Immune Responses To Ocular Antigens

对眼抗原的免疫反应

• 批准号: 7138049
• 负责人: Igal Gery
• 金额: --
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7138049
• 关键词: T cell receptor; T lymphocyte; antigen presentation; autoantigens; autoimmune disorder; cellular immunity; drug screening /evaluation; genetically modified animals; helper T lymphocyte; immune response; immunomodulators; inflammation; interferon inducers; interleukin 1; interleukin 7; laboratory mouse; leukocyte activation /transformation; microorganism toxin; nonsteroidal antiinflammatory agent; oligonucleotides; receptor expression; toll like receptor; uveitis

Targeted at learning about inflammatory eye diseases, this project focused in 2005 on three topics: (1) triggering of pathogenic autoimmune processes by microbial products; (2) active participation of antigen-nonspecific lymphoid cells in immune mediated inflammation; (3) suppression of immune-mediated ocular inflammation by curcumin, a food additive. Topic 1. Microbial products are assumed to play a major role in triggering autoimmune processes responsible for diseases such as multiple sclerosis, rheumatoid arthritis or intraocular conditions grouped under the term ?uveitis?. Little is known, however, about the molecular and cellular mechanisms that are involved in these pathogenic processes. In a study initiated in FY 2004 we set up an experimental system to investigate the capacity of microbe-derived molecules to trigger pathogenic autoimmune processes. In this system, naive lymphocytes specific against hen egg lysozyme (HEL) are adoptively transferred into recipient mice transgenically expressing HEL in their eyes. Ocular inflammation develops in the recipient mice only when the transferred cells become activated, in vivo, and, therefore, the experimental system makes it possible to examine the capacity of agents to trigger pathogenic autoimmunity. The microbial products tested in this study included seven molecules that are known to function as ?Toll-like receptor (TLR)? ligands, namely, molecules that bind to TLRs on antigen presenting cells and stimulate these cells to efficiently activate lymphocytes. Seven microbial products were tested, peptidoglycan, lipoteichoic acid, poly(I:C), that mimics viral RNA, lipopolysaccharide, flagellin, zymosan A, the bacterial oligodeoxynucleotide ?CpG?, and pertussis toxin. Recipient mice treated with any of the seven microbial products developed ocular inflammation, a finding that supports the notion that microbial infection plays a major role in initiating pathogenic autoimmunity. In addition, we found that pertussis toxin surpassed by far the other six tested microbial molecules in triggering severe ocular changes in recipient mice. This observation is currently under further investigation. Topic 2. The pathogenic process of tissue-specific autoimmune disease depends to a large extent on recruitment of antigen-nonspecific cells into the target tissue. Little is known, however, about the recruitment process and the features that characterize the recruited cells. The recruitment of antigen-nonspecific lymphoid cells into an inflammatory site was analyzed by using the experimental system of adoptively transferred ocular inflammation, in which lymphocytes specific against HEL, stimulated in vitro, induced inflammatory changes in eyes of recipient mice expressing HEL in their eyes. The transferred cells were recognized in this system by a specific ?clonotypic? antibody. A sharp increase in number of host lymphoid cells was seen in the spleen of injected recipient mice and many of these cells also exhibited cell surface markers that characterize ?tissue-invading? lymphocytes. The injected donor cells were the first to invade the recipient mouse eyes, but shortly thereafter, host cells also entered the affected eyes and rapidly became the large majority of infiltrating cells. Interestingly, eye infiltrating host cells also resembled donor cells in the affected eye, by acquiring a profile of surface markers that characterizes ?activated? lymphocytes. These results thus show that antigen-nonspecific lymphoid cells are actively involved in the process of immune-mediated inflammation. Topic3. Curcumin, a natural product that is the active component of the food additive turmeric, has been shown to exhibit anti-inflammatory activity. The potential capacity of curcumin in inhibiting immune-mediated ocular inflammation was tested by injecting the compound to mice developing experimental autoimmune uveitis (EAU), an animal model for intra-ocular inflammation. Treatment with curcumin inhibited the development of EAU, as well as the cellular immune response against the retinal antigen that was used for the disease induction. These findings thus suggest that curcumin could be considered in treatment and/or prevention of inflammatory eye disease.

该项目针对学习炎症性眼部疾病，以2005年为重点是三个主题：（1）通过微生物产物触发致病性自身免疫性过程； （2）抗原非特异性淋巴样细胞在免疫介导的炎症中积极参与； （3）食物添加剂姜黄素抑制免疫介导的眼部炎症。 主题1。 假定微生物产物在触发负责疾病的自身免疫过程中起着重要作用，例如多发性硬化症，类风湿关节炎或根据“葡萄膜炎”术语分组的眼内疾病。然而，关于这些致病过程涉及的分子和细胞机制知之甚少。在2004财年发起的一项研究中，我们建立了一个实验系统，以研究微生物衍生分子触发致病自身免疫性过程的能力。在该系统中，针对母鸡溶菌酶（HEL）的天真淋巴细胞被传递到受转基因的HEL的受体小鼠中。只有当转移的细胞在体内激活时，受体小鼠的眼部炎症才会在受体小鼠中出现，因此，实验系统可以检查药物触发致病自身免疫性的能力。这项研究中测试的微生物产物包括七个被称为“ Toll样受体（TLR）”的分子？配体，即在抗原呈递细胞上与TLR结合并刺激这些细胞以有效激活淋巴细胞的分子。测试了七种微生物产物，肽聚糖，脂蛋白酸，poly（i：c），模仿病毒RNA，脂多糖，鞭毛蛋白，Zymosan A，细菌寡脱氧核苷酸？CPG？用七种微生物产物治疗的受体小鼠产生了眼部炎症，这一发现支持微生物感染在启动致病自身免疫中起主要作用的观念。此外，我们发现百日咳毒素超过了其他六个测试的微生物分子在触发受体小鼠的严重眼变化时。目前，该观察结果正在进一步调查中。 主题2。 组织特异性自身免疫性疾病的致病过程在很大程度上取决于将抗原非特异性细胞募集到靶组织中。然而，关于招聘过程和招募细胞表征的特征知之甚少。通过使用采用转移的眼部炎症的实验系统，分析了将抗原非特异性淋巴样细胞募集到炎症部位，其中特异性的淋巴细胞针对HEL，刺激了体外，体外，诱导的，诱导的炎症，引起了表达HEL眼中表达HEL的眼睛的眼睛的炎症变化。在该系统中通过特定的clonotypic识别了转移的细胞？抗体。在注射的受体小鼠的脾脏中看到了宿主淋巴样细胞数量的急剧增加，其中许多细胞还表现出表征对组织影响的细胞表面标记？淋巴细胞。注射的供体细胞是第一个入侵受体小鼠眼睛的细胞，但此后不久，宿主细胞也进入了受影响的眼睛，并迅速成为大多数浸润细胞。有趣的是，通过获取表征表征？激活的表面标记物的特征，眼睛浸润的宿主细胞也类似于受影响的眼睛中的供体细胞？淋巴细胞。因此，这些结果表明，抗原非特异性淋巴样细胞积极参与免疫介导的炎症过程。 主题3。 姜黄素是一种天然产物，是食品添加剂姜黄的活性成分，已显示出具有抗炎活性。通过将化合物注射到产生实验性自身免疫性葡萄膜炎（EAU）的小鼠，这是一种眼内炎症的动物模型，测试了姜黄素在抑制免疫介导的眼部炎症中的潜在能力。姜黄素治疗抑制了EAU的发展，以及用于疾病诱导的视网膜抗原的细胞免疫反应。因此，这些发现表明姜黄素可以在治疗和/或预防炎症性眼病中考虑。