As noted in the goals and objectives stated for this project, it aims to create new models that test distinct hypotheses and provide new understandings for development of novel strategies in the treatment of lymphoma, myeloma, leukemia, breast cancer and renal cancer by hematopoietic stem cell transplantation. Hematopoietic stem cell transplant treatment of these diseases generally results in lymphopenia and immune compromise. This immune compromise is in turn associated with death from infection even late after transplant. The observation that in humans there is the ability to upregulate thymus function in the setting of cancer therapy-associated lymphopenia has been translated to murine models. We have initiated four parallel animal model efforts to identify points of control in thymus function. In experiments utilizing KGF, which was found to upregulate thymus activity, we observed that while thymocyte precursor pool size and molecules involved in migration are not affected, the critical control point at the level of thymus epithelial cells are affected such that this cell population increases proliferation and total number thereby increasing niches for thymocyte maturation and overall thymopoiesis. To identify physiologic regulators of thymus function, we have developed a new transgenic mouse model in which T cells can be quickly and effectively eliminated, thereby developing profound lymphopenia, without tissue injury. We also have a mouse model in which the gene Tbata, which we have characterized, is deleted. We have also developed a murine model of T cell homeostasis and chronic graft versus host disease in which we can study the proliferation and death of subsets of T cells during disease development. This model has been actively pursued and data generated showing the differential expansion and contraction of T cell subsets as cGVHD develops. The differential results reflect target organs versus non-target organs and provide understanding of the lack of regulation by regulatory T cell on the developing disease. We have also developed new models to investigate metabolic basis of acute and chronic GVHD and the role of T cell immune senescence on immune incompetence in the post transplant period. Relevant cancer sites: Non-Hodgkins Lymphoma, Leukemia. Relevant Research Areas: Immunology, Bone Marrow Transplantation, Hematology/Lymph, Stem Cell Research, Regenerative Medicine, Transplantation, Biological Response Modifiers.
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