Career Development Plan: The immediate research objective is to pursue the aims proposed in the currently funded and pending grants. The applicant and colleagues have demonstrated that cytotoxic T lymphocytes (CTL) can be activated through certain adhesion molecules, such as CD44 and gp90MEL-14, to mediate lysis of target cells in the absence of TCR occupancy. Based on this, it was hypothesized that under certain conditions, activated CTL may mediate lysis of endothelial cells which bear ligands for CD44 and gp90MEL-14. Such a mechanism might explain the nonspecific tissue damage seen at sites of inflammation during infections, autoimmunity, transplantation and immunotherapy of cancer. Thus, the aims of the research include studies on the mechanism of activation of CTL via CD44 leading to the cytotoxicity of endothelial cells in vitro and in vivo with particular reference to CD44-hyaluronate interactions. In addition, whether the vascular leak syndrome (VLS) seen in vivo is triggered by lysis of endothelial cells by activated CTL will be investigated with primary focus on Fas and Fas ligand (FasL) interactions and delineating the role of perforin using mice deficient in these molecules. In addition, the applicant has recently demonstrated that in vitro T cell transformation can result from dysregulation in the production of autocrine IL-2. The extra time released by award of this K02 grant will be used to initiate new studies on the role of autocrine growth factors in T cell transformation and to pursue collaborative research in immunotoxicology.
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