Subunit Rotavirus Vaccines and Mucosal Immunity

虽然80%的感染性疾病是由粘膜表面引起的，但我们对粘膜免疫的诱导和调节机制以及利用粘膜免疫系统预防粘膜表面感染的能力了解有限。我们提出了一种通过TH1和Th3而不是TH2细胞因子来调节肠道病毒免疫的新模型。我们认为，转化生长因子-β(Th3)调节抗原特异性的IgA反应。在这项续期拨款申请中提出的研究试图确定我们模型的有效性。轮状病毒和VLP将被用来探测对感染或免疫的反应，以确定诱导保护性肠道免疫反应所需的机制和分子。推测VLP和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Ig G亚类和非常不同的Ig A反应。进一步的假设是，VLP鼻腔给药可以克服已报道的发生在普通粘膜免疫系统中的区域化免疫反应。其具体目的是确定病毒和VLP的保护效力的差异如何受到(1)诱导性或效应性细胞因子反应、(2)B细胞反应或(3)记忆淋巴细胞归巢的差异的调节。定量分析在各种黏膜免疫方案和病毒攻击后诱导的B细胞反应和细胞因子谱，将在正常、特别是耗尽、上调或基因敲除的小鼠中进行。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，它们还将有助于设计更有效的轮状病毒和其他肠道病毒疫苗。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，以应对艾滋病毒等在粘膜表面感染或侵入的病毒病原体。

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.