ALCOHOL AND THE DEVELOPMENT OF NATURAL KILLER CELLS

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Fetal alcohol syndrome (FAS) children have defects in host defense and a concomitant increase in the incidence of life threatening infections. Some children with FAS have long lasting deficiencies in both humoral and cell mediated immunity, suggesting that interuterine exposure to alcohol may interfere with critical events in the development of the immune system. Natural killer (NK) cells, a subset of lymphocytes distinguishable from both T and B cells, have been shown to mediate a number of effector, regulatory, and developmental events in the immune system. NK cells constitute an important component of host defense to microbial (both viral and bacterial) infections as well as host resistance to tumor growth and metastasis. Since NK cells are functional at birth in humans, while the humoral and cell mediated systems are still immature, these effector cells may be particularly important to the infant for the resistance to infection. The maturation of the immune response in the mouse is also age dependent and since functional NK cells do not develop until the time of weaning the mouse provides an excellent model for studying the development of these effector cells. It is known that high blood levels of alcohol can inhibit NK cells, however, it is not known whether or not alcohol exposure in utero or in the neonatal period (via breast feeding) affects the development of NK cells. In this proposal we will determine the effects of ethanol, administered at different stages in development, on the function of NK cells. We will utilize a mouse model which involves the strategy of cross-fostering to expose mice to ethanol at different stages of development, along with pair fed and solid food controls. We propose to determine what effects interuterine and/or neonatal exposure to ethanol have on: 1) the kinetics of neonatal acquisition of NK cells, as determined by flow cytometry using monoclonal antibodies specific for NK cells. 2) the development of NK function, as determined by in vitro lysis of tumor target cells and the capacity of NK progenitors to respond to biological response modifiers. 3) the extent to which changes observed in NK cell function in vitro reflect the ability of these cells to regulate tumor cell growth in vivo. The design of experimental groups will allow us to attribute observed changes in NK cell function to the exposure of the experimental animals to ethanol and to assess the persistence of any effect (in adult animals) of interuterine and/or neonatal exposure to alcohol on in vivo NK function. Because of the potential that diet may induce changes in the measured parameters we have taken care in the experimental design to include groups which will allow us to isolate the effects of alcohol from any diet induced changes. Establishing the consequences of maternal alcohol consumption and neonatal exposure to alcohol on the developing immune system is essential for understanding the basis for the profound immunodeficiency exhibited by some children with FAS. Furthermore, since an increasing number of woman abuse drugs along with alcohol, this research has significant implications in the well being of infants born to women in the population at high risk for AIDS.