A ROLE FOR INNATE IMMUNITY IN SALIVARY IgA RESPONSES

描述：早期的第一个奖项侧重于阐明基本的 诱导和调节的分子和细胞机制 抗原特异性分泌型伊加（S-IgA）抗体（Ab）应答 表面，重点是唾液腺。早期的研究 产生了重要的结果，表明由以下组成的粘膜内联网 α、β-T细胞、γ δ T细胞和上皮细胞在肿瘤发生中起主要作用。 抗原特异性伊加Ab应答的诱导和调节。因此，鼻 用弱免疫原性蛋白卵清蛋白（OVA）免疫， 非肠毒性突变霍乱毒素（CT）作为粘膜佐剂诱导Th 2型 苦参碱介导的唾液S-IgA Ab应答。有趣的是，伽马射线的耗尽 T细胞导致粘膜伊加应答受损，包括 口水此外，这些发现表明，上皮细胞产生了 重要的细胞因子，即，白细胞介素（IL）-7，其是 α-T细胞的发育和分化。这些结果清楚地表明 淋巴细胞和上皮细胞的相互作用，代表先天的和后天的 免疫，是参与诱导的机制的一部分， 抗原特异性伊加Ab应答。这些发现表明， 免疫系统可能是连接先天性和获得性粘膜免疫关键因素 抗原特异性伊加反应所表现的免疫力。最近的研究 确实显示了防御素或趋化因子如 趋化因子或RANTES与OVA诱导的OVA特异性粘膜伊加Ab应答， 包括与唾液腺相关的那些。此外，最近 通过这项研究发现，这些趋化因子的mRNA是 由肠和唾液γ δ T细胞以及上皮细胞表达。 因此，在这个补助金续期申请的总体假设将是， 先天性粘膜免疫系统在获得性免疫中起着特别重要的作用。 免疫用于诱导和调节唾液腺伊加Ab应答。 为了了解其中的细胞和分子机制 在粘膜伊加应答的先天免疫中，以下具体目的是 提出了具体而言，有计划：1）表征先天免疫， 用T-非依赖性的半抗原-LPS衍生物免疫的小鼠的唾液腺 (TI)抗原; 2）检查先天免疫相关的粘膜抗原的作用。 用于诱导唾液中TI抗原特异性免疫的调节剂 腺; 3）免疫诱导之间的桥接机制， 唾液腺特异性抗原诱导的抗原特异性免疫应答 粘膜佐剂和递送系统; 4）评估γ δ T细胞在 连接先天免疫与获得性免疫的唾液内联网;以及5） 确定先天性γ δ T细胞-CD 4和α T细胞如何与伊加相互作用 在SMG的回应。

DESCRIPTION: The earlier FIRST award focused on elucidation of the underlying molecular and cellular mechanisms for the induction and regulation of antigen-specific secretory IgA (S-IgA) antibody (Ab) responses at mucosal surfaces with emphasis on the salivary glands. The earlier studies have produced important results indicating that a mucosal intranet consisting of alpha,beta-T cells, gammadelta T cells and epithelial cells played major roles in the induction and regulation of antigen-specific IgA Ab responses. Thus, nasal immunization with the weakly immunogenic protein ovalbumin (OVA) and the nonenterotoxic mutant cholera toxin (CT) as mucosal adjuvant induced Th2-type cytokine-mediated salivary S-IgA Ab responses. Interestingly, depletion of gammadelat T cells resulted in impaired mucosal IgA responses including those responses in saliva. Further, these findings showed that epithelial cells produced an important cytokine, i.e., interleukin (IL)-7 which is central to the development and differentiation of alphabeta T cells. These results clearly indicate that lymphocyte- epithelial cell interactions, representing innate and acquired immunity, are part of the mechanisms involved in the induction of antigen-specific IgA Ab responses. These findings suggest that the innate immune system may be a key element in bridging innate with acquired mucosal immunity as manifested by antigen-specific IgA responses. Recent studies have indeed shown that nasal application of defensins, or chemokines such as lymphotactin or RANTES with OVA induced OVA-specific mucosal IgA Ab responses, including those associated with the salivary glands. Further, most recent findings through this grant effort showed that mRNA for these chemokines were expressed by intestinal and salivary gammadelta T cells as well as by epithelial cells. Thus, the overall hypothesis in this grant renewal application will be that the innate mucosal immune system plays an especially important role in acquired immunity for the induction and regulation of salivary gland IgA Ab responses. In order to understand the precise cellular and molecular mechanisms involved in innate immunity for mucosal IgA responses, the following Specific Aims are proposed. Specifically, there are plans to: 1) Characterize innate immunity in salivary glands of mice immunized with a hapten-LPS derivative of T-independent (TI) antigen ; 2)Examine the roles for innate immunity-associated mucosal modulators for the induction of TI-antigen-specific immunity in the salivary gland ; 3) The bridging mechanisms between immunity for the induction of antigen-specific immune responses in salivary glands induced by specific mucosal adjuvants and delivery systems ; 4) Assess the roles of gammadelta T cells in the salivary intranet which bridge innate with acquired immunity ; and 5) Determine how innate gammadelta T cells-CD4 about alphabeta T cells interact for IgA responses in the SMG.