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. Premature graft loss and death remain as stubborn adversaries as evidenced by the inexorable and stagnant graft and patient annual attrition rates that plague our patients. Current thinking holds that CNI-toxicity and donor-specific antibodies are predominant drivers of kidney graft failure, whereas the principle causes of premature death are cardiovascular (CV) disease, infection, and malignancy. Until recently, virtually all transplant regimens relied on calcineurin-inhibitors as their cornerstone immunosuppressive agent. The approval of belatacept, a second generation CD28 pathway inhibitor, provides an alternative which addresses some of the limitations inherent in CNI-based immunosuppression and provides a long-awaited tool in the quest for transplantation tolerance. Belatacept avoids CNI-induced nephrotoxicity, is associated with very low de novo DSA rates, and improves the CV risk profile. Unfortunately, barriers to wide-scale application and improving long-term results persist. As foreshadowed by our early studies in mice and NHP identifying costimulation blockade-resistant rejection, the rates and grades of acute cellular rejection are higher with belatacept than CNI. In addition, infection and immune compromise-related mortality will almost certainly continue because like its predecessors, belatacept-based immunosuppression in its current form is continuous and life-long. Furthermore, humoral rejection is emerging as a major cause of late-graft failure, and adequate non-human primate models to address the problem of B cell alloimmunity are urgently needed. The central goal of our research program and this application is to develop clinically applicable approaches to address near-term needs and ultimately to develop broadly applicable tolerance strategies for use in clinical transplantation. This goal will be accomplished via four interrelated projects and two supporting cores.

Public Health Relevance

Transplantation is a cure for many end stage organ diseases, but the immunosuppression required to prevent graft rejection carries with it several side effects that can impact patient health. This program seeks to use pre-clinical models to test new therapeutics for use in transplantation, with the goals of minimizing graft rejection, preserving protective immunity, and maximizing patient health.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI051731-13
Application #
8705982
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Kraemer, Kristy A
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Surgery
Type
Schools of Medicine
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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