Using combination adjuvants to direct and control immune responses at the intestinal mucosa

 描述（由申请方提供）：大多数病原体从粘膜表面进入体内，然而，迄今为止，大多数许可的疫苗都是胃肠外注射，主要是肌内注射。虽然在引发全身免疫方面表现出色，但它们并不总是诱导所需的粘膜免疫应答。这突出了我们对如何操纵免疫以引起粘膜免疫应答以及如何利用这些知识来创建针对粘膜病原体的更好疫苗的理解中的差距。确定佐剂在这种反应中的作用是开发这种疫苗的关键;然而，决定佐剂驱动的粘膜抗体和细胞免疫反应的机制还没有很好地理解。我们的初步实验使用主要组织相容性复合物II类（MHCII）四聚体检查粘膜免疫反应后，皮内免疫与一种新的脱毒细菌ADP-核糖基化肠毒素，称为dmLT，证明我们可以重新靶向内源性Th 17 CD 4 T细胞和B细胞伊加免疫反应的肠粘膜可能通过参与的CD 103+皮肤树突状细胞。我们还表明，在沙门氏菌感染的小鼠模型中，用dmLT加上单个CD 4 T细胞表位进行皮内免疫可以显著降低细菌负荷。除了我们过去的工作之外，这些组合的结果使我们假设用dmLT进行皮内免疫接合CD 103+树突细胞，其引发抗原特异性B细胞和CD 4 T细胞以上调肠道归巢标记物和粘膜运输。我们进一步证实，当这与通过不同信号传导途径起作用的佐剂组合时，细胞和体液免疫都可以被调节以适应感兴趣的粘膜病原体。我们建议：1）评估当用dmLT的皮内免疫与Th 1或Th 2驱动佐剂组合时的抗原摄取和呈递，确定该免疫如何将2）T细胞和3）B细胞引导至粘膜组织，和4）确定该免疫是否保护免于沙门氏菌细菌的致死性肠道感染。这项研究应该提供新的见解佐剂如何调节免疫粘膜，使我们能够引导有利于病原体消除的反应。

 DESCRIPTION (provided by applicant): Most pathogens enter the body at mucosal surfaces, yet, to date, the majority of licensed vaccines are injected parenterally, predominantly intramuscularly. While excellent at eliciting systemic immunity, they do not always induce the required mucosal immune responses. This highlights a gap in our understanding of how immunization may be manipulated to elicit mucosal immune responses and how such knowledge might be exploited to create better vaccines for mucosal pathogens. Defining the role that adjuvants play in this response is key to developing such vaccines; however, the mechanisms that dictate adjuvant driven mucosal antibody and cellular immune responses are not well understood. Our preliminary experiments using major histocompatibility complex class II (MHCII) tetramers to examine mucosal immune responses after intradermal immunization with a novel detoxified bacterial ADP- ribosylating enterotoxin, called dmLT, demonstrate that we can retarget the endogenous Th17 CD4 T cells and B cell IgA immune responses to the intestinal mucosa possibly by engagement of CD103+ skin dendritic cells. We also show intradermal immunization with dmLT plus a single CD4 T cell epitope can significantly reduce bacterial burden in a mouse model of Salmonella infection. These combined results, in addition to our past work, lead us to hypothesize that intradermal immunization with dmLT engages CD103+ dendritic cells, which prime antigen-specific B cells and CD4 T cells to upregulate gut- homing markers and mucosal trafficking. We further posit that when this is combined with adjuvants acting via different signaling pathways, both cellular and humoral immunity can be tuned to adapt to a mucosal pathogen of interest. We propose to: 1) assess antigen uptake and presentation when intradermal immunization with dmLT is combined with Th1 or Th2 driving adjuvants, determine how this immunization directs 2) T cells and 3) B cells to mucosal tissue, and 4) determine if this immunization is protective against a lethal enteric infection with Salmonella bacteria. This investigation should provide novel insights into how adjuvants regulate immunity at the mucosa and allow us to guide the response in favor of pathogen elimination.