Role of CCR7 in Clinical Response in Inflammatory Arthritis

描述（由申请人提供）：类风湿关节炎（RA）是一种慢性炎症性疾病，可导致包括巨噬细胞在内的多种细胞介导的关节破坏。虽然治疗取得了巨大的进步，但有效治疗的作用机制却知之甚少。然而，已发表的研究表明，巨噬细胞在滑膜组织中的浸润程度是临床结果的一个强有力的预测指标。此外，治疗前后的滑膜组织活检检查表明，无论治疗方式如何，CD68+巨噬细胞的减少与DAS28的降低密切相关。滑膜组织巨噬细胞在有效治疗后减少的机制尚不清楚。潜在的机制包括单核细胞进入组织的招募减少，细胞死亡增加，如凋亡，或通过淋巴到淋巴结的组织运输增加。了解负责机制对于确定更安全、合理设计、更有效的治疗方法至关重要，特别是对于那些对现有治疗没有充分反应的人。在英夫利昔单抗治疗开始后1、24和48小时检查滑膜组织凋亡的研究

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in joint destruction mediated by a variety of cells including macrophages. While great advances in therapy have been made, the mechanism of action of effective therapy is poorly understood. However, published studies document that the extent of macrophage infiltration in the synovial tissue is a strong predictor of clinical outcome. Further, examination of synovial tissue biopsies before and after therapy, demonstrate that the reduction of sublining CD68+ macrophages strongly correlates with the reduction of the DAS28, regardless of the therapy. The mechanism by which synovial tissue macrophages are reduced following effective therapy is not known. Potential mechanisms include reduced recruitment of monocytes into the tissue, increased cell death, such as apoptosis, or increased trafficking out of the tissue via the lymphatics to the lymph nodes. An understanding of the responsible mechanism is critical to identify safer, rationally designed, more effective therapy, especially fo those who do not respond adequately to currently available therapy. Studies that examined synovial tissue apoptosis 1, 24 and 48 hours after the initiation of therapy with infliximab, which resulted in significant reduction of synovial tissue macrophages, failed to demonstrate apoptosis employing the gold standard, electron microscopy. Further, employing a technique to directly track the migration of circulating monocytes into RA synovial tissue, no reduction of monocyte migration was observed in patients treated with adalimumab, a therapy that results in rapid reduction of synovial tissue macrophages. Together these observations suggest than neither macrophage apoptosis nor reduction of migration of monocytes into the RA joint is responsible for the clinical response to TNF inhibitors, suggesting a potential role for increased egress of macrophages, and possibly other cell types, from the RA joint as an important mechanism of action. Our preliminary data demonstrate that CCR7 is expressed by RA synovial tissue macrophages. Also we have shown recently that the CCR7 ligands CCL19 and CCL21 are expressed in RA synovial tissue. Further, CCR7, CCL19 and 21 are induced by inflammatory mediators including TNFalpha. Studies in mice with atherosclerosis demonstrate that egress of macrophages from diseased aortas is mediated by CCR7. Additionally, CCR7 deficient mice demonstrate more chronic immune complex mediated arthritis, and the synovitis is highly enriched in macrophages. Therefore, we propose to employ a murine model of arthritis to examine the hypothesis that the mechanism of effective therapy is increased macrophage egress from tissue which is mediated by CCR7. This hypothesis will be tested employing two specific aims: (1) Employing human TNF transgenic mice, determine if the response to treatment with inhibitors of TNF or TNF plus IL-1 will be prevented by the neutralization of CCL19 and CCL21. (2) Employing human TNF transgenic mice, determine if the response to inhibition of TNF or TNF plus IL-1 is mediated by CCR7.