The limiting factor to allogeneic stem cell transplantation is the occurrence of GVHD, which is due to the recognition by alloreactive T lymphocytes of major and minor antigens presented by major histocompatibility complex proteins. GVHD occurs in a subset of organs and involves early migration of alloreactive T cells into these organs followed by T cell expansion and later tissue destruction. The proteins and mechanisms involved in the migration of alloreactive T cells into GVHD target organs is poorly understood. A greater understanding of this might allow for new forms of therapy for the treatment or prevention of GVHD. Our group has focused on the roles of chemokines, chemokine receptors and integrins in the migration of alloreactive T cells into the GI tract, liver, lung and skin. Our group was the first to show that a chemokine, CCL3, plays a role in the trafficking of CD8+ T cells into the liver and lung. We were also the first group to show that CCL3 blockade enhanced the expansion of CD4+ T cells in the liver and that the chemokine receptor CCR5 played a significant role in controlling the expansion and migration of both CD8+and CD4+ T cells into the liver and lung. In this proposal, we will investigate the mechanisms involved in the trafficking and expansion of T cells in the liver and lung. We will use genetic and immunological methods to investigate the following specific aims: 1. The mechanism involved in the increased number of alloreactive CD4+ and CD8+ T cells in the liver and lung after the transfer of T cells that do not express CCR5. 2. We will evaluate the hypothesis that trafficking of T cells into GVHD target organs uses different chemokine receptors for entrance into the specific organs. Specifically, we will investigate the functions of CCR1, CCR9 and CCR10 in the trafficking of T cells into the liver, GI tract and skin respectively. 3. We will investigate the function of CCR5 on recipient APCs in the induction of GVHD 4. We will evaluate if small peptides that could be used clinically are effective in blocking the occurrence of GVHD as a prelude to their use in phase I clinical trials.
