ALCOHOLISM--MODULATION & FUNCTION OF LYMPHOCYTE SUBSETS

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We have demonstrated in alcoholics without active liver disease l) A significant increase in activated CD8 cells and 2) substantial imbalance in the fine subsets of CD4+, CD8+ and CD3- CD19-lymphocytes. In some alcoholics without active liver disease and in many with alcoholic liver disease, there is also a substantial increase in the percentage of T-cells which are CD57+. These and other results indicate a widespread derangement of the cellular immune system, study of which will provide an improved framework for understanding the mixed immune suppression and immune activation commonly present in alcoholics. We propose to characterize the peripheral blood lymphocytes of alcoholics by phenotype and by functional studies. Phenotypic studies will be by three and four-color flow cytometric methods, with special attention to CD3+CD8(hi)CD57+, CD3+CD8(hi)CD57- and CD3-CD19- subsets. Functional studies will focus on the killing activity and the regulatory activity of both whole lymphocyte fraction and subsets obtained by sorting. Functional studies include: l) measurement of fresh and lymphokine activated killing activity by natural killer and MHC-non-restricted T killer cells; 2) measurement of killing activity and its augmentation in the expanded CD3-CD19- cell subfractions we have recently discovered in some alcoholics; 3) the capacity for development of MHC-restricted T-cell cytotoxicity in an allo driven system; and 4) the ability of putative regulatory T-cell subsets to inhibit B-cell proliferation and IgG production in vitro. These measures will be compared in detail between groups of alcoholics with and those without active liver disease, and with both normal and disease controls. The results will provide a detailed picture of the differences in the cytotoxic/suppressor subsets of peripheral blood lymphocytes between normals, alcoholics without active liver disease, and alcoholics with liver disease. There will be special emphasis on the progression of changes in the phenotypic and functional attributes of the relevant lymphocyte subsets during the different stages of alcoholic liver disease.