REGULATION OF ANTIGEN SPECIFIC SALIVARY IMMUNE RESPONSES

这项拨款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的细胞机制 分泌型免疫球蛋白A(S-免疫球蛋白A)在粘膜表面的免疫应答 在唾液腺上。S抗体的诱导是重要的武器 它被认为是免疫系统的主要第一道防线 对抗病原微生物通过粘膜表面的入侵 区域。因为唾液是一种突出的外部分泌物 含S的免疫球蛋白A，其免疫机制的探讨十分重要 为了诱导和调节这一重要的防御因素 粘膜相关组织，重点是唾液腺。对这件事 最后，我们的总体假设是黏膜T细胞互联网存在于 γ-β、α-βT细胞和腺泡/上皮细胞及其相互作用 衍生的细胞因子以及细胞间的接触都起着重要作用。 抗原特异性S-Ig A抗体的诱导和调节 回应。因此，这种粘膜T细胞和腺泡/上皮细胞互联网 可能是连接获得性免疫和先天免疫的关键因素 粘膜表面保护性防御的发展。为了达到这个目的 为了实现我们的主要目标，这项拨款提案包括五个方面 明确的目标。我们的重点将集中在分子和细胞上 诱导和调节抗原[如卵清蛋白]的机制 (OVA)]-通过粘膜T细胞网络特异性的IgA合成。因此，我们 将使用众所周知的粘膜佐剂霍乱毒素(CT)来诱导 唾液腺中抗原特异性S-免疫球蛋白A应答 申请。特别是，基因操纵的突变CT将是一个焦点 以比较Th1和Th2类型的调制 细胞因子的产生诱导抗原特异性的粘膜免疫球蛋白A和 对野生型CT的系统免疫应答。伽马增量T的作用 用于调节粘膜IgA和系统IgE的细胞也将 调查过了。特别是，我们的具体目标分为 以下是五个组成部分。第一个目标是遗传评估。 操控CT黏膜佐剂活性诱导抗原特异性S- 唾液和颌下腺(SMG)中的IGA反应；第二个目标是 卵清蛋白(OVA)特异性CD4Th1和Th2细胞反应的特征 OVA+CT突变体鼻腔免疫SMG诱导的研究 粘膜佐剂；第三个目的是检测唾液腺腺泡 上皮细胞和/或γ-增量T细胞可以调节CD4、α-T细胞 βT细胞表达Th2细胞因子(如IL-5和IL-6) 抗原特异性的IgA B细胞反应；第四个目标是；确定 三联体细胞与腺泡间相互作用的可能机制(S) /上皮细胞、γ-βT细胞和CD4、α-βT细胞通过 细胞因子(S)和细胞表面分子(S)；第五个目的是检测 γ-Delta T细胞在调节唾液免疫球蛋白A和 使用TCRDelta和TCRbeta基因的系统IgE反应破坏了小鼠。

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.