The goal oftheresearch plan is touse host regulatory natural killer (NK) I cells toprevent graftversus host disease (GVHD) and retain graft anti-lymphoma activity after MHC-mismatched bone marrowtransplantation in mice. In particular, we will test the hypothesis that regulatory NK T cells, the predominantT 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 Th2polarization is theorized to attenuate GVHD, but not interfere with BCLi tumor cell killing by donor CD8* Tcells that mediate direct cell contact cytolysis via perform cytolytic molecules. We will test the hypothesisbydetermining whether protection against GVHD that is observed in TLI and ATS conditioned wild-type hosts islost in NK T cell deficient CD1d''' and Ja281''' hosts, and can be restored by the injection of purified NK Tcells from wild-type but not IL-4~/~ host strain mice. We will also determine whether donor CD4+ T cells thatsecrete IL-4 are required for protection against GVHD and for the Th2 polarization process. We will testwhether the polarization process markedly reduces the early rapid expansion of donor T cells in the hosttissues 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 blockdonor T cell expansion and Th1 cytokine secretion in vitro in the mixed leukocyte reaction (MLR), whilepermiting 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 Tcell subset among all T cells after irradiation, also fail to be protected against GVHD after conditioning withTLI and ATS.
Showing the most recent 10 out of 307 publications
