UNIQUE SURFACE STRUCTURES ON SYNOVIAL CELLS

类风湿性关节炎的滑膜炎症和关节破坏是 复杂的过程，涉及浸润性白细胞的激活和 滑膜组织细胞。 申请人的研究计划有 重点研究T细胞表面结构和活化途径 可能与慢性T细胞介导的自身免疫性疾病有关， 特别是类风湿性关节炎。 这些研究使用了一系列 在申请人的实验室中产生的新的单克隆抗体， 已经确定了新的T淋巴细胞表面结构，如CD 60，和新的 或已知结构的功能上感兴趣的表位，例如CD 6、CD 2 CD98 现在已知CD 60在选定的群体上表达， 与自身免疫性病变（如RA滑膜）中的T细胞相互作用， 如在浸润这种病变的主要T细胞亚群上。 的作用 炎症滑膜中细胞间的相互作用和特异性表面 介导这种相互作用的受体正成为更清晰的焦点。 申请人最近已经表明，培养的B型成纤维细胞 滑膜细胞可作为T细胞应答的有效辅助细胞 超抗原和凝集素。 提议在第三个供资周期（第10-14年）进行试验， 将进一步探讨功能的后果和分子基础， 这种滑膜细胞和T细胞的相互作用 这些实验将描绘出 在该系统中重要的粘附和共刺激结构，以及 测量滑膜细胞和T细胞中的细胞因子基因活化。 的 IL-10在塑造T细胞反应模式中可能发挥的作用将 研究，并将研究体内RA滑膜中IL-10的水平。 测定了 其他实验将调查的功能概况 类风湿关节炎中的CD 60 + T细胞和滑膜细胞。 有人提出，CD 60是一种 独特且有价值的功能性T细胞亚群标记物。 的可能性 CD 60的表达也与对以下疾病的不同易感性有关： 将检测细胞凋亡。 最后，一个新的系统，使用RA 将采用SCID小鼠中的滑膜植入来确定是否 CD 60 + T细胞优先选择在滑膜中积聚， 当T淋巴细胞被引入到这样的动物中时， 滑膜外位置。 拟议的实验应该阐明 特定的细胞-细胞相互作用和细胞表面分子在 RA和其他自身免疫性疾病的发病机制。

Synovial inflammation and joint destruction in rheumatoid arthritis are complex processes, involving activation of infiltrating leukocytes and of resident synovial tissue cells. The applicant's research program has focused on the study of T cell surface structures and activation pathways that may be relevant to chronic T cell mediated autoimmune diseases, particularly rheumatoid arthritis. These studies have used a series of novel monoclonal antibodies generated in the applicant's laboratory that have identified new T lymphocyte surface structures such as CD60, and new or functionally interesting epitopes of known structures such as CD6, CD2 and CD98. CD60 is now known to be expressed on selected populations which interact with T cells in autoimmune lesions, such as RA synovium, as well as on the major T cell subset that infiltrates such lesions. The role of cell-cell interactions in inflamed synovium and of the specific surface receptors that mediate such interactions is coming into clearer focus. The applicant has recently shown that cultured type B fibroblastic synoviocytes can function as potent accessory cells for T cell responses to superantigen and lectin. Experiments are proposed for the third funding cycle (years 10-14), that would further probe the functional consequences and molecular basis for this synoviocyte - T cell interaction. Such experiments will delineate the adhesive and co-stimulatory structures important in this system, and measure cytokine gene activation in both synoviocytes and T cells. The possible role of IL-10 in shaping the pattern of the T cell response will be studied, and the levels of IL-10 in RA synovium in vivo will be measured. Other experiments will investigate the functional profile of CD60+ T cells and synoviocytes in RA. It is proposed that CD60 is a unique and valuable functional T cell subset marker. The possibility that expression of CD60 is also associated with differential susceptibility to apoptosis will be examined. Finally, a novel system which uses RA synovial engraftment in SCID mice will be employed to determine whether CD60+ T cells are preferentially selected for accumulation in synovial tissue when T lymphocytes are introduced into such animals in an extrasynovial location. The proposed experiments should shed light on the role of specific cell-cell interactions and cell surface molecules in the pathogenesis of RA and other autoimmune diseases.