Interruption of OX40L signaling prevents costimulation blockade–resistant allograft rejection

William H. Kitchens, Ying Dong, David V. Mathews, Cynthia P. Breeden, Elizabeth Strobert, Maria E. Fuentes, Christian P. Larsen, Mandy L. Ford, Andrew B. Adams

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

The potential of costimulation blockade to serve as a novel transplant immunosuppression strategy has been explored for over 20 years, culminating in the recent clinical approval of belatacept for renal transplant patients. Despite improving long-term graft function and survival compared with calcineurin inhibitors, clinical acceptance of belatacept has been hindered by elevated rates of acute rejection. We examined the signaling pathways required to activate costimulation blockade–resistant alloreactive T cells and identified the OX40/OX40L secondary costimulatory pathway as a promising target. We next sought to improve the clinical efficacy of traditional costimulation blockade using belatacept by coupling it with anti-OX40L. Using a murine transplant model, we demonstrate that combined blockade enhances the suppression of alloreactive T cell proliferation and effector functions including both cytokine release and cytotoxic degranulation. We also show that anti-OX40L may be particularly useful in targeting alloreactive memory T cell responses that are relatively unaffected by traditional costimulation blockade regimens. Finally, we translated this therapy to a clinically relevant nonhuman primate renal transplant model, validating the efficacy of this regimen in a potentially novel steroid- and calcineurin inhibitor–free immunosuppression regimen.

Original languageEnglish (US)
Article numbere90317
JournalJCI Insight
Volume2
Issue number5
DOIs
StatePublished - Mar 9 2017
Externally publishedYes

Bibliographical note

Funding Information:
WK was supported by the fellowship in transplantation from the American Society of Transplant Surgeons. The primate experiments were also supported by the National Institute for Allergy and Infectious Diseases Nonhuman Primate Transplantation Tolerance Cooperative Study Group grant AI051731 from the NIH. Primate experiments were also supported by the Yerkes National Primate Research Center base grant RR00165.

Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.

Fingerprint

Dive into the research topics of 'Interruption of OX40L signaling prevents costimulation blockade–resistant allograft rejection'. Together they form a unique fingerprint.

Cite this