Exploiting immunotherapeutic approaches to define protective immune mechanisms to chronic GI nematode infections

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Gastrointestinal (GI) nematodes continue to infect humans and animals with major socio-economic consequences and impacts on food safety and global food security. These infections adversely affect livestock production with negative effects on weight gain and conception rates in infected hosts. Development of vaccines against parasitic worms is challenging and requires the identification of protective antigens and a clearer understanding of the protective immune mechanism(s). Veterinary vaccines based on purified or recombinant proteins are only partially protective and unable to induce sterilizing immunity, and resistance to anthelmintics is rapidly emerging. The mouse pathogen Heligmosomoides polygyrus bakeri (Hpb) is an ideal tool to study host-parasite interactions in GI nematode infections. Similar to parasitic worms of veterinary importance, Hpb transmission occurs via an oral-fecal route and infection is entirely enteric. Despite inducing a Th2 immune response, Hpb infection is chronic in C57BL/6 (B6) mice and other inbred mouse strains and induces a potent regulatory network including myeloid-derived suppressor cells (MDSC), regulatory T cells (Tregs), and the cytokines IL-10 and TGF-beta. Excretory-secretory (ES) products (proteins, metabolites and miRNAs) released by GI nematodes are responsible for their immunomodulatory effects and considered as important vaccine candidates and novel therapy for autoimmune and inflammatory diseases. Administration of a long acting formulation of murine IL-4:anti-mouse IL-4 monoclonal antibody complexes (IL-4C) to Hpb-infected mice rapidly reduces egg production, decreases adult worm burden, and prevents chronic infection, but the protective mechanism(s) is unknown. We propose to investigate the hypothesis that IL-4C administration to Hpb-infected mice enhances Th2 immunity and decreases the expansion and function of MDSC and Tregs that suppress protective immunity to Hpb. Our specific objectives are to determine: 1) the effects of IL-4C treatment on adult worm burden and egg production in B6 and BALB/c mice that differ in their ability to eliminate primary Hpb infection, IRF8-deficient mice with exaggerated susceptibility to Hpb infection, and out-bred CD-1 mice, and if IL-4C treatment induces sterilizing immunity; 2) the immune mechanisms underlying the protective effect of IL-4C treatment; 3) if IL-4C can be used as an adjuvant to improve the vaccine efficacy of Hpb-derived antigens; and 4) if IL-4C is useful therapeutically in combination with a low dose of anthelmintic drug to circumvent drug resistance. Together, our studies will provide greater insight into the mechanism(s) of protective immunity to GI nematodes and important information for development of effective vaccines and novel immunotherapy for veterinary use as well as for humans against these ubiquitous parasites.