IL-4 and IL-13 gene therapy for arthritis

IL-4 和 IL-13 基因疗法治疗关节炎

• 批准号: 6805525
• 负责人: ALISA E KOCH
• 金额: $ 26.45万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805525
• 关键词: angiogenesis; biological signal transduction; bone; cartilage; chemokine; chemokine receptor; clinical research; enzyme linked immunosorbent assay; gene therapy; human therapy evaluation; immunocytochemistry; inflammation; interleukin 13; interleukin 4; laboratory mouse; laboratory rat; monocyte; nonhuman therapy evaluation; receptor expression; rheumatoid arthritis; synovial fluid; transfection /expression vector; western blottings

Rheumatoid arthritis (RA) is a chronic debilitating disease of the joints characterized by synovial proinflammatory cytokines, bony destruction and angiogenesis. In the ongoing project, we have presented evidence that the "anti-inflammatory"cytokines interleukin (IL)-4 or IL-13 are effective therapeutics when administered via an adenoviral vector approach in 1) rat adjuvant-induced arthritis (AIA), a model for RA and 2) human RA synovial tissue (ST) explant cultures. In rat AIA, these cytokines resulted in a lesser degree of arthritis, decreased synovial proinflammatory monokines, and decreased numbers of ST blood vessels. Similarly, in the RA ST explant model, IL-4 or IL-13 treatment resulted in decreased proinflammatory cytokine production. In the current proposal, we plan to build on our initial observations. Specifically, we will examine whether IL-4 or IL-13 result in decreased 1) angiogenesis, 2) chemokine and chemokine receptor expression, and 3) decreased markers of bone and cartilage destruction in rat AIA. To begin to discern the mechanisms by which IL-4 and IL-13 act, we will define the cellular signaling pathways through which IL-4 and IL-13 mediate their effects on rat AIA joints and on human monocytes and RA synovial fluid monocytes. To further examine the relevance of these cytokines in human systems, we will use RA ST explants to determine whether virally delivered IL-4 or IL-13 inhibit RA ST angiogenesis, chemokine receptor expression, and markers of cartilage and bone destruction. Finally, we will use an RA ST-severe combined mmunodeficiency (SCID) chimera to determine the effects of virally delivered IL-4 or IL-13 on RA ST inflammation and angiogenesis. Cytokine modulation for RA was a mere hope a few years ago. Currently it is a reality for patient care. The experiments proposed in this study should indicate the feasibility of IL-4 and IL-13 as new therapeutics for RA and explore the mechanisms by which they act in RA.

类风湿性关节炎（RA）是一种慢性关节衰弱性疾病，其特征是滑膜炎症 促炎细胞因子、骨破坏和血管生成。在正在进行的项目中，我们提出了证据，表明“抗炎”细胞因子白细胞介素 (IL)-4 或 IL-13 通过腺病毒载体方法在 1) 大鼠佐剂诱导的关节炎 (AIA)（RA 模型）和 2) 人 RA 滑膜组织 (ST) 外植体培养物中给药时是有效的治疗方法。在大鼠 AIA 中，这些细胞因子导致关节炎程度减轻、滑膜促炎单核因子减少以及 ST 血管数量减少。同样，在 RA ST 外植体模型中，IL-4 或 IL-13 治疗导致促炎细胞因子的产生减少。 在当前的提案中，我们计划以我们的初步观察为基础。具体来说，我们将检查 IL-4 或 IL-13 是否会导致大鼠 AIA 中 1) 血管生成、2) 趋化因子和趋化因子受体表达以及 3) 骨和软骨破坏标志物减少。为了开始了解 IL-4 和 IL-13 的作用机制，我们将定义 IL-4 和 IL-13 介导其对大鼠 AIA 关节、人类单核细胞和 RA 滑液单核细胞的影响的细胞信号传导途径。为了进一步检查这些细胞因子在人体系统中的相关性，我们将使用 RA ST 外植体来确定病毒递送的 IL-4 或 IL-13 是否抑制 RA ST 血管生成、趋化因子受体表达以及软骨和骨破坏标志物。最后，我们将使用 RA ST 严重联合免疫缺陷 (SCID) 嵌合体来确定病毒递送的 IL-4 或 IL-13 对 RA ST 炎症和血管生成的影响。几年前，细胞因子调节 RA 还只是一个希望。目前，这已成为患者护理的现实。本研究提出的实验应表明 IL-4 和 IL-13 作为 RA 新疗法的可行性，并探索它们在 RA 中的作用机制。