Patients who have been immunologically sensitized by a previous transplant, pregnancy, or blood transfusion may not receive a renal transplant due to our current difficulty preventing rejection in such patients. In addition, patients successfully transplanted have an approximately 20% risk of developing B cell sensitization to their functioning kidney allograft and of alloantibody shortening the life of their kidney. Costimulation blockade, in particular agents targeting CD28 and CD40, may offer significant advantages over conventional immunosuppressive agents in preventing and overcoming an alloantibody response. CD28 has recently been shown to be expressed on long-lived plasma cells in bone marrow and necessary for their survival and continued antibody production. Our rodent model data suggest that costimulation blockade may be able to down regulate the B cell response in a donor-specific manner. In order to move toward clinical application in humans, we propose to test costimulation blockade in combination with other putative agents including Belimumab (anti-BAFF), anti-APRIL and Bortezomib (proteasome inhibitor) that target the sensitized immune repertoire of NHP's. We plan to test the ability of such agents alone and in combination with donor bone marrow infusion in order to achieve donor-specific desensitization in a clinically relevant rhesus monkey renal allograft model. Briefly, the model uses monkeys sensitized by a previously rejected renal allograft, and ultimately we aim to achieve immunologic unresponsiveness to a second kidney transplanted from the same donor. We will use state of the art methods developed by us to measure not only T and B cell sensitization and desensitization, but also will measure the affect of treatment on the protective immune response that must remain intact for avoidance of infection. We will build upon lessons learned from our previous UOI grant that focused on the T and B cell response in monkeys developing de novo antibody after renal transplantation. We have already learned that CD28 blockade with Belatacept effectively prevents alloantibody from developing in a rigorous NHP model. We now propose to use a difficult but yet more clinically relevant NHP model to evaluate strategies to desensitize the host.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI051731-13
Application #
8705986
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Type
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Hippen, Keli L; Watkins, Benjamin; Tkachev, Victor et al. (2016) Preclinical Testing of Antihuman CD28 Fab' Antibody in a Novel Nonhuman Primate Small Animal Rodent Model of Xenogenic Graft-Versus-Host Disease. Transplantation 100:2630-2639
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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