The long-term goal of this project is to develop an effective strategy for inducing immunological tolerance to allogeneic hematopoietic stem cells in humans. Rejection of hematopoietic cell grafts is mediated by host T cells specific for donor alloantigens and, presumably, also by natural killer (NK) cells in the case of transplants incompatible for HLA-A, B or C alleles. Immunity or tolerance depends on the presence or absence of costimulation delivered by antigen presenting cells (APC) to T cells during antigen presentation. In mice, lymphoid dendritic cells (DC) process and present self-antigens and are presumed responsible for the induction and maintenance of self-tolerance. In humans, lymphoid DC in peripheral blood and lymphoid tissues are HLA-DR+/lin-/CDllc-/CD4+/IL3Ralpha+ cells with plasmacytoid morphology. These cells lack myeloid markers, have high levels of pre- T cell receptor alpha chain expression, and depend on IL3 for their survival and differentiation. They have been designated DC2 because, after appropriate activation, they can induce T cell differentiation into T helper 2 (Th2) cells. Immature DC2, isolated from the blood of normal donors, express low to undetectable levels of costimulation molecules CD40, CD80 and CD86, and are unable to activate proliferation of naive allogenic T cells. Since human DC2 migrate to the lymph nodes during fetal life before exposure to exogenous proteins, it has been proposed that they might be responsible for the induction and maintenance of peripheral tolerance to self-antigens, alike murine lymphoid DC. We will test the hypothesis that presentation of alloantigen by resting human DC2 induces clonal anergy or deletion in both CD4 and CD8 T cells and, perhaps, NK cells.
Specific aims are: I) Determine whether presentation of alloantigen by human lymphoid DC induces unresponsiveness in alloantigen-specific CD4 T cells. 2) Determine whether presentation of alloantigen by human lymphoid DC induces unresponsiveness in alloantigen-specific CD8 T cells. 3) Determine whether presentation of alloantigen by human lymphoid DC induces unresponsiveness in HLA class I incompatible NK cells. Results of these experiments will establish a platform and rationale for testing the adoptive transfer of allogeneic lymphoid DC for the induction of tolerance to hematopoietic stem cells in animal models, and design adoptive therapy trials for induction of tolerance in human transplantation.
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