T CELL RECEPTOR REPERTOIRE AND SUPERANTIGENS IN RHEUMATOID ARTHRITIS

类风湿关节炎中的 T 细胞受体库和超抗原

• 批准号: 6275392
• 负责人: Brian L Kotzin
• 金额: $ 3.14万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6275392
• 关键词: T cell receptor; T lymphocyte; clinical research; human subject; pathologic process; rheumatoid arthritis; superantigens; synovial fluid

Considerable evidence indicates that T cells are important in the immunopathogenesis of rheumatoid arthritis. The major goals of our current studies are to characterize the T cell receptors (TCRs) expressed by clonal CD4+ T cell expansions in the synovial fluid of patients with rheumatoid arthritis and to determine whether these clones are also present in paired samples of another joint of the same patient and in the blood. Additional studies will examine whether these clonal expansions and other specifically expanded T cells are present at later time points. Finally, the TCRs expressed by these clonal expansions will be expressed in T cell hybridomas in order to determine the specificity of these T cells for synovial antigens. In the recent funding period, we have analyzed TCR b-chain (TCRB) sequences in two joints and blood of an additional four patients. Despite marked heterogeneity of the synovial T cell receptor sequences, the results showed that 20-30% of the TCRB sequences found in one joint were also expressed in a second joint but not in peripheral blood T cells of the same individual. Analysis of TCRB complementarity determining region 3 (CDR3) sequences showed the presence of multiple clonal expansions. The same oligoclonal expansions were apparent in both joints of the same patient. A few of the expansions were very large (> 30% of the repertoire within a particular TCRBV subset). Continued analysis of the TCR b-chain and a-chain repertoire showed remarkable homology among clones within an individual patient, strongly suggesting selection by the same synovial antigen. However, we have yet to find the same or highly homologous TCRs among different patients. Together, these studies suggest that a significant proportion of synovial CD4+ T cells have been selected and expanded by conventional antigens in this disease. Hybridomas expressing RA synovial TCRs have been generated, and we are currently screening for responses to candidate synovial antigens and peptides.

大量证据表明，T细胞在免疫系统中是重要的。 类风湿关节炎免疫发病机制 我们的主要目标 目前的研究是表征表达的T细胞受体（TCR）， 通过在关节炎患者的滑液中克隆性CD 4 + T细胞扩增， 类风湿性关节炎，并确定这些克隆是否也 存在于同一患者的另一关节的配对样本中， 血 进一步的研究将检查这些克隆扩增是否 而其它特异性扩增的T细胞在稍后的时间点出现。 最后，这些克隆扩增表达的TCR将被表达， 为了确定这些T细胞的特异性， 滑膜抗原的细胞。 在最近的资助期内，我们 分析了两个关节和血液中的TCR b链（TCRB）序列， 新增4名患者。 尽管滑膜T细胞有明显的异质性， 细胞受体序列，结果表明，20-30%的TCRB 在一个关节中发现的序列也在第二个关节中表达， 在同一个体的外周血T细胞中。 TCRB分析 互补决定区3（CDR 3）序列显示存在 多重克隆扩张的过程 同样的寡克隆扩增， 在同一个病人的两个关节都很明显。 一些资料片是 非常大（在特定的TCRBV亚群中> 30%的库）。 对TCR b链和a链库的持续分析显示， 个体患者内克隆之间的显著同源性， 这表明是由相同的滑膜抗原选择的。 然而，我们还没有 在不同的患者中寻找相同或高度同源的TCR。 总之，这些研究表明，相当大比例的滑膜炎， CD 4 + T细胞已经通过常规抗原选择和扩增， 这种疾病。已经产生了表达RA滑膜TCR的杂交瘤， 我们目前正在筛选对候选人的回应 滑膜 抗原和肽。