Antigen and nonantigen driven TCR repertoires in arthritis

该项目的一个总体目标是在试点试验中描述在接受潜在疾病修饰治疗前后银屑病关节炎滑膜中假定抗原和非抗原驱动的t细胞克隆库的变化。一旦在这方面取得进展，将启动类风湿关节炎的平行研究，作为第二个总体目标。第一个目标是验证这种全库分析方法，以深入了解治疗干预的机制和疗效，并深入了解驱动该疾病的认知免疫识别事件。该项目基于初步观察，即未经治疗的银屑病关节炎中绝大多数滑膜t细胞由明显非抗原驱动的单序列克隆组成，平衡包含寡克隆扩增，推测为自身抗原驱动的CD4和CD8谱系克隆。在服用甲氨蝶呤后，未发炎的滑膜表现出这种多克隆成分的显著减少，并且与来自同一关节的活动性滑膜炎样本中发现的次要特征序列相同的克隆显着扩增。因此，我们假设甲氨蝶呤是一种药物的例子，它可以减少临床滑膜炎基础上的非抗原特异性多克隆募集，但不会显著影响参与驱动银屑病关节炎的基本免疫识别事件的自身反应性t细胞的克隆扩增。提出的实验利用潜力来确定新的治疗药物是否影响滑膜炎的推定抗原特异性寡克隆或非抗原特异性多克隆成分，或两者兼而有之。甲氨蝶呤研究将继续进行，同时还将进行试点研究，探索使用一种新型CD3单抗治疗另一组患者，这种单抗似乎可以使活化的TH1细胞失能，sTNFR:Fc竞争抑制剂Embrel和潜在的CD40L单抗。假设SDF-1在关节自身免疫反应的定位及其随后发展为自身免疫性疾病中发挥重要作用，我们初步概述了CXCR4阻断剂的未来试验，作为一个概念的例子，该概念源于对培养的类风湿关节炎滑膜细胞独特表型的基本基因发现效应。在第二个目标中，提出了额外的拟议研究，以增加关于在甲氨蝶呤给药后更明显的令人惊讶的CD4克隆扩增的性质的信息，并开始了解它们在银屑病关节炎中的作用。假设它们说明了“三细胞相互作用”的一个例子，涉及在同源调节辅助细胞与树突状细胞相互作用的影响下产生效应细胞毒性T淋巴细胞。

One overall goal of this project is to delineate changes in putative antigen and non antigen driven T-cell clonal repertoire in psoriatic arthritis synovia before and after receiving potential disease modifying therapy in pilot trials. Once progress has been made towards this end parallel studies will be initiated in rheumatoid arthritis as the second overall goal. The first objective is to validate this approach of repertoire analysis to gain insight into the mechanism and efficacy of therapeutic interventions and for advancing insight into the cognitive immune recognition events driving the disorder. This project is based on the preliminary observation that the vast majority of synovial T-cells in untreated psoriatic arthritis consists of apparently non antigen driven single sequence clones, with the balance containing oligoclonally expanded, and putatively autoantigen- driven, clones of both CD4 and CD8 lineage. After methotrexate, the uninflammed synovium, in striking contrast, exhibited a profound decrease in this polyclonal component and a marked expansion of clones identical in sequence to those found as a minor feature in the active synovitis sample from the same joint. Accordingly, we hypothesize that methotrexate is an example of an agents that acts to reduce the non antigen-specific polyclonal recruitment that underlies clinical synovitis, but does not significantly affect clonal expansions of autoreactive T-cells involved in the fundamental immune recognition events driving the psoriatic arthritis. The proposed experiments exploit the potential to determine whether novel therapeutic agents affect either the putative antigen specific oligoclonal or the non antigen specific polyclonal component of synovitis, or both. The methotrexate studies will be continued along with pilot studies exploring treatment of an additional group of patients with a novel CD3 Mab that appears to anergize activated TH1 cells, the sTNFR:Fc competitive inhibitor Embrel and, potentially CD40L Mab. With the hypothesis that SDF-1 plays a significant role in the localization of a autoimmune response to the joint and its subsequent development into autoimmune disease, an envisioned future trial of a CXCR4 blocking agent is preliminary sketched as an example of a concept developed out of a fundamental gene discovery effect on the distinctive phenotype of cultured rheumatoid arthritis synoviocytes. In a second objective additional proposed studies are proposed to increase information on the nature of the surprising CD4 clonal expansions that are made more evident upon methotrexate administration and initiate an understanding of their role in psoriatic arthritis. It is hypothesized that they illustrate an instance of the "three cell interaction" involved in the generation of effector cytotoxic T lymphocytes under the influence of a cognate regulatory helper cell interacting with a dendritic cell.