CD4 T cell responses to viruses: role in autoimmunity

CD4 T 细胞对病毒的反应：在自身免疫中的作用

• 批准号: 6748615
• 负责人: MARK P EGGENA
• 金额: $ 11.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748615
• 关键词: CD28 molecule; CD40 molecule; CD95 molecule; Coxsackievirus; Vesiculovirus; autoantigens; autoimmunity; cellular immunity; disease /disorder model; genetically modified animals; helper T lymphocyte; immune tolerance /unresponsiveness; insulin dependent diabetes mellitus; interleukin 2; laboratory mouse; leukocyte activation /transformation; microorganism immunology; ovalbumin; recombinant virus

DESCRIPTION (provided by applicant): It is clear that infections can lead to dysregulation of the immune system resulting in autoimmune disease; however, the mechanisms behind this process are not well understood. CD4 T cells play integral roles both in orchestrating responses to viral pathogens as well as mediating pathology in autoimmune disease. Pathogenic CD4 anti-self responses are normally prevented by mechanisms of peripheral tolerance. Although much has been learned about the regulatory molecules that contribute to tolerance, relatively little is known about the regulation of CD4 responses to viruses. This proposal focuses on using a reductionist approach to study the roles of regulatory molecules in controlling CD4 responses to viruses while simultaneously maintaining self tolerance when the elicited anti-viral response can be deleterious to the host. The two related components of this project are: 1. ) to define the molecular control of CD4 responses to model viruses, focusing on initiation and regulation, and 2.) to examine the interplay between viruses, self-antigens, and T cell regulatory pathways in the development of autoimmunity. An autoimmune diabetes model will be used in which the infecting virus, the host response, and the presence or absence of cross-reactive self antigen can be independently controlled. This will be accomplished by expressing a defined antigen, ovalbumin (OVA), in viruses, as well as pancreatic islets, to study how pathogens can trigger OVA-targeted diabetes in recipients of OVA-specific normal T cells or T cells that lack specific control mechanisms. By engineering viruses that have differing properties with respect to persistence of infection, presence of self-antigen, and ability to elicit organ-specific inflammation, insight will be gained into the contributions of molecular mimicry and bystander activation in breaking tolerance. Understanding the role of these mechanisms, as well as the contribution of regulatory molecules, in the breakdown of tolerance has important implications for both treating and preventing autoimmune disease. Basic knowledge of CD4 responses to viruses may aid in vaccine development, drug design and a better understanding of infectious complications of immunosuppression that accompanies organ transplantation.

描述（由申请人提供）：很明显，感染会导致免疫系统失调，从而导致自身免疫性疾病；然而，这一过程背后的机制尚不清楚。 CD4 T 细胞在协调对病毒病原体的反应以及介导自身免疫性疾病的病理学方面发挥着不可或缺的作用。致病性 CD4 抗自身反应通常可以通过外周耐受机制来预防。尽管人们对有助于耐受的调节分子了解很多，但对 CD4 对病毒反应的调节知之甚少。该提案的重点是使用还原论方法来研究调节分子在控制 CD4 对病毒的反应中的作用，同时在引发的抗病毒反应可能对宿主有害时保持自我耐受。该项目的两个相关组成部分是：1.) 定义 CD4 对模型病毒反应的分子控制，重点关注启动和调节，2.) 检查病毒、自身抗原和 T 细胞调节途径之间的相互作用在自身免疫的发展中。将使用自身免疫糖尿病模型，其中可以独立控制感染病毒、宿主反应以及交叉反应性自身抗原的存在或不存在。这将通过在病毒和胰岛中表达确定的抗原卵清蛋白 (OVA) 来实现，以研究病原体如何在 OVA 特异性正常 T 细胞或缺乏特定控制的 T 细胞的接受者中引发 OVA 靶向糖尿病机制。通过设计在感染持续性、自身抗原的存在以及引发器官特异性炎症的能力方面具有不同特性的病毒，我们将深入了解分子拟态和旁观者激活在打破耐受性方面的贡献。了解这些机制的作用以及调节分子在耐受性破坏中的贡献对于治疗和预防自身免疫性疾病具有重要意义。 CD4 对病毒反应的基本知识可能有助于疫苗开发、药物设计以及更好地了解器官移植伴随的免疫抑制感染并发症。