Transplantation represents the standard-of-care for the treatment of many diseases characterized by endstageorgan failure. After transplantation, patients must rigidly adhere to lifelong, multi-agent treatmentregimens that dramatically increase the risks of cardiovascular disease, infections and malignancies.Immune tolerance, the phenomenon by which the allograft is accepted without immunosuppression whilepreserving the recipient's protective immunity, represents a solution to the problems of acute and chronicrejection and the resulting long-term reliance on toxic immunosuppressive therapies. The development oftolerogenic strategies could not only reduce the risk of these life-threatening complications, but also greatlyexpand the application of organ, tissue and cellular transplantation for diseases such as thehemoglobinopathies and genetic immunodeficiencies, Type I diabetes, and possibly other autoimmunediseases. In rodent models, successful solid-organ transplantation tolerance has been created throughstrategies coupling hematopoietic chimerism-induction with T cell costimulation blockade. However, giventhe significant differences between the rodent and human immune systems, these strategies requirerigorous testing in a translational model prior to their clinical application. Rhesus macaque non-humanprimate models have a number of important attributes that allow them to serve as critical preclinical modelsin order to bridge the basic insights gained in mice to their application to patient care. In this project, we willtake advantage of our ability to induce chimerism using mobilized peripheral blood stem cells from livingRhesus macaque donors to perform a systematic analysis of the impact that a costimulation blockade andchimerism-based tolerance induction strategy has on transplant pairs having varying degrees of MHCdisparity. These studies will focus on the efficacy of the addition of adoptive immunotherapies to ourstandard chimerism-induction regimen in increasing chimerism stability and immune competence aftertransplant. The unifying purpose of our proposal is to develop clinically applicable protocols for the inductionof tolerance to solid organ allografts while preserving immune competence in the transplant recipient.Specifically, in this proposal, we will determine 1) whether adoptive immunotherapy using regulatory T cellsimproves the stability of mixed chimerism and the induction of transplantation tolerance; and 2) whetheradoptive immunotherapy using donor lymphocyte infusions improves immune competence after theinduction of mixed hematopoietic chimerism across MHC barriers.
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