A ROLE FOR INNATE IMMUNITY IN SALIVARY IgA RESPONSES

描述：早些时候的第一个奖项集中在对潜在的 诱导和调控的分子和细胞机制 粘膜抗原特异性分泌型免疫球蛋白A(S-免疫球蛋白A)抗体反应 表面以唾液腺为重点。早期的研究表明 产生了重要的结果，表明粘膜内部网由 α-T细胞、β-T细胞、Gammadelta T细胞和上皮细胞在 抗原特异性IgA抗体反应的诱导和调节。因此，鼻音 弱免疫原性蛋白卵清蛋白(OVA)和小鼠 非肠毒性突变型霍乱毒素作为黏膜佐剂诱导Th2型 细胞因子介导的唾液S-IgA抗体反应有趣的是，Gammadelat的耗尽 T细胞导致黏膜IgA反应受损，包括 唾液。此外，这些发现表明，上皮细胞产生了一种 重要的细胞因子，即白介素7，它是 α-βT细胞的发育和分化。这些结果清楚地表明 淋巴细胞与上皮细胞的相互作用，代表着先天和后天的 免疫，是参与诱导 抗原特异性的IgA抗体反应。这些发现表明，先天的 免疫系统可能是连接先天和后天粘膜的关键因素 免疫：通过抗原特异性的IgA反应表现出来的免疫。最近的研究表明 确实表明，鼻腔应用防御素或趋化因子，如 淋巴动蛋白或RANTES与OVA联合诱导OVA特异性黏膜IgA抗体反应 包括与唾液腺相关的那些。此外，最新的 通过这项赠款工作的发现表明，这些趋化因子的mRNA是 由肠道和唾液中的Gammadelta T细胞以及上皮细胞表达。 因此，这项拨款续期申请的整体假设是 先天性粘膜免疫系统在获得性疾病中发挥着特别重要的作用 诱导和调节唾液腺IgA抗体反应的免疫。 为了了解所涉及的精确的细胞和分子机制 在针对粘膜免疫球蛋白A反应的先天免疫中，有以下特定目的 建议。具体地说，有计划：1)表征先天免疫力 T非依赖性半抗原-内毒素衍生物免疫小鼠的唾液腺 (Ti)抗原；2)研究先天免疫相关粘膜的作用 唾液中诱导TI抗原特异性免疫的调节剂 腺体；3)免疫之间的桥梁机制诱导 特异性抗体诱导的唾液腺抗原特异性免疫反应 黏膜佐剂和递送系统；4)评估Gammadelta T细胞在 连接先天免疫和后天免疫的唾液内联网；5) 确定先天Gammadelta T细胞-CD4Alphabeta T细胞如何与IgA相互作用 在SMG中的回应。

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.