tolerance/immunology , Immunologic Memory/drug effects , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Nitrophenols/pharmacology , Piperazines/pharmacology , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Sulfonamides/pharmacology , T-Lymphocytes/drug effects , Transplantation Chimera , Transplantation, Homologous , bcl-X Protein/genetics , bcl-X Protein/metabolismABSTRACT
Dynamic regulation of the intrinsic apoptosis pathway controls central and peripheral lymphocyte deletion, and may interfere with the pro-apoptotic potency of B-cell lymphoma 2 inhibitors such as ABT-737. By following a T-cell receptor (TCR) transgenic population of alloantigen-specific T cells, we found that sensitivity to ABT-737 radically changed during the course of allo-specific immune responses. Particularly, activated T cells were fully resistant to ABT-737 during the first days after antigen recognition. This phenomenon was caused by a TCR-calcineurin-nuclear factor of activated T cells-dependent upregulation of A1, and was therefore prevented by cyclosporine A (CsA). As a result, exposure to ABT-737 after alloantigen recognition induced selection of alloreactive T cells in vivo, whereas in combination with low-dose CsA, ABT-737 efficiently depleted alloreactive T cells in murine host-versus-graft and graft-versus-host models. Thus, ABT-737 resistance is not a prerogative of neoplastic cells, but it physiologically occurs in T cells after antigen recognition. Reversibility of this process by calcineurin inhibitors opens new pharmacological opportunities to modulate this process in the context of cancer, autoimmunity and transplantation.
