IL 4 AND IL 13 GENE THERAPY FOR ARTHRITIS

类风湿关节炎(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/巨噬细胞和成纤维细胞是关键的产生细胞 一些细胞因子被认为在很大程度上是导致 在RA关节中发现的炎症和关节破坏。为 例如，研究人员其他人已经证明这些巨噬细胞是 促炎细胞因子白细胞介素2的重要产生者 (IL)-8、单核细胞趋化蛋白-1(MCP-1)与生长相关 基因产物GRO-α。这些细胞因子协同起到调节作用 炎症，在某些情况下是血管生成(见Koch等人的《科学》 1798年、1992年)，以及由此产生的联合破坏。虽然有一个 RA的现有治疗方法的数量，在许多患者中 过程仍然很严重，导致了联合破坏， 虚弱和畸形。减少细胞因子的产生可能会有所帮助 治疗疾病的过程。在这份提案中，申请者将审查 两种相关抗炎细胞因子IL-4和IL-13的潜在作用 使用一种不再使用的治疗方法来下调炎症。IL-4是一种 对血管生成也有很强的抑制作用。此外，IL-4和IL-13具有 在一种动物模型上显示出对本有益的影响 关节炎。 申请者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与大鼠关节炎的关系 佐剂性关节炎模型。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 将确定携带IL-4或IL-13的腺病毒载体， 减轻RA ST-重型患者的RA炎症和细胞因子的产生 联合免疫缺陷(SCID)鼠嵌合体。另外，这项工作， 希望这将有助于更好地理解以下方面的要求 其他抗炎基因联合基因治疗类风湿关节炎。申请者 希望使用IL-4或IL-13基因的基因治疗将会取得成果 在一种很有希望的治疗类风湿性关节炎的新疗法中，每个人都会困扰许多患者 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.