DEPLETION OF AUTOREACTIVE/T CELLS IN MULTIPLE SCLEROSIS

多发性硬化症中自身反应性/T 细胞的消耗

基本信息

批准号：
2750964
负责人：
JINGWU Z ZHANG
金额：
$ 19.01万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-30 至 2001-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (Adapted from Investigator's abstract): Myelin basic protein (MBP)-specific T-cells may play an important role in the pathogenesis of multiple sclerosis (MS). Vaccination with irradiated autologous MBP-reactive T-cells (T-cell vaccination) induces cytolytic anti-clonotypic T-cells that specifically recognize and lyse the immunizing T-cells, resulting in selective depletion of circulating MBP-reactive T-cells in patients with MS. The current application is designed to elucidate molecular mechanisms underlying T-cell vaccination and clonotypic regulation of MBP-reactive T-cells in MS. There are three specific aims: (1) to generate and characterize anti-clonotypic T-cells that are induced by T-cell vaccination and specifically regulate MBP reactive T-cells in MS. Selection of DR2 restricted 84-102 specific T-cells for vaccination is based on potential structural similarities in their T-cell receptors (TCR) and their representative value for a large proportion of the MS population, (2) to locate and identify the target TCR regions and common sequence motifs recognized by anti-clonotypic T-cells and (3) to design MHC class I bound TCR peptides and evaluate their specificities and efficiency in eliciting cytolytic anti-clonotypic T-cells in DR2 MS patients. The purpose of this study is to improve and simplify the current T-cell vaccination protocol using a peptide-based vaccination approach. A large panel of cytolytic anti-clonotypic T-cell lines will be generated from MS patients vaccinated with autologous DR2-restricted T-cell clones specific for the immunodominant MBP peptide (84-102). The resulting anti-clonotypic T-cell lines will be characterized for their recognition pattern(s) towards the immunizing T-cell clones. V or V gene segments of the immunizing T-cell clones will be introduced genetically into autologous B-cells with truncation/deletion to identify and narrow down the TCR region/sequences capable of eliciting the anti-clonotypic T-cell responses. Specific attention will be given to identifying common sequence motifs within the target region(s) in the context of appropriate MHC class I molecule(s). Based on the obtained sequences data, a panel of short peptides will be designed and evaluated for their specificity and efficiency in eliciting cytolytic anti-clonotypic T-cell responses in DR2 MS patients. A MHC class I bound peptide(s) designed to incorporate common sequence motifs characteristic of DR2-restricted 84-102 specific T-cells will have great potential in the treatment of a large proportion of patients with MS.

描述（改编自研究者的摘要）：髓磷脂碱性蛋白 (MBP) 特异性 T 细胞可能在疾病发病机制中发挥重要作用多发性硬化症（MS）。使用经过辐照的自体疫苗接种 MBP 反应性 T 细胞（T 细胞疫苗接种）诱导细胞溶解性抗克隆型特异性识别并裂解免疫 T 细胞的 T 细胞，导致循环 MBP 反应性 T 细胞的选择性耗竭多发性硬化症患者。当前的应用程序旨在阐明 T 细胞疫苗接种和克隆型调控的分子机制 MS 中的 MBP 反应性 T 细胞。具体目标有以下三点：（1）生成并表征由 T 细胞诱导的抗克隆型 T 细胞疫苗接种并特异性调节 MS 中的 MBP 反应性 T 细胞。选择用于疫苗接种的 DR2 限制性 84-102 特异性 T 细胞的数量基于它们的 T 细胞受体 (TCR) 和它们的潜在结构相似性大多数 MS 人群的代表值，(2) 至定位并识别目标 TCR 区域和常见序列基序被抗克隆型 T 细胞识别并 (3) 设计 MHC I 类结合 TCR 肽并评估其诱导的特异性和效率 DR2 MS 患者体内的溶细胞性抗克隆型 T 细胞。这样做的目的研究旨在改进和简化当前的 T 细胞疫苗接种方案使用基于肽的疫苗接种方法。将产生一大组溶细胞性抗克隆型 T 细胞系来自接种自体 DR2 限制性 T 细胞克隆疫苗的多发性硬化症患者对免疫显性 MBP 肽具有特异性 (84-102)。由此产生的抗克隆型 T 细胞系的识别特征将得到表征免疫 T 细胞克隆的模式。 V或V基因片段免疫T细胞克隆将被基因导入自体通过截短/缺失的 B 细胞来识别和缩小 TCR 范围能够引发抗克隆型T细胞反应的区域/序列。将特别注意识别共同序列基序在适当的 MHC I 类背景下的目标区域内分子。根据获得的序列数据，一组短将设计并评估肽的特异性和效率在 DR2 MS 患者中引发溶细胞性抗克隆型 T 细胞反应。设计用于整合常见序列的 MHC I 类结合肽 DR2 限制的 84-102 特异性 T 细胞的基序特征将具有治疗大部分多发性硬化症患者的巨大潜力。