Studies with animal models and human subjects indicate that ethanol (RtOH) can be immunosuppressive. However, very little is known of the effects of EtOH on the immune system when a large quantity is consumed during a single drinking episode. This type of drinking behavior is quite common in the U.S., and it is important to determine its effects on the immune system and to determine the mechanism(s) responsible for these effects. Preliminary studies indicate that a single dose of EtOH in mice suppresses the antibody-forming cell (AFC) response to sheep erythrocytes (SRBC) in vivo and in vitro. Suppression can be blocked by the glucocorticoid antagonist, RU 486, suggesting a role for endogenous glucocorticoids. Therefore, this project will focus on the following HYPOTHESIS: A single dose of ethanol by gavage suppresses T-dependent primary humoral immune responses in B6C3F1 female mice by mechanisms that are predominantly glucocorticoid-dependent.
Specific aims are proposed that will provide four independent lines of evidence that should confirm or refute this hypothesis. First, the effects of a broad range of EtOH doses on serum corlticosterone levels and on suppression of the primary humoral immune response will be compared. Close correlation between these parameters would be consistent with a cause- effect relationship, whereas lack of correlation would not. Second, a dosage and mode of administration of exogenous corticosterone will be identified that produces similar corticosterone blood levels and kinetics as noted in EtOH-treated mice. The effects of EtOH and exogenous corticosterone on the primary humoral immune response will then be compared. Similar effects would be consistent with a role for endogenous glucocorticoids in EtOH-induced immunosuppression, whereas less profound effects in corticosterone-treated mice than in EtOH-treated mice would suggest that endogenous glucocorticoids are not involved in EtOH-induced immunosuppression or that they act synergistically with other EtOH-induced changes. Third, the effects of EtOH and exogenous glucocorticoids on cell numbers and subpopulation ratios in the spleen will be compared. Similar patterns of changes would be consistent with a role for corticosterone in EtOH-mediated effects, whereas different patterns of changes would suggest mechanisms other than endogenous glucocorticoids. Fourth, the effects of the glucocorticoid antagonist, RU 486, on EtOH-induced change in the primary humoral immune response and on cell numbers and subpopulations in the spleen will be measured. Inhibition of athe effects of EtOH by RU 486 would be consistent with an important role for glucocorticoids, whereas absence of inhibition would not be consistent with such a role. Other proposed experiments will evaluate the possible role of handling and gavage-related stress and hypothermia in EtOH-induced increases in corticosterone levels and in immunosuppression. The overall health and nutritional status of EtOH-treated mice will be evaluated by histopathological and clinical chemistry assessment to confirm that immunological changes are not secondary to EtOH toxicity or nutritional deprivation. Finally, direct effects of EtOH and its major metabolites on the immune system will be evaluated in vitro to assess the role of such effects in EtOH-induced immunosuppression. It is expected that these experiments will thoroughly characterize a mouse model for the effects of binge drinking on the immune system and will determine the role of endogenous glucocorticoids in suppression of the primary humoral immune response in that model.
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