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

胃肠道（GI）线虫继续感染人类和动物，对食品安全和全球粮食安全造成重大社会经济后果和影响。这些感染对牲畜生产产生不利影响，对受感染宿主的体重增加和受孕率产生负面影响。针对寄生蠕虫的疫苗的开发是具有挑战性的，并且需要鉴定保护性抗原和更清楚地理解保护性免疫机制。基于纯化或重组蛋白质的兽用疫苗仅具有部分保护性，不能诱导杀菌免疫，对驱虫药的耐药性正在迅速出现。小鼠病原体Heligmosomoides polygyrus bakeri（Hpb）是研究胃肠道线虫感染中宿主-寄生虫相互作用的理想工具。类似于兽医学上重要的寄生蠕虫，Hpb通过口-粪途径传播，感染完全是肠道的。尽管诱导Th 2免疫应答，但Hpb感染在C57 BL/6（B6）小鼠和其他近交系小鼠品系中是慢性的，并诱导有效的调节网络，包括骨髓源性抑制细胞（MDSC）、调节性T细胞（TcR）和细胞因子IL-10和TGF-β。胃肠道线虫释放的排泄分泌（ES）产物（蛋白质、代谢物和miRNA）负责其免疫调节作用，并被认为是重要的疫苗候选物和自身免疫性和炎性疾病的新疗法。对Hp感染的小鼠给予鼠IL-4：抗小鼠IL-4单克隆抗体复合物（IL-4C）的长效制剂可迅速减少虫卵产生，降低成虫负荷，并预防慢性感染，但保护机制尚不清楚。我们建议调查的假设，IL-4C管理Hp感染的小鼠增强Th 2免疫，并降低MDSC和Tcls的扩展和功能，抑制保护性免疫Hpb。我们的具体目标是确定：1）IL-4C处理对B6和BALB/c小鼠（它们消除原发性Hpb感染的能力不同）、IRF 8缺陷小鼠（对Hpb感染的敏感性增加）和远交系CD-1小鼠中成虫负荷和卵产生的影响，以及IL-4C处理是否诱导绝育免疫; 2）IL-4C治疗保护作用的免疫机制：3）IL-4C能否作为佐剂提高Hp抗原的疫苗效力;和4）如果IL-4C在治疗上与低剂量的驱蠕虫药物组合以避免耐药性是有用的。总之，我们的研究将为GI线虫的保护性免疫机制提供更深入的了解，并为开发有效的疫苗和新型免疫疗法提供重要信息，用于兽医和人类对抗这些无处不在的寄生虫。

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.