Bcl-2 inhibition to overcome memory cell barriers in transplantation.
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.
Institute of Physiology, University of Zürich, Zürich, Switzerland; Division of Nephrology, University Hospital Zürich, Zürich, Switzerland.
P E
PE
Cippà
S S
SS
Gabriel
A K
AK
Kraus
J
J
Chen
T
T
Wekerle
A
A
Guimezanes
R P
RP
Wüthrich
T
T
Fehr
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001713:Biphenyl Compounds / Q000494:pharmacology; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D005434:Flow Cytometry; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016038:Skin Transplantation; D013449:Sulfonamides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D013449:Sulfonamides; D051020:bcl-X Protein
ABT-737; Bcl-2; apoptosis; memory T cells; tolerance; transplantation