A novel role for Reelin therapeutics in rheumatoid arthritis

摘要 软骨和骨骼的慢性炎症病理是损伤的主要来源 类风湿关节炎(RA)滑膜关节的观察。尽管这些疾病的确切病因 疾病通常是未知的，过度的白细胞外渗是导致 组织损伤/炎症和我们最近的数据显示血浆蛋白的显著作用， 在这一过程中发挥重要作用。此外，我们现在已经证明，使用反卷缩技术是可能的 单抗，以耗尽Reelin的血浆，从而导致显著减少 多种血管黏附分子的表达。因此，与当前的 耗尽单个黏附分子或免疫受体的方法，我们的抗卷曲 Approach系统地下调所有主要的炎症驱动的黏附蛋白 血管内皮细胞。本提案的目的是展示Reelin在RA中的作用 通过1)鉴定高亲和力Reelin抗体和2)验证 使用抗Reelin抗体减轻RA小鼠模型中的慢性炎症环境。

Abstract Chronic inflammatory pathology of cartilage and bone represents a major source of damage to the synovial joints observed in rheumatoid arthritis (RA). Although the precise etiology of these diseases is often unknown, excessive leukocyte extravasation is a substantial contributor to the tissue damage/inflammation and our recent data show a prominent role of the plasma protein, Reelin in this process. Furthermore, we have now shown that it is possible, using anti-Reelin monoclonal antibodies, to deplete the plasma of Reelin, which results in a significant reduction of a wide range of vascular adhesion molecule expression. Thus, in contrast to the current methods of depleting individual adhesion molecules or immune receptors, our anti-Reelin approach systematically downregulates all major inflammation-driven adhesion proteins on the vascular endothelium. The purpose of this proposal is to demonstrate the role of Reelin in RA by 1) identifying high affinity Reelin antibodies and 2) validating the therapeutic potential of mitigating chronic inflammatory milieu with an anti-Reelin antibody in an RA mouse model.