Graft-versus-host disease (GVHD) results in multiorgan system damage and is a significant source of clinical morbidity and mortality post-BMT. In murine allogeneic BMT experiments, we have observed that rapamycin (RPM) is one of the most potent immunosuppressive agent in the prevention and therapy of lethal GVHD that our laboratory has tested in the past 15 years. However, GVHD prevention occurred at the expense of an autoimmune-like syndrome characterized by ulcerative skin lesions, alopecia, bile duct proliferation, and mononuclear infiltration without destruction in the lung. The overall goals of this proposal are to optimize the use of RPM on the thymic T-cell education process. RPM inhibits T-cell cytokine responsiveness. Our preliminary data supports the hypothesis that RPM given the irradiated rodent recipients of bone marrow (BM), results in a T-cell mediated autoimmunity presumably by interfering with the regulation of T-cell development in the thymus and in the periphery. We will ask: 1. Does RPM interfere with thymic clonal selection and/or clonal deletion of T-cell antigen receptor (TCR) expressing alpha/beta (alpha/beta)+ or TCR gamma/delta (gamma/delta)+ cells? Our preliminary data suggest that RPM administration inhibits the typical deletion process of certain T-cell antigen receptor (TCR) alpha/beta+ VB specific T-cells. We will extend these studies using well-defined T-cell receptor (TCR) alpha/beta transgenic (Tg+/+) mice in which a high proportion of thymic T-cells are either deleted (in males) or positively selected (in females) to prove that RPM interferes with clonal deletion and clonal selection (respectively) of TCR alpha/beta+ cells. Using Tg+/+ TCR gamma/delta mice, we will also ask if RPM can inhibit TCR gamma/delta that positively or negatively selected. 2. What are the consequences of RPM on the functional capacity of peripheral and thymic derived T-cell populations? The functional capacity of VB or Vgamma/ T-cells that escape positive or negative selection in RPM-treated mice will be assessed. If these cells are functional, we will ask if the associated autoimmune-like abnormalities are a direct result of non- deleted and functional TCR alpha/beta+ (or TCR gamma/delta+ cells) thymic or peripheral mature T-cell populations. The requirement for an irradiated thymus in generation of the autoimmune syndrome will also be investigated if TCR alpha/beta+ or TCR gamma/delta+ T-cells clonal deletion is inhibited. Improving our knowledge of the actions of RPM in vivo will allow us to better employ this drug in human BMT recipients as well as extend our knowledge of the processes involved with thymic and peripheral selection, deletion, and anergy.
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