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Bcl-2 inhibition to overcome memory cell barriers in transplantation


Cippà, P E; Gabriel, S S; Kraus, A K; Chen, J; Wekerle, T; Guimezanes, A; Wüthrich, R P; Fehr, T (2014). Bcl-2 inhibition to overcome memory cell barriers in transplantation. American Journal of Transplantation, 14(2):333-342.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nephrology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:February 2014
Deposited On:04 Feb 2015 11:51
Last Modified:18 Aug 2018 19:06
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1600-6135
OA Status:Closed
Publisher DOI:https://doi.org/10.1111/ajt.12554
PubMed ID:24472193
Project Information:
  • : FunderSNSF
  • : Grant ID323530-133893
  • : Project TitlePharmacologic apoptosis modulation in lymphocytes: a novel approach to prevent allograft rejection andinduce tolerance

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