Tolerance and autoimmunity in the eye

眼睛的耐受性和自身免疫性

• 批准号: 7009207
• 负责人: Jerold G Woodward
• 金额: $ 32.36万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009207
• 关键词: Tolerance; autoimmunity; eye

DESCRIPTION (provided by applicant): Autoimmune uveitis is a sight threatening autoimmune disease affecting some 20/100,000 people per year. Like other autoimmune diseases, uveitis appears to result form the aberrant activation of T cells toward self antigen present within the eye. How the T cells become activated, and the mechanism of autoimmune tissue destruction is poorly understood. In mice, experimental autoimmune uveitis (EAU) can be induced by immunization with the retinal antigen, interphotoreceptor retinol binding protein (IRBP). This laboratory has optimized the production of human recombinant IRBP, and will use this to probe the nature of the IRBP specific T cells which mediate EAU. One of the fundamental processes in T cell activation is the interaction of the T cell with the antigen presenting cell, yet nothing is known about how this interaction affects EAU in vivo. In the first aim, the role of the antigen presenting cell in the priming and effector function of the IRBP specific T cell will be studied. This will be accomplished through in vivo modulation of APC function and adoptive transfer studies. These experiments will answer important questions regarding how the autoreactive T cell becomes activated, and the nature of the antigen presenting cell within the eye itself which is responsible for T cell effector function. While the transfer of EAU into na?ve mice with IRBP specific T cells has been demonstrated, the nature of the T cell that is capable of inducing disease is not known. In the second aim, a panel of IRBP specific T cell clones will be characterized for a variety of functional properties, as well as their ability to transfer EAU to normal mice. In the third aim, T cell receptor genes from select clones will be isolated and used to produce transgenic mice. These mice will provide a valuable new model system in which to further study the mechanism of EAU. Toward this aim, we will also further develop a transgenic model system in which ovalbumin is expressed in the retina. This will involve the production of new transgenic mice which express a form of ovalbumin which will be retained within the retina, rather than being secreted. Together, these studies will provide important new information as well as produce a new model system resulting in much greater understanding of the mechanisms of autoimmune uveitis.

描述（由申请人提供）：自身免疫性葡萄膜炎是一种威胁自身免疫性疾病，每年影响约20/100,000人。像其他自身免疫性疾病一样，葡萄膜炎似乎会导致T细胞的异常激活朝着眼睛内部的自抗原。 T细胞如何被激活以及自身免疫组织破坏的机制知之甚少。在小鼠中，可以通过视网膜抗原，photoreceptor pectopector视乙醇结合蛋白（IRBP）免疫来诱导实验性自身免疫性葡萄膜炎（EAU）。该实验室已经优化了人类重组IRBP的产生，并将使用它来探测介导EAU的IRBP特异性T细胞的性质。 T细胞激活中的基本过程之一是T细胞与抗原呈现细胞的相互作用，但这种相互作用如何影响体内EAU。在第一个目标中，将研究抗原呈现细胞在IRBP特异性T细胞的启动和效应子功能中的作用。这将通过体内调节APC函数和收养转移研究来实现。这些实验将回答有关自动反应性T细胞如何激活的重要问题，以及眼睛本身中抗原呈现细胞的性质，这是造成T细胞效应功能的原因。尽管已经证明了将EAU转移到具有IRBP特异性T细胞的Na ve小鼠中，但尚不清楚能够诱导疾病的T细胞的性质。在第二个目标中，将对各种功能特性以及将EAU转移到正常小鼠的能力来表征IRBP特异性T细胞克隆。在第三个目标中，将分离出来自精选克隆的T细胞受体基因并用于产生转基因小鼠。这些小鼠将提供一个有价值的新模型系统，以进一步研究EAU的机制。为了实现这一目标，我们还将进一步开发一种转基因模型系统，其中卵蛋白在视网膜中表达。这将涉及新的转基因小鼠的生产，该小鼠表达一种形式的椭圆蛋白，该形式将保留在视网膜内，而不是分泌。这些研究将共同​​提供重要的新信息，并产生一个新的模型系统，从而更了解自身免疫性葡萄膜炎的机制。

项目成果

Reduced T cell-dependent humoral immune response in microsomal prostaglandin E synthase-1 null mice is mediated by nonhematopoietic cells.

• DOI: 10.4049/jimmunol.1301942
• 发表时间: 2013-11-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kojima F;Frolov A;Matnani R;Woodward JG;Crofford LJ
• 通讯作者: Crofford LJ