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Author Notes:

*Corresponding Author Contact Information: Leslie S. Kean, 101 Woodruff Circle, NE, Room 5203, Emory University School of Medicine, Atlanta, GA 30322 Department Fax: 404-727-3660 Phone: 404-727-5265 Leslie.Kean@emory.edu

Subject:

Research Funding:

This work was supported by Yerkes National Primate Research Center Base Grant, #RR00165.

CPL was supported by NIH grant #s 2U19 AI051731, and 2P01 AI044644.

LSK was supported by grant #s 5K08 AI065822, 2U19 AI051731, 1R01 HL095791 and 2U24 RR018109, and by a Burroughs Wellcome Fund Career Award in the Biomedical Sciences.

Reagents used were produced by the Nonhuman Primate Reagent Resource supported by NIAID contract #HHSN272200900037C.

ADK was supported by JDRF 1-2008-594, 1U01AI079223-01A1, 5 U19 AI051731

Keywords:

  • Costimulation Blockade
  • Non-human Primate
  • Mixed Chimerism
  • Biomarkers

CD40 Blockade Combines with CTLA4Ig and Sirolimus To Produce Mixed Chimerism in an MHC-defined Rhesus Macaque Transplant Model

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Journal Title:

American Journal of Transplantation

Volume:

Volume 12, Number 1

Publisher:

, Pages 115-125

Type of Work:

Article | Post-print: After Peer Review

Abstract:

In murine models, T-cell costimulation blockade of the CD28:B7 and CD154:CD40 pathways synergistically promotes immune tolerance after transplantation. While CD28 blockade has been successfully translated to the clinic, translation of blockade of the CD154:CD40 pathway has been less successful, in large part due to thromboembolic complications associated with anti-CD154 antibodies. Translation of CD40 blockade has also been slow, in part due to the fact that synergy between CD40 blockade and CD28 blockade had not yet been demonstrated in either primate models or humans. Here we show that a novel, non-depleting CD40 monoclonal antibody, 3A8, can combine with combined CTLA4Ig and sirolimus in a well-established primate bone marrow chimerism-induction model. Prolonged engraftment required the presence of all three agents during maintenance therapy, and resulted in graft acceptance for the duration of immunosuppressive treatment, with rejection resulting upon immunosuppression withdrawal. Flow cytometric analysis revealed that upregulation of CD95 expression on both CD4+ and CD8+ T-cells correlated with rejection, suggesting that CD95 may be a robust biomarker of graft loss. These results are the first to demonstrate prolonged chimerism in primates treated with CD28/mTOR blockade and non-depletional CD40 blockade, and support further investigation of combined costimulation blockade targeting the CD28 and CD40 pathways.

Copyright information:

©Copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons

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