Anti-idiotypic immune regulation by T cell vaccination

T细胞疫苗接种的抗独特型免疫调节

基本信息

批准号：
6317146
负责人：
JINGWU Z ZHANG
金额：
$ 33.41万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-15 至 2005-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The anti-idiotypic regulatory network comprised of anti-idiotypic (anti-id) T cells and antibodies is critical in the regulation of autoreactive T cells and B cells, and can be stimulated by immunization with inactivated autoreactive T cells (T cell vaccination). T cell vaccination with irradiated autologous myelin basic protein (MBP)-reactive T cells that are implicated in the pathogenesis of multiple sclerosis (MS) results in depletion of MBP-reactive T cells and correlates with clinical improvement in patients with MS. It has been shown that T cell vaccination induces anti-id T cell and B cell responses in recognition of the variable and hypervariable sequences of the T cell receptor (TCR) expressed by the immunizing MBP-reactive T cells in MS patients. This project is proposed to define the complete distribution pattern of the idiotypic epitopes and to identify the dominant idiotypic epitopes responsible for eliciting anti-id immune responses in T cell vaccination. In particular, the study is designed to evaluate whether TCR (hyper)variable regions most frequently used among MBP-reactive T cells in MS patients contain dominant idiotypic epitopes for anti-idiotypic B cells and T cells and whether TCR peptides incorporating the identified dominant idiotypic epitopes are effective in inhibiting MBP-reactive T cells by up-regulating anti-idiotypic immune responses. The project has three specific aims. Aim 1: Recombinant full-length TCR incorporating the most frequently utilized (hyper)variable regions among MBP-reactive T cells will be made to generate and select anti-idiotypic B cell lines and T cell lines from immunized MS patients. Aim 2: The resulting anti-id antibodies and T cell lines recognizing the full-length TCR will be examined to map the complete idiotypic epitopes and determine whether the (hyper)variable sequences contain the dominant idiotypic epitopes using overlapping TCR peptides. The antibodies and T cell lines will be further characterized for the reactivity to the whole immunizing T cells and the regulatory properties on the immunizing MBP-reactive T cells. Aim 3: The selected TCR peptides will be evaluated in vitro for the ability to stimulate anti-idiotypic B cells and T cells in relationship to their inhibitory effect on MBP-reactive T cells derived from MS patients. The results will help to determine the value of the TCR peptides in therapeutic regulation of MBP-reactive T cells in a subset of MS patients where the T cells express the common TCR sequence features. The long-term goal of the study is to define the mechanism of T cell vaccination and develop a practical peptide-based vaccination approach.

描述（由申请人提供）：抗独特型监管网络由抗独特型（抗独特型）T 细胞和抗体组成，在自身反应性 T 细胞和 B 细胞的调节，并且可以被刺激使用灭活的自身反应性 T 细胞进行免疫（T 细胞疫苗接种）。 T细胞接种经辐照的自体髓磷脂碱性蛋白 (MBP) 反应性 T 疫苗与多发性硬化症 (MS) 发病机制有关的细胞导致 MBP 反应性 T 细胞耗竭，并与临床相关 MS 患者的改善。研究表明，T细胞疫苗接种诱导抗 id T 细胞和 B 细胞反应以识别变量并 T 细胞受体 (TCR) 表达的高变序列对 MS 患者进行 MBP 反应性 T 细胞免疫。该项目旨在定义完整的分布模式独特型表位并鉴定负责的显性独特型表位用于在 T 细胞疫苗接种中引发抗 id 免疫反应。尤其，该研究旨在评估 TCR（高）可变区域是否最 MS 患者中经常使用的 MBP 反应性 T 细胞含有显性的抗独特型 B 细胞和 T 细胞的独特型表位以及 TCR 是否包含已识别的显性独特型表位的肽是有效的通过上调抗独特型免疫抑制 MBP 反应性 T 细胞回应。该项目有三个具体目标。目标 1：重组全长 TCR 包含最常用的（超）可变区域 MBP 反应性 T 细胞将产生并选择抗独特型 B 细胞来自免疫多发性硬化症患者的细胞系和 T 细胞系。目标 2：由此产生的反身份识别将检查识别全长 TCR 的抗体和 T 细胞系绘制完整的独特型表位并确定（超）变量是否序列包含使用重叠 TCR 的显性独特型表位肽。抗体和 T 细胞系将被进一步表征对整个免疫 T 细胞的反应性以及对 T 细胞的调节特性免疫 MBP 反应性 T 细胞。目标 3：选定的 TCR 肽将是体外评估刺激抗独特型 B 细胞和 T 细胞的能力细胞及其对 MBP 反应性 T 细胞的抑制作用源自多发性硬化症患者。结果将有助于确定该项目的价值 TCR 肽在 MBP 反应性 T 细胞亚群中的治疗调节作用 MS 患者的 T 细胞表达常见的 TCR 序列特征。这该研究的长期目标是明确T细胞疫苗接种的机制并开发一种实用的基于肽的疫苗接种方法。