PATHOGENIC AND REGULATORY AUTOIMMUNE T CELL REPERTOIRES

致病性和调节性自身免疫 T 细胞库

• 批准号: 6511557
• 负责人: ELI E SERCARZ
• 金额: $ 31.5万
• 依托单位: TORREY PINES INST FOR MOLECULAR STUDIES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6511557
• 关键词: T cell receptor; T lymphocyte; autoantigens; autoimmunity; cyclophosphamide; disease /disorder model; experimental allergic encephalomyelitis; glutamate decarboxylase; immunoregulation; insulin dependent diabetes mellitus; laboratory mouse; multiple sclerosis

DESCRIPTION: (Adapted from the Investigator's abstract): Evidence now suggests that autoimmune T cells specific to self-determinants use a set of widely shared TcR receptors. This "public" repertoire to self-Ag, as defined by its TcRs, can be targeted for regulation by CD4+ and CD8+ T cells (TREG), which recognize processed TcR from the pathogenic effector T cells (TEFF). Here, the pathogenic and regulatory T cells will be identified and expanded, respectively, in models of multiple sclerosis (relapsing-EAE, an induced model in the SJL mouse), and Type I diabetes (a spontaneous model in the NOD). Public repertoires to candidate autoantigenic determinants and potential regulatory determinants will be defined by TcR CDR3 length spectratyping, also known as "immunoscope" analysis. In conjunction with specific immunization regimens to putative autoantigens, this analysis will define the public TEFF in SJL and NOD mice. These studies will permit the synthesis of potential regulatory peptides, scTcR, and DNA vaccines designed to elicit an anti-TEFF response. In relapsing EAE, a sequential pattern of response and remission to a succession of well-defined pathogenic determinants will aid in the identification of the public clonotypes. The NOR mouse, of identical MHC but resistant to diabetes, and its F1 with NOD, will be used to elucidate pathogenic (and regulatory) populations by employing cyclophosphamide to neutralize the regulation in the NOR and R1. Various approaches to enhance the appearance of regulatory T cells will be used. In total, these studies will demonstrate whether therapeutic induction of TREG with specificity for the processed TcRs of a public repertoire of TEFF can prevent disease, and if such processes are a natural part of effective immune regulation.

描述：(改编自调查人员摘要)：现在有证据表明 针对自我决定因素的自身免疫T细胞使用一组广泛的 共享TCR受体。根据其定义，这是Self-Ag的“公共”曲目 TCRs可被CD4+和CD8+T细胞(Treg)靶向调节 从致病效应T细胞(TEFF)中识别处理过的TCR。在这里， 致病和调节性T细胞将被识别和扩增， 分别在多发性硬化症模型(复发-EAE，一种诱导模型 SJL小鼠)和I型糖尿病(自发的NOD模型)。公众 候选自身抗原决定簇和潜在的调控 决定因素将由TCR CDR3长度谱型定义，也称为 “免疫镜”分析。与特定的免疫方案相结合 推测为自身抗原，这一分析将确定SJL和NOD中的公共Teff 老鼠。这些研究将允许合成潜在的调节肽， ScTcR和DNA疫苗，旨在引起抗画眉鸟反应。故态复萌 EAE，一种连续的反应和缓解的顺序模式 明确定义的致病决定因素将有助于识别 公共克隆类型。NOR小鼠，具有相同的MHC，但对糖尿病具有抵抗力， 以及它的F1与NOD，将用于阐明致病(和调节) 通过使用环磷酰胺中和调节 NOR和R1。增强调节性T细胞外观的各种方法 将会被使用。总之，这些研究将证明是否具有治疗作用 对公众加工的TCRs具有特异性的Treg诱导 如果这样的过程是自然的，那么羽毛可以预防疾病。 有效免疫调节的一部分。