Subunit Rotavirus Vaccines and Mucosal Immunity

虽然80%的感染性疾病是在粘膜表面发起的，我们的知识的诱导和调节粘膜免疫的机制和我们的能力，利用粘膜免疫系统，以防止感染或跨粘膜表面是有限的。我们提出了一种新的模型，调节肠道免疫肠道病毒的TH 1和TH 3，但不是TH 2细胞因子。我们提出TGF-β（TH 3）调节抗原特异性伊加应答。本更新补助金申请中提出的研究旨在确定我们模型的有效性。轮状病毒和VLP将用于探测对感染或免疫的应答，以确定诱导保护性肠道免疫应答所需的机制和分子。假设VLP和活轮状病毒通过不同的机制诱导保护性免疫，因为它们诱导不同的IgG亚类和截然不同的伊加反应。进一步假设鼻内给予的VLP可以克服据报道在常见粘膜免疫系统中发生的区室化免疫应答。具体目的是确定病毒和VLP的保护功效的差异如何受到（1）诱导或效应细胞因子应答，（2）B细胞应答或（3）记忆淋巴细胞归巢的差异的调节。将在正常、特异性β-耗竭、β-上调或敲除小鼠中对各种粘膜免疫方案和病毒攻击后诱导的B细胞应答和细胞因子谱进行定量分析。这些基础研究的结果将有助于理解粘膜表面的免疫调节和功能，并可能证实一种新的调节机制。此外，它们将促进轮状病毒和其他肠道病毒的更有效疫苗的设计。从这些基础研究中获得的知识也将有助于开发新的有效疫苗策略，用于感染或侵入粘膜表面的病毒病原体，如HIV。

Although 80% of infectious diseases are initiated at mucosal surfaces, our knowledge of the mechanisms of induction and regulation of mucosal immunity and our ability to exploit the mucosal immune system to prevent infections at or across mucosal surfaces is limited. We have proposed a novel model for regulation of intestinal immunity to enteric viruses by TH1 and TH3, but not TH2 cytokines. We propose that TGF- beta (TH3) regulates the antigen-specific IgA response. Studies proposed in this renewal grant application seek to determine the validity of our model. Rotavirus and VLPs will be used to probe the responses to infection or immunization to define the mechanisms and molecules necessary to induce protective intestinal immune responses. It is hypothesized that VLPs and live rotavirus induce protective immunity by different mechanisms since they induce different IgG subclasses and widely divergent IgA responses. It is further hypothesized that VLPs administered intranasally can overcome the compartmentalized immune responses reported to occur in the common mucosal immune system. The specific aims are to determine how differences in protective efficacy of virus and VLPs are regulated by differences in (1) inductive or effector cytokine responses, (2) B cell responses, or (3) homing of memory lymphocytes. Quantitative analysis of the B cell responses and cytokine profiles induced following a variety of mucosal immunization protocols and virus challenge will be performed in normal, specifically-- depleted, -upregulated or knockout mice. The results from these basic studies will be relevant to understanding immune regulation and functions at mucosal surfaces and may confirm a novel regulatory mechanism. Further, they will facilitate the design of more effective vaccines for rotavirus and other enteric viruses. The knowledge gained from these basic studies also will be useful in development of new effective vaccine strategies for viral pathogens such as HIV that infect at or invade across mucosal surfaces.