Targeting myeloid cells for regulation of alum-based immunity

明矾是目前抗感染原亚单位疫苗中使用最广泛的佐剂。粘膜组织 是病原体进入的主要门户。与全身的一般血流相比， 粘膜组织含有大量的伊加产生细胞。这种免疫球蛋白同种型 有助于通过多种机制保护暴露的粘膜表面， 病原体与宿主细胞（上皮细胞和树突细胞）结合，中和管腔中的毒素，以及 中和上皮细胞内的病毒。注射疫苗可在小鼠中诱导高水平的IgG应答。 它们可以促进血液循环，但它们不能有效地诱导分泌型IgA应答，而分泌型IgA应答是最佳免疫调节所需的。 保护粘膜表面。与注射疫苗相比，粘膜疫苗通过口腔， 直肠、鼻腔或舌下途径靶向粘膜相关类肉瘤组织，在那里它们可以诱导先天性 诱导分泌型伊加应答所必需的信号。尽管对粘膜疫苗进行了数十年的研究， 到目前为止，只有两种口服疫苗和一种鼻内疫苗在美国获得许可使用。这项建议会 解决了佐剂明矾触发限制抗体呼吸的先天信号的总体假设 反应和防止伊加的产生。我们最新的数据表明， 由骨髓细胞产生的IgA在防止基于明矾的注射疫苗产生伊加方面起着核心作用， 靶向这些分子将通过增加伊加的产生来改善保护。目标1将侧重于 非粘膜部位髓样细胞先天性抑制伊加应答的潜在机制。目标2将 鉴定抑制该分子家族的药理学试剂靶向的细胞和信号通路 调节全身免疫后全身和粘膜免疫应答的诱导。目标3将 确定针对伊加反应的先天抑制因子的策略是否促进广泛的全身性和 粘膜免疫，可保护相关动物模型免受肠道病毒感染。

Alum is the most widely used adjuvant in current subunit vaccines against infectious agents. Mucosal tissues represent the main portal of entry of pathogens. In contrast with the general bloodstream in the systemic compartment, mucosal tissues contain a large number of IgA producing cells. This immunoglobulin isotype contributes to the protection of exposed mucosal surfaces via a number of mechanisms including prevention of pathogen binding to host cells (epithelial cells and dendritic cells), neutralization of toxins in the lumen, and neutralization of viruses within epithelial cells. Injected vaccines can induce high levels of IgG responses in the bloodstream, but they are not effective at inducing secretory IgA responses which are needed for optimal protection of mucosal surfaces. In contrast with injected vaccines, mucosal vaccines delivered through the oral, rectal, nasal or sublingual routes target Mucosal-Associated Lymphoid Tissues where they can induce innate signals necessary for induction of secretory IgA responses. Despite decades of research on mucosal vaccines, to date, only two oral vaccines and one intranasal vaccine are licensed for use in the US. This proposal will address the overall hypothesis that the adjuvant alum triggers innate signals that restrict the breath of antibody responses and prevent the production of IgA. Our newly generated data suggest that a family of molecules produced by myeloid cells plays a central role in preventing IgA production by alum-based injected vaccines and targeting those molecules will improve protection by increasing IgA production. Aim 1 will focus on the mechanisms underlying innate suppression of IgA responses by myeloid cells in non-mucosal sites. Aim 2 will identify the cells and signaling pathways targeted by pharmacological agents inhibiting this family of molecules to regulate induction of systemic and mucosal immune responses after systemic immunization. Aim 3 will establish whether strategies targeting the innate suppressors of IgA responses promote broad systemic and mucosal immunity and can protect a relevant animal model against infection with an enteric virus.