Long-lived memory T cells that recognize donor alloantigens may jeopardize the survival of life-saving organ transplants. We propose here that allospecific memory T cells are an important impediment to achieving allograft acceptance because of their unique abilities to persist in the recipient and to respond to donor antigens under much less stringent conditions than those required for naive T cells. To test this hypothesis, we plan to explore the fundamental mechanisms that govern the long-term maintenance and the recall response of allospecific memory T cells in the mouse and to investigate whether targeting one or more of these mechanisms promotes allograft acceptance.
The specific aims are: (1) To investigate the anatomic requirements for the maintenance and recall of allospecific memory T cells. Specifically, we will study the role of secondary lymphoid organs; (2) To investigate the functional requirements for the maintenance and recall of allospecific memory T cells. Specifically, we will study the roles of IL-15 and T cell costimulation; and (3) To investigate whether suppressing allospecific T cell memory by targeting IL-15 or the common cytokine receptor gamma-chain facilitates allograft acceptance and tolerance induction. Mutant, gene-knockout, and T cell receptor transgenic mouse strains will be used to track memory T cells and study their biology. The vascularized heterotopic heart allograft model will be used to investigate the role of T cell memory in organ transplantation. Understanding the fundamental mechanisms that govern the maintenance and recall of alloreactive memory T cells could provide insights into devising clinical strategies for achieving permanent allograft acceptance and transplantation tolerance.
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| Tieu, Roger; Lakkis, Fadi G; Oberbarnscheidt, Martin H (2016) Getting Down and Dirty: Germ-Exposed Laboratory Mice as a Model of the Adult Human Immune System. Transplantation 100:2490-2491 |
| Alegre, Maria-Luisa; Lakkis, Fadi G; Morelli, Adrian E (2016) Antigen Presentation in Transplantation. Trends Immunol 37:831-843 |
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