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Interruption of OX40L signaling prevents costimulation blockade–resistant allograft rejection
William H. Kitchens, … , Mandy L. Ford, Andrew B. Adams
William H. Kitchens, … , Mandy L. Ford, Andrew B. Adams
Published March 9, 2017
Citation Information: JCI Insight. 2017;2(5):e90317. https://doi.org/10.1172/jci.insight.90317.
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Research Article Immunology Transplantation

Interruption of OX40L signaling prevents costimulation blockade–resistant allograft rejection

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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.

Authors

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

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Figure 1

Combined costimulation blockade (CoB) and OX40L blockade inhibits naive alloreactive T cell expansion in vivo and prolongs skin graft survival.

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Combined costimulation blockade (CoB) and OX40L blockade inhibits naive ...
(A) In vivo mixed lymphocyte reaction was performed by adoptively transferring CFSE-labeled C57BL/6 splenocytes into sublethally irradiated BALB/c mice treated with CoB plus a secondary costimulatory receptor antagonist. Splenocytes were harvested after 72 hours and were assessed for CFSE-labeled cell division. Treatment with either CoB + anti-ICOSL or CoB + anti-OX40L suppressed alloproliferation (n = 5 per group, representative of 2 independent experiments). (B) Only CoB + anti-OX40L prolongs survival of BALB/c to C57BL/6 skin grafts (n = 7 per group, P < 0.01 by log-rank test). MST, median survival time. TRANCE, TNF-related activation-induced cytokine.

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