Chemokines in pathogenesis of Experimental Arthritis

描述（由申请人提供）：单核细胞趋化蛋白-1（MCP-1/CCL 2）及其高亲和力受体CCR 2在白细胞迁移和炎症反应的产生中起关键作用。MCP-1/CCR 2轴在炎症消退中的作用尚未研究。在三种不同的小鼠关节炎模型中，我发现CC趋化因子受体（CCR）2的遗传失活导致更严重的慢性持续性关节炎。CCR 2的基因失活不仅导致树突状细胞（DC）和单核细胞迁移的实质性破坏，而且CCR 2无效状态的特征在于参与耐受性产生的DC亚型的丧失。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CCR 2无效状态的一部分发生，可能会大大有助于在CCR 2 KO小鼠中观察到的更严重的关节炎表型。因此，在本申请中，我们将集中于梳理CCR 2调节关节炎的潜在机制。为此，我们将提出以下两个具体目的：目的#1将检验CCR 2在实验性关节炎中的调节作用部分地通过其对DC和/或单核细胞巨噬细胞生物学的作用介导的假设。目的#2将检验CCR 2依赖性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。提出的研究是重要的，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，并且它们是相关的，因为它们解决了趋化因子生物学中具有潜在治疗意义的关键领域，即CCR 2和RA发病机制之间的致病联系。这项研究是创新的，因为它利用了最先进的技术，使用MicroSPECT，PET和CT成像的小动物。风湿性关节炎影响1%的美国人口，旨在阻断CCR 2的疗法正在进行II期临床试验。因此，从探索CCR 2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衰弱性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.