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

利用免疫治疗方法来定义慢性胃肠道线虫感染的保护性免疫机制

• 批准号: RGPIN-2018-06366
• 负责人: Stevenson, Mary
• 金额: $ 2.33万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=665946
• 关键词: Exploiting; immunotherapeutic; approaches; define; protective

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.

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。开发针对寄生虫的疫苗具有挑战性，需要识别保护性抗原并更清楚地了解保护性免疫机制。基于纯化或重组蛋白的兽用疫苗仅具有部分保护作用，无法诱导灭菌免疫，并且对驱虫药的耐药性正在迅速出现。小鼠病原体 Heligmosomoides polygyrus bagi (Hpb) 是研究胃肠道线虫感染中宿主与寄生虫相互作用的理想工具。与具有兽医重要性的寄生虫类似，Hpb 传播通过口腔-粪便途径发生，并且感染完全是肠道的。尽管诱导 Th2 免疫反应，但 Hpb 感染在 C57BL/6 (B6) 小鼠和其他近交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 (Treg) 以及细胞因子 IL-10 和 TGF-β。胃肠道线虫释放的排泄分泌 (ES) 产品（蛋白质、代谢物和 miRNA）负责其免疫调节作用，被认为是重要的候选疫苗和自身免疫性疾病和炎症性疾病的新疗法。对 Hpb 感染的小鼠施用鼠 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产卵量，减少成虫负担，并预防慢性感染，但保护机制尚不清楚。我们建议研究这样的假设：对 Hpb 感染的小鼠施用 IL-4C 可以增强 Th2 免疫力，并降低抑制 Hpb 保护性免疫的 MDSC 和 Tregs 的扩张和功能。我们的具体目标是确定：1​​) IL-4C 治疗对消除原发性 Hpb 感染能力不同的 B6 和 BALB/c 小鼠、对 Hpb 感染高度易感性的 IRF8 缺陷小鼠和远交 CD-1 小鼠中成虫负担和产卵的影响，以及 IL-4C 治疗是否诱导绝育免疫； 2) IL-4C治疗保护作用背后的免疫机制； 3）IL-4C是否可以作为佐剂来提高Hpb源性抗原的疫苗效力； 4) IL-4C 与低剂量驱虫药联合使用是否可用于治疗以避免耐药性。总之，我们的研究将为胃肠道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，以供兽医和人类使用以对抗这些普遍存在的寄生虫。