Alcohol and Immunoregulatory Pathways

Roselle, Gary

Abstract

The alcoholic is afflicted with a wide variety of intra- and extra- cellular bacterial pathogens, perhaps related to lifestyle, socioeconomic deprivation, and alterations of host response related to ethanolism. The purpose of this proposal is to examine one of the underlying mechanisms relating ethanol to an abnormal host response. It is known that ethanol adversely affects in vitro, mitogen-induced lymphocyte blastogenesis in man, ferrets, rats, and guinea pigs. Since hormonal abnormalities are known to occur in the alcoholic, including feminization, we studied the effect of ethanol on thymic estrogen receptors and thymocyte blastogenic response in the rat. This model was chosen because, in previous work, we have shown an interactive pathway linking the testes, the thymus, and the thymic estrogen receptors. Specifically, in the non-ethanol-fed rat, estrogen decreases the Concanavalin A induced lymphocyte blastogenic response of normal thymocytes through alteration of thymic stromal estrogen receptors and consequent modulation of production of serum substances by these cells. These data were confirmed by removal of the estrogen effect by castration of serum donor animals, resulting in an enhanced thymic cell response to mitogen stimulation. Thymectomy of serum donor animals abolished this effect. In addition, castration led to a decrease in thymic stromal estrogen receptors. In the ethanol-fed rat, we found a decrease in mitogen-induced thymocyte DNA synthesis, while thymic stromal estrogen receptors increased. We hypothesize that ethanol increases the concentration of estrogen receptors located in the thymic stromal epithelium, which regulate production of thymic factors responsible for modulation of lymphocyte responsiveness. Because alcoholics are plagued by granulomatous diseases such as tuberculosis, we will study migration inhibitory factor as a probe to examine the relationship of ethanol to pathogen containment, as manifested in the granulomatous response. Using ethanol feeding, hormonal manipulation, and lymphokine assays in the rat, we will examine the immunoregulatory axis consisting of oral ethanol, the testes, the thymus, and the final outcome of this interaction, migration inhibitory factor activity.