SELECTIVE REDUCTION IN IMMUNE CLEARANCE BY ALCOHOL

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This proposal examines the effect of ethanol on immune clearance, an important immune mechanism of host defense against infection. We have developed a method to measure the kinetics of immune clearance in vivo that allows independent quantitation of the complement and Fc-gamma receptor mediated components of this process, and have documented that both acute and chronic administration of ethanol to mice is followed by inhibition of complement dependent immune clearance with sparing of immune clearance mediated by Fc-gamma receptors. This initial selective decrease in clearance is followed by a recovery that results in a small but reproducible long-term enhancement of complement dependent clearance and tolerance to subsequent inhibition by an ethanol challenge. Kinetic analysis of the mechanisms underlying these changes suggests that the initial decrease is related to a decrease in both capture and phagocytosis of the sRBC probe while the prolonged enhancement involves primarily a reduction in release of captured sRBC before they are ingested. The next phase of this work will refine the "clinical" aspects of the effect of ethanol on immune clearance in mice and begin to study details of the mechanisms underlying these changes. The experiments are designed to avoid potential artifacts in Kupffer cell or splenic macrophage function induced by isolation techniques and will-emphasize in vivo and in situ protocols coupling kinetic analysis of clearance with immunohistologic and molecular techniques. We will clarify the conditions for tolerance in this system, and determine whether the effects of ethanol differ on immune and non- immune clearance. Studies on mechanism will determine whether ethanol primarily affects macrophages in the liver or has a selective effect on complement receptor mediated function of macrophages in general. Expression of complement and Fc-gamma receptors will be measured by immunohistologic, molecular, and ligand binding techniques in liver and splenic macrophages at selected times after ethanol administration to determine if the serial changes in clearance are accompanied by changes in these receptors. We will also examine changes in blood flow and endotoxin from gut bacteria as possible mediators of these changes. When the pattern of the effect of ethanol on clearance and the associated underlying mechanisms are better understood, kinetic analysis of in vivo immune clearance should be a powerful tool for the study of the susceptibility and resistance to infection in alcoholism and other diseases.