Immune responses must induce the proper effector mechanisms to protect animals against infections. Specific cytokines are often required to induce the proper effector mechanisms. The cytokine IL-4, which is produced in response to nematode infections, is important in protective immunity against gastrointestinal nematodes. We have demonstrated that the ability of mice to limit a challenge infection with a nematode that causes a chronic gastrointestinal infection, Heligmosomoides polygyrus, is dependent upon production of IL-4, that treatment with IL-4 can cure a primary H. polygyrus infection, and that IL-4-induced cure is dependent upon an intact immune system. In contrast, the cytokine IFN-gamma, which often opposes the effects of IL-4, exacerbates H. polygyrus infections. The cytokines IL- 2 and IL-4 promote the differentiation of naive T cells into IL-4 secreting cells. Consequently, we want to determine if treatment of mice with these cytokines can influence the T cell response to H. polygyrus to enhance the production of IL-4 and other Th2-associated cytokines and to limit challenge infections with this parasite. Our experimental approach will utilize complexes of IL-4 or IL-2 with neutralizing monoclonal antibodies, which have a much greater in vivo cytokine agonist effect and half-life than the free cytokines. We will study the ability of IL-4 and IL-2 complexes, alone and in combination, to enhance protective immunity induced by immunization with H. polygyrus antigens or by an initial infection with H. polygyrus and to modify cytokine production in response to a challenge infection with H. polygyrus. Doses, ratios of cytokine to anticytokine antibody in complexes, routes of cytokine administration, and administration schedules will be optimized. Effects of cytokine complexes on antibody, mast cell, and eosinophil responses will be investigated. The relative roles of T cells and B cells in cytokine-promoted immunity will be examined. The ability of cytokine complexes to protect mouse strains that are normally particularly susceptible to H. polygyrus will be determined. These studies should define methods that can be used to promote immunity to gastrointestinal nematodes of the genera Necator, Ancylostoma, Ascaris, Trichuris, and Strongyloides, which infect approximately one billion people worldwide and are believed to cause approximately 1,000,000 deaths a year.
