The approval of belatacept, a 2rd generation CD28 pathway costimulation blocker, represents a new class of immunosuppressive agents. The design, translation and clinical evaluation of belatacept was the culmination of efforts by industry and academia to rationally engineer a new therapeutic. The result is an agent that better preserves renal function, reduces donor-specific antibody formation and mitigates cardiovascular side effects. Despite these significant advances, important challenges remain as belatacept treatment is associated with higher rates and grades of rejection. In addition, current immunosuppressive strategies, including belatacept-based regimens, lack the ability to specifically target donor-reactive responses resulting in a generalized state of immune compromise and infectious susceptibility. Our early studies in mice and non-human primates (NHP) identified costimulation blockade resistant rejection (CoBRR) as an important area for investigation and emphasized the potential benefits of developing a successful tolerance strategy. The recent clinical results with belatacept highlight the pressing need to understand the cellular and molecular pathways that contribute to CoBRR and to develop targeted strategies to overcome them, including clinically applicable tolerance regimens. In the first aim of our project we will evaluate novel 3rd generation costimulation blockade therapeutics in collaboration with our partners in industry including domain antibodies designed to safely and specifically block both the CD28 and CD40 pathways. We anticipate that there will still be a CoBRR response and have new data from preliminary murine and NHP studies suggesting a critical role for the IL-17 pathway. We have also identified a successful strategy utilizing an antibody targeting both IL-12 and IL-23 to control this break-through rejection response.
In aim 2 we will further test this novel IL-12/23 therapy in combination with optimized 3rd generation costimulation blockade. We will synthesize observations from the first two aims to define a successful therapeutic regimen that we will then couple to our novel pulsed donor antigen tolerance strategy. Results from these studies will help develop a clinically translatable tolerance strategy, which avoids the morbidity and mortality of chronic continuous immunosuppression. The new knowledge obtained in these studies will be significant and wilt contribute to improved outcomes, enhanced quality of life, and reduced morbidity by avoiding rejection, simplifying regimens, and avoiding infection as a result of long-term immunosuppression.

Public Health Relevance

Transplantation offers the promise of life saving and health restoring therapy for hundreds of thousands of patients suffering from end-stage organ failure. Outstanding short-term outcomes have been achieved through the development of multi-drug life-long continuous immunosuppressive regimens. Despite these achievements, significant challenges remain that compromise the long-term outcomes and limit the application of transplantation. This grant proposes translational studies to address those challenges.

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-MFH-I)
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Emory University
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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
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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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