Rapamycin and CTLA4Ig synergize to induce stable mixed chimerism without the need for CD40 blockade

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
N PilatT Wekerle

Abstract

The mixed chimerism approach achieves donor-specific tolerance in organ transplantation, but clinical use is inhibited by the toxicities of current bone marrow (BM) transplantation (BMT) protocols. Blocking the CD40:CD154 pathway with anti-CD154 monoclonal antibodies (mAbs) is exceptionally potent in inducing mixed chimerism, but these mAbs are clinically not available. Defining the roles of donor and recipient CD40 in a murine allogeneic BMT model, we show that CD4 or CD8 activation through an intact direct or CD4 T cell activation through the indirect pathway is sufficient to trigger BM rejection despite CTLA4Ig treatment. In the absence of CD4 T cells, CD8 T cell activation via the direct pathway, in contrast, leads to a state of split tolerance. Interruption of the CD40 signals in both the direct and indirect pathway of allorecognition or lack of recipient CD154 is required for the induction of chimerism and tolerance. We developed a novel BMT protocol that induces mixed chimerism and donor-specific tolerance to fully mismatched cardiac allografts relying on CD28 costimulation blockade and mTOR inhibition without targeting the CD40 pathway. Notably, MHC-mismatched/minor antigen-matched skin grafts survive indefinitely where...Continue Reading

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Citations

Dec 5, 2015·Frontiers in Immunology·Paulina RuizMaria Rosa Bono
Jul 23, 2015·European Journal of Immunology·Karin HockThomas Wekerle
Apr 11, 2017·Clinical and Experimental Immunology·B Mahr, T Wekerle
Jun 7, 2018·Expert Review of Clinical Immunology·Christoph SchwarzThomas Wekerle
Aug 17, 2018·Transplantation·Christoph Schwarz, Thomas Wekerle
Dec 1, 2017·Current Opinion in Organ Transplantation·Joanna W EtraGerald Brandacher
Nov 28, 2019·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Riccardo SchweizerJan A Plock
Nov 19, 2017·Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society·Hwajung KimKyung-Suk Suh
Jul 31, 2018·Journal of Immunology Research·Nina PilatThomas Wekerle
Nov 5, 2015·Current Opinion in Organ Transplantation·Riccardo SchweizerJan A Plock
Nov 3, 2016·Current Opinion in Organ Transplantation·Min HuShounan Yi

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