Alcohol-induced aberrations in the immune system include increased susceptibility to infections and delayed type hypersensitivity response which have been linked to alterations in monocyte, T cell and NK cell functions. The investigator's data from the previous funding period suggest that even acute, moderate, in vivo alcohol consumption in humans can decrease monocyte capacity to produce inflammatory mediators TNFalpha and IL-1beta, as well as production of immunoregulatory cytokines IL-12, IL-10 and IFNY. Therefore, the investigators hypothesize that acute in vivo alcohol consumption in humans alters monocyte accessory cell function, antigen presentation capacity, immunoregulatory monocyte mediator production, and expression of co-stimulatory molecules that will contribute to abnormal T lymphocyte functions and altered cytokine profile associated with alcohol use. They further postulate that acute alcohol intake results in impaired antimicrobial response to intact bacterial or viral pathogens and decreased monocyte-derived inflammatory cytokine and chemokine production which in turn, contribute to defective host defense and increased susceptibility to infections. These hypotheses will be tested in non-alcoholic humans after acute, in vivo alcohol consumption as well as in vitro alcohol stimulation experiments.
The specific aims of this proposal are: 1) To assess the effect of in vivo acute alcohol consumption on monocyte-T cell interactions by evaluating accessory cell function of blood monocytes, monocyte subpopulations defined by FgammaRI expression, and peripheral blood-derived dendritic cells in antigen-specific, superantigen-, alloantigen-induced, and antigen-independent T cell proliferation. 2) To study intra-and intercellular mechanisms by which monocytes affect T cell activation after acute alcohol use by examining: a) changes in monocyte expression of co-stimulatory molecules (B7); b) the role of monocytes in ethanol-induced apoptosis of mononuclear and T cells; c) alterations in the production of mediators critical to induction (IL- 12, IL-18) or inhibition (IL-10, TGFbeta) of a cellular immune response. 3) To evaluate the effect of acute alcohol consumption on monocyte defense against intact pathogens such as Streptococcus pneumoniae and influenza A virus by measuring: a) differences in infectivity between ethanol-exposed and control monocytes, b) role of ethanol-induced changes in inflammatory cytokine (TN and ]IL- 1 ), CC (MCP- 1, RANTES, MIP- l,) and CXC (IL-8) chemokine production in response to intact pathogens. Results from these experiments will improve the understanding of the immunomodulatory effects of acute, moderate alcohol use in humans.
