Antigen and nonantigen driven TCR repertoires in arthritis

该项目的一个总体目标是描述在初步试验中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，将在类风湿性关节炎中启动平行研究，作为第二个总体目标。第一个目标是验证这种库分析方法，以深入了解治疗干预的机制和疗效，并推进对驱动疾病的认知免疫识别事件的了解。该项目基于以下初步观察：未治疗的银屑病关节炎中的绝大多数滑膜T细胞由明显非抗原驱动的单序列克隆组成，其余部分含有寡克隆扩增的和脓毒自身抗原驱动的CD 4和CD 8谱系克隆。甲氨蝶呤后，未发炎的滑膜，在鲜明的对比，表现出深刻的减少，这种多克隆组分和显着的扩增克隆相同的序列中发现的一个小功能，在活动性滑膜炎样品从相同的关节。因此，我们假设甲氨蝶呤是一个例子的代理，以减少非抗原特异性多克隆募集的基础临床滑膜炎，但不显着影响自身反应性T细胞的克隆扩增参与的基本免疫识别事件驱动银屑病关节炎。拟议的实验利用的潜力，以确定是否新的治疗剂影响的推定的抗原特异性寡克隆或非抗原特异性多克隆组分的滑膜炎，或两者兼而有之。将继续进行甲氨蝶呤研究，沿着探索用似乎能使活化的TH 1细胞无反应的新型CD 3 Mab、sTNFR：Fc竞争性抑制剂Embrel和潜在的CD 40 L Mab治疗另一组患者的初步研究。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起着重要作用，CXCR 4阻断剂的设想未来试验初步勾勒出一个概念的例子，该概念是从对培养的类风湿性关节炎滑膜细胞的独特表型的基本基因发现作用中发展出来的。在第二个目标中，提出了额外的拟议研究，以增加关于令人惊讶的CD 4克隆扩增的性质的信息，这些克隆扩增在甲氨蝶呤给药后变得更加明显，并开始了解它们在银屑病关节炎中的作用。据推测，它们说明了“三细胞相互作用”的一个实例，涉及在与树突状细胞相互作用的同源调节辅助细胞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.