title: Interruption of OX40L signaling prevents costimulation blockade-resistant allograft rejection.
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.affiliation: Emory Transplant Center.|Yerkes National Primate Research Center, Atlanta, Georgia, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Kitchens
authors.affiliation: Emory Transplant Center.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Emory Transplant Center.
authors.forename: David V
authors.initials: DV
authors.lastname: Mathews
authors.affiliation: Emory Transplant Center.
authors.forename: Cynthia P
authors.initials: CP
authors.lastname: Breeden
authors.affiliation: Yerkes National Primate Research Center, Atlanta, Georgia, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Strobert
authors.affiliation: Hoffmann-La Roche Pharmaceuticals, Nutley, New Jersey, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Fuentes
authors.affiliation: Emory Transplant Center.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
authors.affiliation: Emory Transplant Center.
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
authors.affiliation: Emory Transplant Center.|Yerkes National Primate Research Center, Atlanta, Georgia, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Adams
mesh_terms: D064591:Allografts / Q000276:immunology*; D000818:Animals; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival; D006801:Humans; D007156:Immunologic Memory; D016030:Kidney Transplantation; D007959:Lymphocyte Culture Test, Mixed; D008253:Macaca mulatta; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D053278:OX40 Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D053278:OX40 Ligand; C089251:TNFSF4 protein, human