IL 4 AND IL 13 GENE THERAPY FOR ARTHRITIS

风湿性关节炎（RA）滑膜组织（ST）是一种侵袭性组织 充满巨噬细胞、淋巴细胞、成纤维细胞和新形成的 血管 单核细胞/巨噬细胞和成纤维细胞是关键生产者 在很大程度上， 在RA关节中发现的炎症和关节破坏。 为 例如，其他研究人员已经表明，这些巨噬细胞是 促炎细胞因子白细胞介素的重要生产者 单核细胞趋化蛋白-1（MCP-1）和生长相关因子 基因产物Gro-alpha 这些细胞因子协同作用， 炎症，在某些情况下是血管生成（参见Koch等人，科学 1798年，1992年），以及由此产生的共同破坏。 虽然有 许多现有的RA治疗方法，在许多患者中， 过程仍然非常严重，导致关节破坏， 虚弱和畸形。 减少细胞因子的产生可能有助于 治疗疾病的过程。 在这份提案中，申请人将审查 IL-4和IL-13这两种相关的细胞因子 来降低炎症反应。 IL-4是一种 血管生成的有效抑制剂。 此外，IL-4和IL-13具有 已经显示出对动物模型具有良好的有益效果， 关节炎 申请人将决定他们是否可以调整这两个课程 促炎细胞因子的产生和大鼠关节炎 泻药诱导的关节炎模型。 他们将首先优化基因 使用携带lacZ的腺病毒载体的递送系统。 最后他们 将决定携带IL-4或IL-13的腺病毒载体， 减轻RA ST-重度患者中的RA炎症和细胞因子产生 联合免疫缺陷（SCID）小鼠嵌合体。 此外，这项工作， 我们希望，这将导致更好地了解的要求， 用其他抗炎基因治疗RA。 申请人 希望使用IL-4或IL-13基因基因治疗将导致 在一个有前途的新疗法类风湿关节炎，这折磨着许多患者， 年

Rheumatoid arthritis (RA) synovial tissue(ST) is an aggressive tissue replete with macrophages, lymphocytes, fibroblasts, and newly formed blood vessels. Monocyte/macrophages and fibroblasts are key producers of a number of cytokines thought to be responsible, in large part, for the inflammation and joint destruction found in the RA joint. For Instance, the investigator others have shown that these macrophages are important producers of the pro-inflammatory cytokines interleukin (IL)-8, monocyte chemo-attractant protein-1 (MCP-1), and growth related gene product gro-alpha. These cytokines act in concert to mediate Inflammation, in some cases angiogenesis (see Koch, et al., Science 1798, 1992), and the resultant joint destruction. While there are a number of existing therapies for RA, in many patients the disease process still is very severe, resulting in joint destruction, debilitation, and deformity. Mitigating cytokine production may help treat the disease process. In this proposal the applicants will examine the potential of two related antiinflammatory cytokines, IL-4 and IL-13 to downregulate inflammation using a gone therapy approach. IL-4 is a potent inhibitor of angiogenesis as well. Moreover, IL-4 and IL-13 have been shown to have a ben beneficial effect on an animal model of arthritis. The applicants will determine whether they can modulate both the course of pro-inflammatory cytokine production and arthritis in a rat adjuvant-induced arthritis model. They will initially optimize the gene delivery system using adenoviral vectors bearing lacZ. Finally, they will determine whether adenoviral vectors, bearing IL-4 or IL-13, mitigate RA inflammation and cytokine production in an RA ST-severe combined immunodeficient (SCID) mouse chimera. Additionally, this work, it is hoped, will lead to a better understanding of the requirements for gene therapy in RA with other anti-inflammatory genes. The applicants hope that use of gene therapy employing IL-4 or IL-13 genes will result in a promising new therapy for RA, which afflicts many patients each year.