Study results from my laboratory and reported by other researchers have shown that ethanol (ETOH) consumption by experimental animals and human beings is associated with an increased susceptibility to infectious diseases. Overall, this is associated mostly with defects in the generation of cell-mediated immune responses and the effector functions of lymphoid cells, including T and natural killer cells as well as macrophages. We and others have shown that ETOH consumption is also associated with activation of the hypothalamic-pituitary- adrenal (HPA) axis and that many of the changes in lymphoid cell numbers and function can be attributed to the resulting corticosteroids produced as a result of this activation. The general hypothesis to be tested in the studies proposed in this application is that the corticosteroids produced by ETOH-fed animals suppress innate and acquired immune responses that are necessary for host defenses against infectious microorganisms. This hypothesis and other more specific hypotheses resulting from the general hypothesis will be tested by using a murine model of ETOH consumption in a liquid diet with a pair-feeding paradigm. With the use of adrenalectomized mice we will determine whether immune responses to model T-cell-dependent antigens such as phosphocholine conjugated to key hole limpet hemocyananin or infectious microorganisms, including Listeria monocytogenes, Salmonella typhimurium, Nippostrongylus brasiliensis, and murine cytomegalovirus, are decreased by corticosteroids produced as a result of ETOH consumption. With this approach the role of ETOH-associated corticosteroid production on the cellular effectors of immunity, including natural killer cells, CD4+ and CD8+T cells, and macrophages will be tested. By using the various infectious model systems in place in this laboratory the ETOH-mediated effects on the subsets of helper T cells (TH-1 and TH-2) will also be defined.
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