Targeting myeloid cells for regulation of alum-based immunity

明胶是当前亚单位疫苗中使用最广泛的佐剂，以对抗感染性病原体。粘膜组织 代表病原体进入的主要入口。与全身血液循环形成对比 在隔室，粘膜组织中含有大量产生IgA的细胞。这种免疫球蛋白同型 通过一系列机制有助于保护暴露的粘膜表面，包括预防 病原体与宿主细胞(上皮细胞和树突状细胞)结合，中和管腔中的毒素，以及 中和上皮细胞内的病毒。注射疫苗可诱导高水平的免疫球蛋白G反应 血流，但它们不能有效地诱导最佳所需的分泌型IgA反应 粘膜表面的保护。与注射疫苗相比，黏膜疫苗通过口服递送， 直肠、鼻腔或舌下途径以粘膜相关淋巴组织为靶点，在那里它们可以诱导先天的 诱导分泌型IgA反应所需的信号。尽管几十年来对粘膜疫苗的研究， 到目前为止，只有两种口服疫苗和一种鼻腔疫苗获得了在美国使用的许可。这项提议将 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 并防止产生免疫球蛋白A。我们新产生的数据表明，一系列分子 由髓系细胞产生的物质在防止明矾注射疫苗产生IgA方面发挥核心作用 以这些分子为靶点将通过增加IgA的产生来提高保护作用。目标1将专注于 非粘膜部位髓系细胞先天抑制IgA反应的机制。目标2将 确定抑制这一家族分子的药物靶向的细胞和信号通路 调节全身免疫后系统和粘膜免疫反应的诱导。目标3将 确定针对免疫球蛋白A反应的先天抑制者的策略是否促进广泛的系统性和 粘膜免疫，并能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.