SELECTIVE REDUCTION IN IMMUNE CLEARANCE BY ALCOHOL

这项建议考察了乙醇对免疫清除的影响，以及 宿主抵御感染的重要免疫机制。我们有 建立了一种测量体内免疫清除动力学的方法 这允许对补码和Fc-Gamma进行独立量化 受体介导的这一过程的组成部分，并已证明 小鼠急性和慢性给予乙醇后， 免疫保护抑制补体依赖的免疫清除 Fc-γ受体介导的清除。这种最初的选择性下降 在清除之后是一个复苏，导致一个小但 补体依赖清除和补体依赖清除的可重复性长期增强 对乙醇挑战的后续抑制的耐受性。动能 对这些变化背后机制的分析表明， 最初的减少与捕获和吞噬作用的减少有关。 虽然延长的增强主要涉及到 减少捕获的SRBC在被摄取之前的释放。下一个 这项工作的这一阶段将细化临床方面的效果 乙醇对小鼠免疫清除的影响并开始研究 这些变化背后的机制。这些实验旨在避免 库普弗细胞或脾巨噬细胞功能中潜在的伪影 通过分离技术和Will-强调体内和原位方案 免疫组织学与分子生物学结合的清除动力学分析 技巧。我们将阐明在这个体系中容忍的条件， 并确定乙醇对免疫和非免疫系统的影响是否不同 免疫清除。对机理的研究将决定乙醇是否 主要影响肝脏中的巨噬细胞或对 补体受体介导的巨噬细胞功能。 补体和Fc-γ受体的表达将通过 免疫组织学、分子和配体结合技术在肝脏和 乙醇给药后不同时间的脾巨噬细胞 确定间隙的连续变化是否伴随着 这些受体。我们还将检查血流和内毒素的变化 肠道细菌可能是这些变化的媒介。当图案出现在 乙醇对清除的影响以及与之相关的潜在的 更好地了解体内免疫的机制，动力学分析 清除应成为研究易感性的有力工具 以及对酒精中毒和其他疾病感染的抵抗力。

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.