This proposal investigates a largely unexplored mechanism by which ethanol (EtOH) consumption may lead to increased risk of infection, namely, impairment of dendritic cell (DC) function. The long-term objective of the planned experiments is to understand how EtOH-exposed DC contribute to dysfunctional immune responses. In collaboration with the other IRPG members (investigating EtOH-induced B, T, and NK cell dysfunction), these studies will ultimately lead to new therapies designed to decrease infectious morbidity in alcoholics. DC are critical for initiation of effective immune responses, as they provide antigen-specific activation of naive T cells. EtOH has been shown to affect antigen-presenting cell function in alcoholic humans and animal models of EtOH consumption, but the specific mechanisms and cell types responsible for this deficit have not been closely examined. Our laboratory studies the effect of EtOH on DC function in vivo using a model in which mice receive 20% EtOH in their drinking water. Mice maintained on this regimen for many months show no stress-induced changes, thus allowing evaluation of alterations induced by chronic EtOH exposure. EtOH-exposed mice show persistently decreased DC numbers, as well as altered DC function.
The specific aims of this study focus on understanding the mechanisms by which EtOH exposure results in diminished DC numbers, and delineating aspects of DC function that are affected by EtOH. Investigations into the mechanism of diminished DC numbers include studies of the effect of EtOH on DC precursor differentiation, DC lifespan, sensitivity to apoptosis, and migration of newly formed DC into peripheral tissues. Investigations into mechanisms for loss of DC function include studies of the effect of EtOH on antigen processing, presentation, costimulatory molecule expression, cytokine secretion, migration in response to maturation stimuli, and the ability of EtOH-exposed DC to induce tolerance/anergy. All proposed experiments are performed using in vivo or very short term in vitro approaches. This serves to maintain the effect of """"""""physiologically"""""""" relevant EtOH concentrations throughout the course of the study, and to allow assessment of DC function within their usual microenvironment. The results will lead to new information on the effect of EtOH on DC function. This in turn will elucidate new approaches for enhancing immunity and preventing infection in alcoholics, as the appropriate points of intervention become clear.
