PATHOGENIC AND REGULATORY AUTOIMMUNE T CELL REPERTOIRES

描述：（改编自研究者的摘要）：现在的证据表明 特定于自我决定因子的自身免疫 T 细胞使用一组广泛的 共有 TcR 受体。这个“公共”曲目是自我Ag，由其定义 TcR 可以作为 CD4 和 CD8 T 细胞 (TREG) 调节的目标， 识别来自致病性效应 T 细胞 (TEFF) 的经过加工的 TcR。在这里， 致病性和调节性 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）中 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监管的库 决定因素将由 TcR CDR3 长度光谱分型定义，也称为 “免疫镜”分析。与特定的免疫方案相结合 假定的自身抗原，该分析将定义 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 疫苗旨在引发抗 TEFF 反应。复发中 EAE，对一系列事件的反应和缓解的顺序模式 明确的致病决定因素将有助于识别 公共克隆型。 NOR 小鼠具有相同的 MHC 但对糖尿病具有抵抗力， 及其 F1 与 NOD，将用于阐明致病性（和调节性） 通过使用环磷酰胺来中和体内的调节 NOR 和 R1。增强调节性 T 细胞外观的多种方法 将被使用。总的来说，这些研究将证明治疗是否有效 针对公共处理的 TcR 特异性诱导 TREG TEFF 的全部功能可以预防疾病，如果这些过程是自然的 有效免疫调节的一部分。

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.