ALCOHOLISM--MODULATION & FUNCTION OF LYMPHOCYTE SUBSETS

描述：(改编自《调查者摘要》)酒精中毒及其危害 并发症在美国造成了惊人的医疗费用。 传染性疾病是免疫缺陷的结果，而 自身抗体支持自身免疫可能有助于 器官和组织受损。最近，我们和其他人已经证明 酗酒者有1)慢性显著激活的T细胞，2)丧失或 几个淋巴细胞亚群的减少，3)单核细胞的大量激活， 4)体外功能变化。已知的细胞亚集被改变 酗酒者的典型表型包括CD8+T细胞和CD5+B细胞，以及 T细胞对同种异体抗原反应的丧失 无自体单核细胞。我们认为子集和子集的丢失 激活的单核细胞对剩余淋巴细胞亚群的影响如下 对这些患者的大部分免疫功能障碍负有责任。这个 提案将通过1)描述酗酒者亚群丢失的机制 细胞死亡相关标记物的表达及细胞凋亡程度的评价 在已知在酗酒者中丢失的激活细胞类型中，2)测量 细胞因子平衡和激活的单核细胞的相对数量，3) 活化的T细胞对抗原反应的抑制作用分析 4)细胞因子平衡(TH1/TH2)的研究。 酒精中毒不同阶段的剩余淋巴细胞亚群。这些 将对新鲜和培养的外周血进行评估 酒精中毒患者外周血中淋巴细胞和单核细胞的比较 与正常对照组比较。乙醇的影响将直接测量在 这些相同的功能是通过使用短期和长期细胞培养在 存在受到严密控制的持续酒精暴露。这些方法 的分析都是标准化的，目前在 调查员的实验室。这些包括流式细胞术，修改 几种细胞杀伤实验和细胞增殖实验。的目标是 这些调查对提高认识具有重要意义 慢性酒精中毒的免疫学变化是发病和死亡的基础 年传染病和器官损伤增加导致的死亡 这些病人。这一理解将是主动行动的核心 免疫疗法和其他干预措施旨在减少发病率和 这种疾病的死亡率。

DESCRIPTION: (Adapted from the Investigator's Abstract) Alcoholism and its complications exact a staggering medical cost in the U.S. The increase in infectious diseases is a result of immunodeficiency, and the presence of autoantibodies supports the possibility that autoimmunity may contribute to the organ and tissue damage. Recently, we and others have shown that alcoholics have 1) chronically and markedly activated T-cells, 2) loss or reduction of several lymphocyte subsets, 3) substantial monocyte activation, and 4) functional changes in vitro. Cellular subsets known to be altered phenotypically in alcoholics include CD8+ T-cells, and CD5+ B-cells, and loss of T-cell response to alloantigen in the presence but not in the absence of autologous monocytes. We believe that the loss of subsets and the influence of activated monocytes on the remaining lymphocyte subsets are responsible for much of the immune dysfunction in these patients. The proposal will characterize the mechanisms of subset loss in alcoholics by 1) evaluation of cell-death related marker expression and extent of apoptosis in the activated cell types known to be lost in alcoholics, 2) measurement of the cytokine balance and relative numbers of activated monocytes, 3) analysis of inhibition of T-cell responses to antigen by the activated monocytes, and 4) investigation of the cytokine balance (TH1/TH2) of the remaining lymphocyte subsets in various stages of alcoholism. These evaluations will be carried out on fresh and cultured peripheral blood lymphocytes and monocytes from alcoholic humans under treatment and compared with normal controls. The effect of ethanol will be directly measured on these same functions by the use of short and long-term cell cultures in the presence of carefully controlled continuous ethanol exposures. The methods of analysis are all well-standardized and currently in use in the investigator's laboratory. These include flow cytometry, modifications of several cell-killing assays, and cell proliferation assays. The goal of these investigations is to improve understanding of the significant immunologic changes in chronic alcoholism that underlie the morbidity and death resulting from the increased infectious diseases and organ damage in these patients. This understanding will lie at the heart of initiative for immunotherapy and other interventions designed to reduce the morbidity and mortality in this disease.