Opiate abuse is a major public health problem and a controversial social issue imparting considerable economic and personal costs to societies both in the US and internationally. Opioid addicts are prone to both bacterial and viral infections. Chronic morphine treatment has been shown to alter a number of immune parameters including suppression of cellular immunity. Opioid withdrawal exacerbates this cellular immune defect. Differentiation of T-helper cells toward Th2 effectors cells results in impaired cellular immunity. It is thought that T-helper cell differentiation into Th2 effector cell populations is a major contributing factor to impaired cellular immunity following injury, infection and addiction. We have recently shown that chronic morphine treatment in-vitro directs T-helper cells towards Th2 differentiation. The control of T-helper cell differentiation is a function of a number of factors; the most important of which is cytokine environment. Cytokine environment is controlled by regulation of key transcriptional """"""""switches"""""""" (GATA-3, T-bet) that regulate T-helper cell differentiation. The central hypothesis in this proposal is that chronic morphine treatment differentially modulates the transcriptional """"""""switches"""""""" GATA-3 and T-bet, which then directs CD4+ differentiation. In this proposal we will investigate the following:
Specific Aim 1 : We will investigate mediators of signal transduction pathway by which chronic morphine treatment in-vivo regulate the transcriptional """"""""switches"""""""" T-bet and GATA 3 in CD4+ T-cells.
Specific Aim 2 : We will investigate the signal transduction mechanisms by which chronic morphine treatment in vitro regulates the transcriptional """"""""switches"""""""" T-bet and GATA 3 in CD4+ T-cells.
Specific Aim 3 : We will investigate the signal transduction mechanisms by which morphine withdrawal in-vivo and in-vitro regulate the transcriptional """"""""switches"""""""" T-bet and GATA 3 in CD4+ T-cells. Experiments outlined in these specific aims will help identify how morphine modulates T-helper cell cytokine responses and T-helper cell differentiation and may explain defects observed in cellular immune response in the drug abuse population. Therapies that prevent Th2 differentiation and promote Th1 cytokine synthesis may therefore prove beneficial in the immunosuppressed drug abuse population.
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