title: Targeting apoptosis to induce stable mixed hematopoietic chimerism and long-term allograft survival without myelosuppressive conditioning in mice.
abstract: Induction of mixed hematopoietic chimerism results in donor-specific immunological tolerance by apoptosis-mediated deletion of donor-reactive lymphocytes. A broad clinical application of this approach is currently hampered by limited predictability and toxicity of the available conditioning protocols. We developed a new therapeutic approach to induce mixed chimerism and tolerance by a direct pharmacological modulation of the intrinsic apoptosis pathway in peripheral T cells. The proapoptotic small-molecule Bcl-2 inhibitor ABT-737 promoted mixed chimerism induction and reversed the antitolerogenic effect of calcineurin inhibitors by boosting the critical role of the proapoptotic Bcl-2 factor Bim. A short conditioning protocol with ABT-737 in combination with costimulation blockade and low-dose cyclosporine A resulted in a complete deletion of peripheral donor-reactive lymphocytes and was sufficient to induce mixed chimerism and robust systemic tolerance across full major histocompatibility complex barriers, without myelosuppression and by using moderate doses of bone marrow cells. Thus, immunological tolerance can be achieved by direct modulation of the intrinsic apoptosis pathway in peripheral lymphocytes-a new approach to translate immunological tolerance into clinically applicable protocols.
authors.affiliation: Institute of Physiology, University of Zürich, Zürich, Switzerland;
authors.forename: Pietro E
authors.initials: PE
authors.lastname: Cippà
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Gabriel
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.forename: Philip D
authors.initials: PD
authors.lastname: Bardwell
authors.forename: Andrew
authors.initials: A
authors.lastname: Bushell
authors.forename: Annick
authors.initials: A
authors.lastname: Guimezanes
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kraus
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
authors.forename: Rudolf P
authors.initials: RP
authors.lastname: Wüthrich
authors.forename: Thomas
authors.initials: T
authors.lastname: Fehr
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D006085:Graft Survival / Q000187:drug effects* / Q000502:physiology; D006410:Hematopoiesis / Q000187:drug effects* / Q000502:physiology; D007165:Immunosuppression Therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy / Q000379:methods*; D009596:Nitrophenols / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D018183:Transplantation Chimera / Q000276:immunology / Q000502:physiology; D019172:Transplantation Conditioning / Q000379:methods; D023001:Transplantation Tolerance / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides