REGULATION OF ANTIGEN SPECIFIC SALIVARY IMMUNE RESPONSES

这项资助的一个主要目标是阐明潜在的分子和 诱导和调节抗原特异性 分泌型伊加（S-IgA）免疫反应在粘膜表面，重点 对唾液腺的影响S-IgA抗体的诱导是一个重要的手段 被认为是免疫系统的主要第一道防线 防止病原微生物通过粘膜表面侵入 区由于唾液是一种外部分泌物的突出例子， 含有S-IgA，重要的是要检查免疫机制 对于这种重要的防御因子的诱导和调节， 粘膜相关组织，重点是唾液腺。本 最后，我们的总体假设是，粘膜T细胞互联网存在， γ-δ、α-β T细胞和腺泡/上皮细胞及其 衍生的细胞因子以及细胞与细胞的接触都起着重要的作用 在抗原特异性S-IgA抗体的诱导和调节中 应答因此，这种粘膜T细胞和腺泡/上皮细胞互联网 可能是一个关键因素，桥梁后天免疫和先天免疫， 在粘膜表面形成保护性防御。为了 为了实现我们的主要目标，这项赠款提案包括五个 具体目标。我们的重点将集中在分子和细胞 诱导和调节抗原的机制[例如，卵白蛋白 （0 VA）]特异性伊加合成。因此我们 将使用众所周知的粘膜佐剂霍乱毒素（CT）以诱导 唾液腺中抗原特异性S-IgA反应 应用程序.特别是，基因操作的突变CT将是一个焦点 为了比较Th 1型和Th 2型的调节， 用于诱导抗原特异性粘膜伊加的细胞因子产生， 针对野生型CT的全身性IgE免疫应答。γ-δ T的作用 用于调节粘膜伊加和系统性IgE的细胞也将被 研究了特别是，我们的具体目标分为： 五个组成部分。第一个目的是评估遗传 用于粘膜佐剂活性以诱导抗原特异性S- 唾液和颌下腺（SMG）中的伊加反应;第二个目的是 抗原（OVA）特异性CD 4 + Th 1和Th 2细胞应答的特征 通过用OVA加CT突变体鼻内免疫在SMG中诱导， 粘膜佐剂;第三个目的是测试唾液腺腺泡是否 /上皮细胞和/或γ-δ T细胞可以调节CD 4+，α- 用于表达Th 2-细胞因子的β T细胞（例如，IL-5和IL-6） 抗原特异性伊加B细胞应答;第四个目的是;确定 腺泡间三联体细胞间相互作用的可能机制 /上皮细胞、γ-δ T细胞和CD 4+、α-β T细胞， 细胞因子和细胞表面分子;第五个目的是检查 γ-δ T细胞对调节唾液伊加和 使用TCR δ和TCR β基因破坏小鼠的全身性IgE应答。

A major goal of this grant is to elucidate the underlying molecular and cellular mechanisms for the induction and regulation of antigen-specific secretory IgA (S-IgA) immune responses at mucosal surfaces with emphasis on salivary gland. The induction of S-IgA antibodies is an important arm of the immune system and is considered to be a major first line of defense against invasion of pathogenic microorganisms through the mucosal surface area. Since saliva is a prominent example of an external secretions containing S-IgA, it is important to examine the immunological mechanisms for the induction and regulation of this important defense factors in mucosa-associated tissues, with emphasis on the salivary glands. To this end, our overall hypothesis is that a mucosal T cell internet exists where gamma-delta, alpha-beta T cells and acinar/ epithelial cells and their derived cytokines as well as cell-to-cell contact all play an major role in the induction and regulation of antigen-specific S-IgA antibodies responses. Thus, this mucosal T cell and acinar / epithelial cell internet may be a key element which bridges acquired and innate immunity for the development of a protective defense at mucosal surfaces. For the purpose of accomplishing our major goal, this grant proposal consists of five specific aims. Our emphasis will be focused on the molecular and cellular mechanisms for the induction and regulation of antigen [e.g., ovalbumin (OVA)] -specific IgA synthesis by the mucosal T cell internet. Thus, we will use well known mucosal adjuvant, cholera toxin (CT) in order to induce antigen-specific S-IgA responses in salivary gland for this grant application. Especially, genetically manipulated mutant CT will be a focus of the grant in order to compare the modulation of Th1- and Th2-type cytokine production for the induction of antigen-specific mucosal IgA and systemic IgE immune responses to wild type CT. The role of gamma-delta T cells for the regulation of mucosal IgA and systemic IgE will also be investigated. In particular, our specific aims are divided into the following five components. The first aim is the assess of genetically manipulated CT for mucosal adjuvant activity to induce antigen-specific S- IgA responses in saliva and submandibular gland (SMG) ; the second aim is characterize of antigen (OVA) -specific CD4+ Th1 and Th2 cell responses induced in SMG by intranasal immunization with OVA plus CT mutants as mucosal adjuvants; the third aim is to test whether salivary gland acinar /epithelial cells and / or gamma-delta T cells can regulate CD4+, alpha- beta T cells for the expression of Th2-cytokines (e.g., IL-5 and IL-6) for antigen-specific IgA B cell responses; the fourth aim is to; determine possible mechanism(s) for triad cell-to-cell interactions among acinar /epithelial cells, gamma-delta T cells and CD4+, alpha-beta T cells via cytokine(s) and cell surface molecule(s); the fifth aim is to examine the contribution of gamma-delta T cells for the regulation salivary IgA and systemic IgE responses using TCRdelta and TCRbeta gene disrupted mice.