MECHANISM OF THYMIC ATROPHY INDUCED BY ALCOHOL

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DESCRIPTION (provided by applicant): Alcohol consumption suppresses immune function. Alcoholics have an increased incidence of infectious and autoimmune diseases. Alcohol consumption induces loss in thymic weight and cellularity, but the underlying biological mechanism is unknown. In preliminary experiments alcohol consumption accelerated thymus atrophy and aging. Alcohol consumption dramatically increased the CD4+CD8+CD25+ subpopulation in the thymus. These cells were also increased with age., The hypothesis of this proposal is that the thymic atrophy from alcohol consumption is due to changes in the microenvironment of the thymus. These alterations inhibit the development of thymic T cells and increase the percentage of CD4+CD8+CD25+ cells. These cells in turn suppress thymocyte growth and accelerate thymic atrophy. Thus, the peripheral T cell compartment contains fewer naive T cells. The memory T cells increase to compensate for this decrease. The new result of this decrease is a decline in T cell- mediated immune function. The effects of 20% w/v alcohol consumption on the thymus will be studied in female C57BL/6 mice. The specific aims are: 1) Determine if the microenvironment of the thymus is altered in alcohol-consuming mice. Identify the factors that induce CD4+CD8+CD25+ development, differentiation and proliferation. 2) Characterize the biological functions of the CD4+CD8+CD25+ cell population using in vitro and in vivo model systems. 3) Determine if the alteration of specific peripheral T cell subpopulations is related to the increase in thymic CD4+CD8+CD25+ cells. In aim 1, thymic cytokine expression will be assessed by Rnase protection and ELISA assays. Semi-quantitative RT-PCR will be used to study the effect of alcohol consumption on expression of the recombination activating gene. The proliferative state of the CD4+CD8+CD25+ will be determined by BrdU labeling and flow cytometric analysis. In aim 2 the biological functions of the CD4+CD8+CD25+ cell population will be examined in vitro and in vivo model systems using thymic organ culture and cell transfer experiments into SCID mice. In aim 3 the effect of alcohol consumption to modulate naive T cells and memory T cells in the periphery will be studied. The long term objective of this research is to understand the mechanism underlying the loss in thymic cellularity induced by high alcohol consumption and to determine the reversibility of this effect.