The goals of the proposed research are to identify two types of regulatory T cells, NK T cells and CD4+CD25+ T cells, in the peripheral blood (PB) and/or other lymphoid tissues in mice and humans, and to determine the ability of the Treg cells to alter the alloreactivity of conventional, non-regulatory T cells (Tnon-reg cells) in the context of allogeneic bone marrow (BM) or """"""""mobilized"""""""" PB hematopoietic progenitor transplantation. In the proposed mouse studies, we will determine whether defined mixtures of C57BL/6 Treg and Tnon-reg cells allow for full chimerism and tumor cell eradication without graft versus host disease (GVHD) after injection into lethally irradiated BALB/c hosts. We will test the hypothesis that tumor eradication mediated by donor CD8+Tnon-reg cells via perforin and FasL pathways are not inhibited by Treg cells. We will also test the hypothesis that Treg cells inhibit GVHD by suppressing the expansion of donor Tnon-reg cells, and by suppressing changes in cell trafficking molecules on Tnon-reg cells that ordinarily allow them to migrate from the lymphoid tissues to sites of GVHD target tissue injury such as the gut and liver. Key trafficking molecules to be studied include CD62L, beta7integrin, CCR7, and CXCR3. We will determine whether deficiencies in these molecules prevent GVHD. Expression of these molecules will be measured by flow cytometry and real-time PCR analyses. Finally we will identify the levels of Treg cells in normal human PB mononuclear cells (PBMC), and assay their capacity to inhibit alloreactivity of Tnon-reg cells in vitro in the mixed leukocyte reaction (MLR) and cell mediated lympholysis (CML) assays.
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