This proposal examines the effect of ethanol on immune clearance, an important immune mechanism of host defense. Preliminary experiments demonstrated that chronic ethanol feeding of BALB/c mice decreases in vivo immune clearance mediated by complement(C3b), but does not effect clearance mediated by the Fc portion of IgG. This newly recognized defect may be important in the susceptibility to infection associated with the use of ethanol. The parameters of this clearance defect will be defined and the hypothesis that it's selective nature is the result of the preferential effect of ethanol on fixed tissue macrophages in the liver will be tested. Data from clearance of IgG-sensitized erythrocytes are analyzed by an iterative curve fitting process based on a rate equation which was derived from a validated model of immune clearance. Four rate constants are obtained that define the major steps in immune clearance: hepatic(C3b) sequestration, hepatic(C3b) mediated phagocytosis, C3b deactivation and return of deactivated cells back to the circulation and splenic (Fc) mediated clearance. The technique allows independent quantitative evaluation of the C3b and Fc mediated in vivo clearance pathways under a variety of experimental conditions. The dose range of ethanol effecting clearance as well as the timing and duration of the defect, the difference in acute bolus and chronic feeding and the effect in another mouse strain known to ingest ethanol will be determined. The selective effect on complement mediated clearance will be confirmed by increasing the role of Fc mediated clearance to bring out subtle changes in the Fc pathway by treatment with cobra venom factor and the use of a mouse strain with a genetic relative defect in complement clearance. The relative number of functional C3b receptors and the rates constant governing their activity will be determined in ethanol and control mice by kinetic techniques. The hypothesis that the selective decrease in complement clearance is due to preferential damage to Kupffer cells by products of ethanol metabolism in hepatocytes will be examined using a combination of surgical and kinetic techniques as well as selective inhibition of the steps in ethanol metabolism with 4-methyl pyrazole and cyanamide. Knowledge gained in these studies should establish one mechanism through which alcohol can act as a cofactor in the development of infectious diseases.
| Messner, R P; Meryhew, N L; DeMaster, E G (1994) Selective, prolonged alteration of complement-mediated immune clearance after acute exposure of mice to ethanol. Clin Immunol Immunopathol 70:73-80 |
| Messner, R P; Meryhew, N L; DeMaster, E G (1993) Effect of ethanol on immune clearance in mice: biphasic alteration of complement-mediated clearance with chronic ethanol ingestion. J Lab Clin Med 122:506-17 |
