The goal oftheresearch plan is touse host regulatory natural killer (NK) I cells toprevent graft versus host disease (GVHD) and retain graft anti-lymphoma activity after MHC-mismatched bone marrow transplantation in mice. In particular, we will test the hypothesis that regulatory NK T cells, the predominant T cell subset after conditioning hosts with total lymphoid irradiation (TLI) and anti-thymoctye serum (ATS), prevents GVHD by secreting IL-4, and polarizing donor T cells to a Th2 cytokine profile. The Th2 polarization is theorized to attenuate GVHD, but not interfere with BCLi tumor cell killing by donor CD8* T cells that mediate direct cell contact cytolysis via perform cytolytic molecules. We will test the hypothesisby determining whether protection against GVHD that is observed in TLI and ATS conditioned wild-type hosts is lost in NK T cell deficient CD1d''"""""""" and Ja281''"""""""" hosts, and can be restored by the injection of purified NK T cells from wild-type but not IL-4~/~ host strain mice. We will also determine whether donor CD4+ T cells that secrete IL-4 are required for protection against GVHD and for the Th2 polarization process. We will test whether the polarization process markedly reduces the early rapid expansion of donor T cells in the host tissues as measured by flow cytometry and bioluminescence imaging, and the early secretion of pro- inflammatory Th1 cytokines that injure host tissues. NK T cells will be studied for their capacity to block donor T cell expansion and Th1 cytokine secretion in vitro in the mixed leukocyte reaction (MLR), while permiting the differentiation of CDS* cytolytic T cell precursors into effector killer cells that can kill tumor cells. Finally, we will determine whether p53""""""""7""""""""and Bcl-2 transgenic hosts that fail to show an increase in the NK T cell subset among all T cells after irradiation, also fail to be protected against GVHD after conditioning with TLI and ATS.
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