EMORY UNIVERSITY

Transplantation is the preferred method of treatment for many forms of end-stage organ failure. Current therapy in clinical transplantation relies on potent non-specific immunosuppressive drugs to inhibit rejection. While short-term results have improved, long-term outcomes remain inadequate. Furthermore, patients must adhere to life-long immunosuppressive drug treatment regimens that dramatically increase the risks of cardiovascular disease, infection and malignancy. Strategies to promote the acceptance of allogeneic tissues without the need for immunosuppression could reduce the risk of these complications and expand the application of transplantation. Many experimental therapies facilitate allograft survival without chronic immunosuppression. However, essentially all have been far more successful in immunologically naïve experimental animals than in more immunologically experienced animals or humans. The unifying hypothesis and theme of this Program is that donor-allospecific memory T cells generated during protective immune responses against environmental pathogens constitute an important barrier to tolerance induction in adults, and that a more thorough understanding of the relationship between human acquisition and maintenance of T cell memory and alloreactivity will foster the translation of burgeoning therapeutic anti-rejection approaches into clinically relevant therapies. Accordingly, this program will define memory T cell characteristics that engender their role in allograft rejection and establish the means by, and extent to, which environmental antigen exposure leads to more vigorous alloimmunity. The Program is comprised of two interrelated projects. Project I explores the functional roles and costimulatory requirements of CD4+ memory T cells, specifically defining those phenotypic characteristics that portend therapeutically relevant immune memory. Project II establishes the relationship between latent viral infection and the generation of allospecific memory with specific attention given toward gamma herpesvirus infection, a highly prevalent and clinically relevant viral class. The knowledge gained through these studies will facilitate development of new therapies to control transplant rejection without impairing protective immunity.

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