Transplant Models

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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. 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 efforts to identify points of control in thymus function. In experiments utilizing IGF-1, which was found to upregulate thymus activity, we observed that while thymocyte precursor pool size and molecules involved in migration are affected, the critical control point was at the level of expanding maturational niches for incoming thymocytes. Cessation of androgen signaling, which also results in increased thymus activity, involved upregualtion of the molecule CCL25 which in turn enhanced immigation of thymocyte precusors into the thymus. CCL25 was found to be necessary for upregulation of thymus function in this setting. Both of these approaches for increasing thymus function and in turn enhancing T cell immune reconstitution in the setting of cancer therapy can be applied to clinical trials.