Ocular 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膜免疫系统(OMIS)。小眼是保护眼睛免受感染的免疫屏障。这将在一个实验性的兔子模型中完成，该模型的眼睛解剖结构、免疫组织学和对HSV感染的免疫反应与人类相似。 我们以前的工作表明，对HSV-1的眼粘膜保护是由局部粘膜介导的，而不是HSV糖蛋白D(GD)和强佐剂的全身免疫。在该模型中，粘膜保护是由于细胞免疫，而不是分泌型(SLGA)或血清(Ig G)抗体。利用最新发展的技术，保护性免疫原性HSV-1 gD表位将被用于研究眼粘膜免疫和保护的机制。这些测试多肽，配方新颖，“安全”，高效的粘膜佐剂，将局部给药到眼睛，以诱导最大的局部OMIS免疫。本研究将在以下特定目标下进行：目的1.验证已发现的可刺激小鼠粘膜免疫系统的HSV-1 gD多肽表位也将刺激兔OMI并保护眼睛免受HSV攻击的假设；目的2--测试局部眼部注射已确定的保护性最好的Gd多肽将激活OMIS中Th1免疫反应的假设。目的3A-验证鼻腔相关淋巴组织(NALT)免疫对于OMIS反应和眼睛保护至关重要的假设，并调查局部注射AIM 1中确定的GD多肽后OMIS是否是常见粘膜免疫系统的一部分；以及目标3B-使用我们的测试抗原和分离的NALT实验系统，我们将验证NALT对于诱导OMIS耐受是必需的假设，反之，OMIS是否参与NALT耐受。 这项研究将为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。它将测试抗原呈递和粘膜佐剂方面的新技术、新方法，这些可能是开发有效的眼睛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机制”。

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".