REGULATION OF ANTIGEN SPECIFIC SALIVARY IMMUNE RESPONSES

抗原特异性唾液免疫反应的调节

• 批准号: 2668269
• 负责人: Kohtaro Fujihashi
• 金额: $ 9.45万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2668269
• 关键词: CD4 molecule; T cell receptor; T lymphocyte; acinar cell; antibody formation; antibody specificity; antigen antibody reaction; antigen presentation; cell cell interaction; cellular immunity; cholera toxin; cytokine; enzyme linked immunosorbent assay; epithelium; flow cytometry; genetic manipulation; immunoglobulin A; immunoglobulin E; laboratory mouse; microorganism immunology; mucosal immunity; polymerase chain reaction; salivary glands; secretory immune system

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.

该赠款的主要目标是阐明基本的分子和 诱导和调节抗原特异性的细胞机制 分泌性IgA（S-IGA）在粘膜表面的免疫反应重点 在唾液腺上。 S-IGA抗体的诱导是重要的手臂 免疫系统的构成，被认为是主要的第一道防线 反对通过粘膜表面入侵致病性微生物 区域。由于唾液是外部分泌的重要例子 包含S-IGA，重要的是检查免疫学机制 为了诱导和调节这种重要的防御因素 粘膜相关组织，重点是唾液腺。对此 最后，我们的总体假设是存在粘膜T细胞互联网 伽玛 - 戴尔塔，α-βT细胞和腺泡/上皮细胞及其 衍生的细胞因子以及细胞对细胞接触都起着重要作用 在抗原特异性S-IGA抗体的诱导和调节中 回答。因此，这种粘膜T细胞和腺泡 /上皮细胞互联网 可能是桥接获得的关键要素 在粘膜表面开发保护性防御。目的 为了实现我们的主要目标，该赠款提案包括五个 具体目标。我们的重点将集中于分子和细胞 抗原诱导和调节的机制[例如，椭圆蛋白 （OVA）] - 粘膜T细胞Internet的特异性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 该赠款的唾液腺中抗原特异性的S-IGA反应 应用。特别是，遗传操纵的突变体CT将成为重点 为了比较Th1-和Th2型的调制 诱导抗原特异性粘膜IgA的细胞因子产生 全身IgE免疫反应对野生型CT。伽玛 - 戴尔塔t的角色 调节粘膜IgA和全身IgE的细胞也将是 调查。特别是，我们的具体目标分为 以下五个组件。第一个目的是对遗传学评估 操纵CT粘膜辅助活性，以诱导抗原特异性S- 唾液和下颌腺（SMG）中的IGA反应；第二个目标是 抗原（OVA）特异性CD4+ Th1和Th2细胞反应的特征 用oVA加上CT突变体在SMG中诱导SMG，作为 粘膜佐剂；第三个目的是测试唾液腺腺泡是否 /上皮细胞和 /或伽马 - 戴尔塔T细胞可以调节CD4+，α- βT细胞表达Th2-循环动物的表达（例如IL-5和IL-6） 抗原特异性IgA B细胞反应；第四个目标是决定 粉刺之间三合会细胞之间相互作用的可能机制 /通过 细胞因子（S）和细胞表面分子；第五个目标是检查 伽马 - 戴尔塔T细胞对调节唾液IgA和 使用TCRDELTA和TCRBETA基因破坏小鼠的全身IgE反应。