Transplantation has emerged as the preferred method of treatment for many forms of end-stage organ failure. While short-term results have improved, long-term outcomes remain inadequate. To maintain their allografts, patients must rigidly adhere to life-long treatment regimens using costly immunosuppressive agents that dramatically increase the risks of cardiovascular disease, infections and malignancies. The development of strategies to promote the acceptance of allogeneic tissues without the need for chromic immunosuppression could not only reduce the risk of these life-threatening complications, but also greatly expand the application of organ, tissue and cellular transplantation for diseases such as the hemoglobinopathies and genetic immunodeficiencies, Type I diabetes, and possibly other autoimmune diseases. We have developed novel non-myeloablative protocols using CD28 and CD40/CD154 T cell costimulation blockade-based therapeutics to permit the induction of high levels of hematopoietic chimerism in Rhesus macaques. However, in the setting of full MHC disparity, this chimerism was transient, did not confer immune tolerance to solid organ transplants, and resulted in significant immunodeficiency in transplant recipients. However, our preliminary data suggests that in the setting of increased MHC matching between transplant donors and recipients, costimulation blockade-based induction of durable chimerism and resultant tolerance to solid organ transplants is achievable, with preservation of protective immunity. The goal of this project is to build on our preliminary findings and develop and optimize strategies to induce stable macrochimerism and transplantation tolerance to renal allografts in non-human primates. Specifically, in this proposal we will determine 1) the effect of increasing MHC matching on chimerism durability and tolerance to solid organ transplants in the context of costimulation blockade-based immunosuppression, 2) the necessary components to our costimulation blockade based immunomodulation strategy in inducing durable chimerism and tolerance, and 3) the effect that depletion of recipient natural killer cells, or delivery of adoptive immunotherapy with either regulatory or conventional T cells will have on chimerism, survival of renal allografts, the anti-donor immune response and on post-transplant protective immunity. The unifying purpose of our proposal is to develop clinically applicable protocols for the induction of tolerance to solid organ allografts while preserving immune competence in the transplant recipient.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-PA-I (M1))
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Kraemer, Kristy A
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Emory University
Schools of Medicine
United States
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Mathews, David V; Dong, Ying; Higginbotham, Laura B et al. (2018) CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection. J Clin Invest 128:4557-4572
Kean, Leslie S (2018) Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis. Blood 131:2630-2639
Colonna, Lucrezia; Peterson, Christopher W; Schell, John B et al. (2018) Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation. Nat Commun 9:4438
Song, M; Mulvihill, M S; Williams, K D et al. (2018) Fatal SV40-associated pneumonia and nephropathy following renal allotransplantation in rhesus macaque. J Med Primatol 47:81-84
Taraseviciute, Agne; Tkachev, Victor; Ponce, Rafael et al. (2018) Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates. Cancer Discov 8:750-763
Ezekian, Brian; Schroder, Paul M; Freischlag, Kyle et al. (2018) Contemporary Strategies and Barriers to Transplantation Tolerance. Transplantation 102:1213-1222
Kean, Leslie S; Turka, Laurence A; Blazar, Bruce R (2017) Advances in targeting co-inhibitory and co-stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy. Immunol Rev 276:192-212
Kwun, Jean; Manook, Miriam; Page, Eugenia et al. (2017) Crosstalk Between T and B Cells in the Germinal Center After Transplantation. Transplantation 101:704-712
Mathews, D V; Wakwe, W C; Kim, S C et al. (2017) Belatacept-Resistant Rejection Is Associated With CD28+ Memory CD8 T Cells. Am J Transplant 17:2285-2299
Manook, M; Kwun, J; Burghuber, C et al. (2017) Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation. Am J Transplant 17:2055-2064

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