Studies are proposed to examine the impact of opioids on the development of T cells using murine models of T cell differentiation. These studies are significant because of the need to understand those factors which control the maintenance of mature T cells in individuals who abuse opioid drugs. It is well established that the thymus is a primary site of HIV infection and the infection appears to involve both T cells and dendritic cells in the thymus. The infection appears to lead to reduced CD4+ cells in the thymus and this may be due to either direct or indirect killing mechanisms mediated by the HIV. Recent studies have established that the infection of the thymus with HIV leads to a subsequent reduction in the production of mature and functional CD4+ cells in the periphery. Factors which result in reduced levels of replacement CD4+ cells are clearly critical for the preservation of the immune system in the AIDS patient. The failure of the immune system to produce adequate replacement of CD4+ cells contributes significantly to the degeneration of the immune response in the late stages of AIDS. Several studies using experimental animal models have shown that the administration of opioids results in a reduction in the number of thymocytes, and in particular a reduction of cells at the critical CD4+CD8+CD3+ intermediate stage of differentiation. The mechanism of this effect is not well understood, and because of the common use of opioid drugs in the AIDS patient, it is important to understand the impact of the opioids on the development of T cells. We propose to carry out studies to address three specific aims. First, we wish to determine the relationship between T cell differentiation and the expression of the mu-, kappa-, delta-opioid receptors. Second, we wish to assess the impact of opioid administration on the differentiation of T cells in the thymus. And finally, we wish to determine the effect of opioid administration on the functional capacity of the developing T cells in the thymus. It is hoped that these studies will provide valuable information relating to the control of the T cell arm of the immune system in opioid abuse.
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