Role of CCR7 in Clinical Response in Inflammatory Arthritis

CCR7 在炎症性关节炎临床反应中的作用

• 批准号: 8575034
• 负责人: Richard M. Pope
• 金额: $ 19.7万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8575034
• 关键词: Address; Affect; Antigen-Antibody Complex; Aorta; Apoptosis; Arthritis; Atherosclerosis; B-Lymphocytes; Biological Markers; Biopsy; CCL19 gene; CCL21 gene; CCR1 gene; CCR5 gene; Cartilage; Cell Death; Cell Death Induction; Cells; Chronic; Clinical; Clinical Trials; Data; Dendritic Cells; Disease; Disease-Modifying Second-Line Drugs; Electron Microscopy; Fibroblasts; Gold; Hour; Human; Hyperplasia; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1; Joints; Ligands; Lymphatic; Lymphocyte; Mediating; Methotrexate; Modeling; Mus; Outcome; Pathogenesis; Pathway interactions; Patients; Publishing; Rheumatoid Arthritis; Role; Synovitis; T-Lymphocyte; TNF gene; Techniques; Testing; Tissues; Transgenic Mice; adalimumab; angiogenesis; base; cell type; chemokine; chemokine receptor; design; effective therapy; evidence base; infliximab; inhibitor/antagonist; joint destruction; lymph nodes; macrophage; migration; monocyte; mouse model; novel; novel strategies; prevent; public health relevance; response; rituximab; therapy development; trafficking

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.

描述（由申请人提供）：类风湿性关节炎（RA）是一种慢性炎症性疾病，可能导致由包括巨噬细胞在内的多种细胞介导的关节破坏。尽管治疗已取得巨大进步，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，滑膜组织中巨噬细胞浸润的程度是临床结果的有力预测因子。此外，治疗前后滑膜组织活检的检查表明，无论采用何种治疗，下层 CD68+ 巨噬细胞的减少与 DAS28 的减少密切相关。有效治疗后滑膜组织巨噬细胞减少的机制尚不清楚。潜在的机制包括减少单核细胞招募到组织中、增加细胞死亡（例如细胞凋亡）或增加通过淋巴管从组织运输到淋巴结。了解相关机制对于确定更安全、设计合理、更有效的治疗至关重要，特别是对于那些对当前可用治疗没有充分反应的患者。研究在开始英夫利昔单抗治疗后 1、24 和 48 小时检查滑膜组织细胞凋亡，结果 导致滑膜组织巨噬细胞显着减少，但未能使用金标准电子显微镜证明细胞凋亡。此外，采用直接跟踪循环单核细胞迁移到 RA 滑膜组织的技术，在接受阿达木单抗治疗的患者中没有观察到单核细胞迁移的减少，阿达木单抗是一种导致滑膜组织巨噬细胞快速减少的疗法。总之，这些观察结果表明巨噬细胞凋亡和单核细胞迁移到 RA 关节的减少都不是 TNF 抑制剂的临床反应的原因，这表明巨噬细胞和可能的其他细胞类型从 RA 关节的流出增加作为重要的作用机制具有潜在作用。 我们的初步数据表明 CCR7 由 RA 滑膜组织巨噬细胞表达。我们最近还发现 CCR7 配体 CCL19 和 CCL21 在 RA 滑膜组织中表达。此外，CCR7、CCL19和21由包括TNFα在内的炎症介质诱导。对患有动脉粥样硬化的小鼠进行的研究表明，巨噬细胞从患病主动脉中流出是由 CCR7 介导的。此外，CCR7缺陷小鼠表现出更多的慢性免疫复合物介导的关节炎，并且滑膜炎中巨噬细胞高度丰富。因此，我们建议采用小鼠关节炎模型来检验以下假设：有效治疗的机制是由 CCR7 介导的增加巨噬细胞从组织中的流出。该假设将通过两个具体目标进行测试：（1）使用人 TNF 转基因小鼠，确定对 TNF 或 TNF 加 IL-1 抑制剂治疗的反应是否会因 CCL19 和 CCL21 的中和而被阻止。 (2)采用人TNF转基因小鼠，确定对TNF或TNF加IL-1的抑制的反应是否由CCR7介导。