The purpose of this project is to delineate the mechanisms involved in regulating immune responses in filarial and nonfilarial disease states. New models for examining in vitro the early immune response to parasite antigens have been developed; so that naive (CD45 RA+) cells can be primed for the production of cytokines in response preferentially to parasite antigen upon restimulation. The data indicate that helminth antigens are capable of driving the immune response toward the production of IL-4, IL-5 and IL-10. Using selected recombinant filarial antigens, the role the antigens themselves play in the induction of a Th2 response and the B-cell response it subsequently influences (IgE/IgG4) has also been studied. Similarly, new ways of assessing eosinophil activation have also been developed. Immunoregulatory studies have examined the phenomenon of antigen-specific anergy in microfilaremic patients by showing this anergy to be a result of the production of the antiproliferative cytokine, IL-10. This IL-10 is preferentially induced by stage-specifiic (microfilarial) antigens; the effect of IL-10 is, in part, mediated by the modulation of the costimulatory molecules, CD80/CD86 and its ligand, CD28. The genetics underlying susceptibility and resistance to filarial infection has been studied by HLA Class II typing along with allotyping. A particular KM allotype has been shown to be associated with resistance to onchocerciasis in Afro-Ecuadorian populations, and an HLA Class II haplotype, DRB1*08042-DQA1*0401-DQB1*0402, is associated with resistance in the Amerindian population. Further, a new TNF-alpha promoter polymorphism (TNFAp4) has also been identified and studied at the population level.
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