UNIQUE SURFACE STRUCTURES ON SYNOVIAL CELLS

类风湿关节炎的滑膜炎症和关节破坏 复杂的过程，包括激活浸润性白细胞和 常驻滑膜组织细胞。申请者的研究计划有 重点研究T细胞表面结构和活化途径 这可能与慢性T细胞介导的自身免疫性疾病有关， 尤其是类风湿性关节炎。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抗 发现了新的T淋巴细胞表面结构，如CD60和新的 或功能上感兴趣的已知结构的表位，如CD6、CD2 和CD98。现已知CD60在特定的人群上表达， 与自身免疫性病变中的T细胞相互作用，如RA滑膜 与浸润性病变的主要T细胞亚群一样。的作用 炎症滑膜和特定表面的细胞间相互作用 调节这种相互作用的受体正变得更加清晰。 申请人最近表明，培养的B型成纤维细胞 滑膜细胞可作为T细胞反应的有效辅助细胞 超抗原和凝集素。 建议在第三个供资周期(10-14年)进行试验， 将进一步探讨其功能后果和分子基础 这种滑膜细胞与T细胞的相互作用。这样的实验将描绘出 在这个系统中很重要的粘附性和共刺激结构，以及 检测滑膜细胞和T细胞中细胞因子基因的活性。这个 IL-10在塑造T细胞反应模式中的可能作用将 正在研究中，体内RA滑膜中IL-10的水平将 量过了。其他实验将研究细胞的功能分布。 CD60+T细胞和滑膜细胞在类风湿关节炎中的表达有人认为CD60是一种 独特且有价值的功能T细胞亚群标记物。有没有可能 CD60的表达也与肿瘤的分化易感性有关 将对细胞凋亡进行检测。最后，提出了一种使用RA的新型系统 将利用SCID小鼠的滑膜植入来确定 CD60+T细胞被优先选择在滑膜中积聚 当T淋巴细胞被引入这种动物体内时的组织 滑膜外位置。拟议中的实验应该会揭示 特定的细胞间相互作用和细胞表面分子在细胞周期中的作用 类风湿关节炎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.