Ocular Mucosal Immunity

眼粘膜免疫

• 批准号: 6931033
• 负责人: ANTHONY BART NESBURN
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931033
• 关键词: cellular immunity; disease /disorder model; drug screening /evaluation; immune response; immune tolerance /unresponsiveness; immunologic substance development /preparation; immunomodulators; laboratory rabbit; model design /development; mucosal immunity; nonhuman therapy evaluation; ocular herpes; secretory immune system; topical drug application; virus antigen

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop a better understanding of the Ocular Mucosal Immune System (OMIS). The OMIS is the immune barrier that protects the eye from infection. This will be done in an experimental rabbit model whose ocular anatomy; immuno-histology and immune response to HSV infection mimics that of man. Our previous work has shown in rabbits mucosal ocular protection against HSV-1 was mediated by local mucosal, but not systemic immunization with HSV glycoprotein D (gD) and strong adjuvant. The mucosal protection in this model is due to cell-mediated immunity rather than secreted (slgA) or serum (IgG) antibodies. Using recently developed technologies, protective immunogenic HSV-1 gD peptide epitopes will be used to investigate the mechanism of ocular mucosal immunity and protection. These test peptides, formulated with novel, "safe" highly effective mucosal adjuvants will be administered topically to the eye to induce maximal local OMIS immunity. This research will be performed in these Specific Aims: Aim 1. Test the hypothesis that HSV-1 gD peptide epitopes found to stimulate the mouse mucosal immune system will also stimulate the rabbit OMIS and protect the eye against HSV challenge; Aim 2 -- Test the hypothesis that topical ocular delivery of the best protective gD peptides identified Aim 1 will activate Th1 immune responses in the OMIS. Aim 3A--Test the hypothesis that Nasal Associated Lymphoid Tissue (NALT) immunization is essential for OMIS responses and ocular protection and investigate whether the OMIS is part of the common mucosal immune system after topical delivery of gD peptides identified in Aim 1; and Aim 3B--Using high doses of our test antigens and the isolated NALT experimental system, we will test the hypothesis that NALT is necessary for induction of OMIS tolerance and, inversely, whether OMIS is involved in NALT tolerance. This research will provide important new information regarding the immunological composition and function of OMIS and explore means of inducing ocular mucosal immune protection and tolerance. It will test new technologies, new approaches in antigen presentation and mucosl adjuvants that could be stepping-stones to developing efficient ocular immunoprotective therapies. This addresses the NEI's Corneal Diseases Program objectives to "Further study of the mechanisms of mucosal immunity".

描述（由申请人提供）：本提案的总体目标是更好地了解眼粘液免疫系统（OMIS）。OMIS是保护眼睛免受感染的免疫屏障。这将在实验兔模型中进行，该模型的眼部解剖学、免疫组织学和对HSV感染的免疫应答模拟人类。 我们以前的工作表明，兔眼粘膜对HSV-1的保护作用是由局部粘膜介导的，而不是由HSV糖蛋白D（gD）和强佐剂的全身免疫介导的。该模型中的粘膜保护是由于细胞介导的免疫而不是分泌的（sIgA）或血清（IgG）抗体。利用最近开发的技术，保护性免疫原性HSV-1 gD肽表位将用于研究眼粘膜免疫和保护的机制。这些测试肽与新型的、“安全的”高效粘膜佐剂一起配制，将被局部施用到眼睛以诱导最大的局部OMIS免疫。这项研究将在这些具体目标中进行：目标1。测试发现刺激小鼠粘膜免疫系统的HSV-1 gD肽表位也将刺激兔OMIS并保护眼睛免受HSV攻击的假设;目的2 -测试局部眼部递送Aim 1鉴定的最佳保护性gD肽将激活OMIS中的Th 1免疫应答的假设。目的3A-检验鼻相关类扁桃体组织（NALT）免疫对于OMIS应答和眼保护是必需的这一假设，并研究在局部递送目的1中鉴定的gD肽后，OMIS是否是常见粘膜免疫系统的一部分;目标3B--使用高剂量的我们的测试抗原和分离的NALT实验系统，我们将检验NALT是诱导OMIS耐受所必需的假设，以及OMIS是否参与NALT耐受。 本研究将为阐明OMIS的免疫学组成和功能提供重要的新信息，并探索诱导眼粘膜免疫保护和耐受的方法。它将测试新技术，抗原呈递和粘膜佐剂的新方法，这可能是开发有效的眼部免疫保护疗法的垫脚石。这解决了NEI的角膜疾病计划的目标，即“进一步研究粘膜免疫的机制”。