Breedveld F C, Struyk L, van Laar J M, Miltenburg A M, de Vries R R, van den Elsen P J
University Hospital, Department of Rheumatology, Leiden, The Netherlands.
Immunol Rev. 1995 Apr;144:5-16. doi: 10.1111/j.1600-065x.1995.tb00063.x.
TCR repertoire studies in RA have yielded conflicting data. These studies were initiated on the premise that clonal expression of T cells at the site of inflammation could serve as a target for immune therapies designed on the basis of the option to inactivate or eliminate the presumed pathogenic T cells. These analyses have demonstrated the existence of a highly diverse overall TCR repertoire on the basis of extensive usage of TCR V genes both in synovial fluid and tissue. However, clusters of RA patients can be recognized who share increased usage frequencies of defined TCR V genes among synovial fluid or synovial tissue lymphocytes. Subsequent analysis of the CDR3 regions among diverse overall TCR repertoires have revealed the presence of conserved amino acid sequences in the CDR3 regions of the variable portions of TCRs in T lymphocytes derived from the site of inflammation. These findings suggest that a selective, antigen-driven expansion of T lymphocytes is occurring in the inflamed joints. Parallel to the TCR-repertoire studies, we investigated whether vaccines prepared from synovial T cells could modulate T-cell reactivity. The studies were based on previous work on TCV in animals, revealing that attenuated non-specific T-cell lines could serve as a vaccine. The results obtained in 13 RA patients showed no clear indication for a cellular or humoral immune response. Our experience with TCV in RA patients showed that this technique is feasible and safe. We found some evidence for a modulated T-cell reactivity both in vivo and in vitro. These results show at least some immunomodulatory effect af T-cell vaccination, although the antigen specificity of the effect of this intervention remains to be shown. Because of the convincing studies in animals and MS patients, further studies in RA should focus on the effect of vaccination using vaccines prepared from disease-inducing cells. In this respect, determination of the CDR3 regions of synovial T cells could lead to the identification of those T cells that are relevant for the disease.
类风湿关节炎（RA）中的T细胞受体库研究得出了相互矛盾的数据。这些研究基于这样一个前提，即炎症部位T细胞的克隆性表达可作为基于灭活或消除假定致病T细胞选项设计的免疫疗法的靶点。这些分析表明，基于滑膜液和组织中TCR V基因的广泛使用，存在高度多样化的总体T细胞受体库。然而，可以识别出一些类风湿关节炎患者群体，他们在滑膜液或滑膜组织淋巴细胞中共享特定TCR V基因的使用频率增加。随后对不同总体T细胞受体库中的互补决定区3（CDR3）区域进行分析，发现炎症部位来源的T淋巴细胞中TCR可变区CDR3区域存在保守氨基酸序列。这些发现表明，炎症关节中正在发生T淋巴细胞的选择性、抗原驱动的扩增。与T细胞受体库研究并行，我们研究了由滑膜T细胞制备的疫苗是否能调节T细胞反应性。这些研究基于先前在动物中对T细胞疫苗（TCV）的研究，表明减毒的非特异性T细胞系可作为疫苗。在13名类风湿关节炎患者中获得的结果没有显示出明显的细胞或体液免疫反应迹象。我们在类风湿关节炎患者中使用TCV的经验表明，该技术是可行且安全的。我们发现了一些体内和体外T细胞反应性受到调节的证据。这些结果表明，T细胞疫苗接种至少有一些免疫调节作用，尽管这种干预效果的抗原特异性仍有待证明。由于在动物和多发性硬化症（MS）患者中进行的令人信服的研究，类风湿关节炎的进一步研究应集中在使用由致病细胞制备的疫苗进行接种的效果上。在这方面，确定滑膜T细胞的CDR3区域可能会导致识别与疾病相关的那些T细胞。
