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.

类风湿关节炎（RA）是一种以滑膜为特征的关节的慢性衰弱疾病 促炎细胞因子，骨破坏和血管生成。在正在进行的项目中，我们提供了证据表明，当通过腺病毒载体方法中施用1个大鼠佐剂诱导的关节炎（AIA），RA和2）RA和2）RA ra ra nynovial组织（ST）explants cruitter（ST）explistanter（ST）explants clubtanters（ST）换文化的“抗炎”细胞因子白介素（IL）-4或IL-13是有效的治疗剂。在大鼠AIA中，这些细胞因子导致关节炎程度较低，滑膜促炎性单因子降低和ST血管数量减少。同样，在RA ST Explant模型中，IL-4或IL-13治疗导致促炎细胞因子的产生降低。 在当前的提案中，我们计划基于最初的观察。具体而言，我们将检查IL-4或IL-13是否导致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AIA的骨骼和软骨破坏的标记降低。为了开始辨别IL-4和IL-13作用的机制，我们将定义IL-4和IL-13介导其对大鼠AIA关节以及人类单核细胞和RA滑膜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类系统中的相关性，我们将使用RA ST Epplants来确定病毒传递的IL-4或IL-13是否抑制了RA ST血管生成，趋化因子受体表达以及软骨和骨骼破坏的标志物。最后，我们将使用RA ST-Sterevere组合的MMUNODFICITION（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，RA的细胞因子调节仅是希望。目前，这是患者护理的现实。本研究提出的实验应表明IL-4和IL-13作为RA的新疗法的可行性，并探索它们在RA中作用的机制。