Kidney transplantation's considerable benefit is offset by the infectious and metabolic morbidity related to its required immunosuppressive drugs. Recently, belatacept, a CD28-B7 costimulation pathway inhibitor, has been approved for use with substantial evidence suggesting that it can prevent kidney rejection with less morbidity, and perhaps serve as a centerpiece agent for tolerance regimens. However, although belatacept appears to control naive immune responses well and evoke few off-target side effects, its control of memory T cell (TM) responses is less robust than hoped and its use is associated with significant morbidity related to the Epstein-Barr Virus (EBV). This Project will leverage substantial investigator experience and extensive preliminary data to develop logical adjuvant therapies that can be paired with belatacept. In particular, it will study altered integrin adhesion molecule expression as a means of identifying TMS with potential to cause belatacept-resistant rejection, and test four novel biologic agents for their ability to improve belatacept's antirejection effect in a rhesus monkey model of kidney transplantation without evoking the side effects related to existing standard immunosuppressive drugs. The ultimate goal is to develop one or more translatable regimens that can mediate lasting, well-tolerated, antigen-specific immune modulation to prevent allograft rejection. There are 3 Specific Aims. 1) To determine the effects of leukocyte function antigen (LFA)-Idirected therapy as an adjuvant to belatacept-based maintenance immunosuppression. We will test two novel LFA-1-specific monoclonal antibodies (Mabs) with identical specificity but distinct isotype, loGI or lgG4, for their efficacy in preventing belatacept-resistant rejection, and assess their effect on protective immunity, particularly toward the EBV-homologue, lymphocryptovirus (LCV). 2) To determine the role of an activation-induced LFA-1 conformational modification in mediating rejection and test the novel conformation specific, anti-LFA-1 Mab, AL-57. as an adjuvant to belatacept. We will define the AL-57 epitope in rhesus alio- and viral-specific immunity and test AL-57 for its ability to prevent or reverse rejection. 3) To define the effects of very late antigen (VLA)-4-specific therapy as an adjuvant to belatacept. We will test the VLA-4- specific Mab natalizumab for its efficacy in preventing or reversing belatacept-resistant rejection, and assess its effect on protective immunity. From these studies we will examine new approaches toward immunosuppression, using translatable agents in a clinically relevant pre-clinical model while concurrently providing new insights into the role of integrins in viral- and allo-immunity.
Organ transplantation is the preferred therapy for most forms of end-stage kidney, heart and liver failure, but its practice remains imperfect. This project will develop improved methods for delivering transplant related therapy, and in doing so, provide new opportunities to provide transplant-based therapies for patients with end organ failure. The project will investigate agents that cold be readily translated into clinical therapies and thus provide needed pre-clinical data in support of required clinical trials.
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|Burghuber, C K; Kwun, J; Page, E J et al. (2016) Antibody-Mediated Rejection in Sensitized Nonhuman Primates: Modeling Human Biology. Am J Transplant 16:1726-38|
|Zheng, H B; Watkins, B; Tkachev, V et al. (2016) The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques. Am J Transplant :|
|Kwun, Jean; Manook, Miriam; Page, Eugenia et al. (2016) Cross-talk between T and B Cells in the Germinal Center following Transplantation. Transplantation :|
|Hippen, Keli L; Watkins, Benjamin; Tkachev, Victor et al. (2016) Preclinical testing of anti-human CD28 Fab' antibody in a novel nonhuman primate (NHP) small animal rodent model of xenogenic graft-versus-host disease (GVHD). Transplantation :|
|Furlan, Scott N; Watkins, Benjamin; Tkachev, Victor et al. (2016) Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells. Blood 128:2568-2579|
|Anderson, D J; Lo, D J; Leopardi, F et al. (2016) Anti-Leukocyte Function-Associated Antigen 1 Therapy in a Nonhuman Primate Renal Transplant Model of Costimulation Blockade-Resistant Rejection. Am J Transplant 16:1456-64|
|Furlan, Scott N; Watkins, Benjamin; Tkachev, Victor et al. (2015) Transcriptome analysis of GVHD reveals aurora kinase A as a targetable pathway for disease prevention. Sci Transl Med 7:315ra191|
|Lo, D J; Anderson, D J; Song, M et al. (2015) A pilot trial targeting the ICOS-ICOS-L pathway in nonhuman primate kidney transplantation. Am J Transplant 15:984-92|
|Lei, J; Kim, J I; Shi, S et al. (2015) Pilot Study Evaluating Regulatory T Cell-Promoting Immunosuppression and Nonimmunogenic Donor Antigen Delivery in a Nonhuman Primate Islet Allotransplantation Model. Am J Transplant :|
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