PATHOGENIC AND REGULATORY AUTOIMMUNE T CELL REPERTOIRES

描述：（改编自研究者摘要）：现在有证据表明 自身免疫T细胞特异性自身决定因素使用一组广泛的 共享TcR受体。这种“公共”剧目自我银，如其定义的 TcR可以被靶向用于由CD 4+和CD 8 + T细胞（Treg）调节， 识别来自致病性效应T细胞（TEFF）的加工TcR。这里 将鉴定和扩增致病性和调节性T细胞， 分别在多发性硬化模型（复发-EAE，诱导模型 SJL小鼠）和I型糖尿病（NOD中的自发模型）。公共 候选自身抗原决定簇和潜在的调节因子 决定簇将通过TcR CDR 3长度谱分析来定义，也称为 “免疫镜”分析。与特定的免疫方案结合， 假定的自身抗原，该分析将定义SJL和NOD中的公共TEFF 小鼠这些研究将允许合成潜在的调节肽， scTcR和设计用于引发抗TEFF应答的DNA疫苗。复发性 EAE是一种对一系列EAE的反应和缓解的顺序模式， 明确的致病决定因素将有助于确定 公共克隆型。NOR小鼠具有相同的MHC，但对糖尿病有抵抗力， 及其与NOD的F1，将用于阐明致病性（和调节性） 人群采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 将用于总的来说，这些研究将证明是否治疗 对公众的经加工的TcR具有特异性的TREG的诱导 TEFF的所有功能可以预防疾病，如果这些过程是自然的， 有效的免疫调节。

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.