Chemokines in pathogenesis of Experimental Arthritis

描述(申请人提供)：单核细胞趋化蛋白-1(MCP-1/CCL2)及其高亲和力受体CCR2在白细胞迁移和炎症反应的产生中起关键作用。MCP-1/CCR2轴在炎症消退中的作用尚不清楚。在三种不同的小鼠关节炎模型中，我已经证明了CC趋化因子受体(CCR)2的遗传失活会导致更严重的慢性持续性关节炎。CCR2的基因失活不仅导致树突状细胞(DC)和单核细胞迁移的严重破坏，而且CCR2缺失状态的特征是与耐受性的产生有关的DC亚型的丢失。我们推测，由于DC和单核细胞在RA和CIA的不同阶段发挥关键作用，这些细胞类型的缺陷作为CCR2缺失状态的一部分，可能在很大程度上导致CCR2 KO小鼠出现更严重的关节炎表型。因此，在本申请中，我们将重点梳理CCR2调节关节炎的潜在机制。为此，我们将解决以下两个具体目标：目标1将测试CCR2在实验性关节炎中的调节作用部分是通过其对DC和/或单核巨噬细胞生物学的影响而介导的假设。目的#2将验证CCR2依赖的细胞过程调节致关节炎抗体沉积和/或清除的动力学的假设。这些研究具有重要意义，因为它们将利用我们在免疫学、趋化因子生物学和小动物成像方面的专业知识来填补RA发病机制中的重要知识空白，而且它们具有相关性，因为它们解决了趋化因子生物学中具有潜在治疗意义的一个关键领域，即CCR2和RA发病机制之间的致病联系。这项拟议的研究具有创新性，因为它利用了最先进的技术，使用了针对小动物的MicroSPECT、PET和CT成像。类风湿性关节炎影响了美国1%的人口，旨在阻断CCR2的疗法正在进行第二阶段的临床试验。因此，从探索CCR2如何调节关节炎的拟议研究中获得的信息将对治疗这种慢性减退疾病的潜在治疗策略产生重大影响。

DESCRIPTION (provided by applicant): Monocyte chemotactic protien-1 (MCP-1/CCL2) and its high affinity receptor CCR2 play a critical role in leukocyte migration and the generation of inflammatory response. The role of MCP-1/CCR2 axis in resolution of inflammation has not been explored. In three different murine models of arthritis I have shown that genetic inactivation of the CC chemokine receptor (CCR)2 leads to a more severe chronic persistent arthritis. Genetic inactivation of CCR2 results not only in substantial disruptions in Dendritic Cells (DC) and monocyte migration, but also, the CCR2 null state is characterized by the loss of a subtype of DCs implicated in the generation of tolerance. We surmised that because DC and monocytes play critical roles in the different phases of RA and CIA, defects in these cell types occurring as part of the CCR2 null state may greatly contribute to the more severe arthritic phenotype seen in CCR2 KO mice. Thus, in this application we will focus on teasing apart the potential mechanisms by which CCR2 modulates arthritis. To do so we will address the following two Specific Aims : Aim #1 will test the hypothesis that the regulatory role of CCR2 in experimental arthritis is mediated in part via its effects on DCs and/or monocyte macrophage biology. Aim #2 will test the hypothesis that CCR2-dependent cellular processes modulate the kinetics of arthritogenic antibodies deposition and /or clearance. The studies proposed are significant because they will capitalize on our expertise in immunology, chemokine biology and small animal imaging to fill important knowledge gaps in RA pathogenesis, and they are relevant because they address a critical area in chemokine biology with potential therapeutic implications, namely the pathogenic link between CCR2 and RA pathogenesis. The proposed research is innovative because it utilizes state-of-the-art techniques using MicroSPECT, PET and CT imaging for small animals. Rheumatoid Arthritis affects 1% of US population, and therapies designed to block CCR2 are in phase II clinical trials. Thus information obtained from proposed studies which explore how CCR2 modulates arthritis will have significant impact on potential therapeutic strategies to treat this chronic deblitating disease.