IL-4 and IL-13 gene therapy for arthritis

类风湿关节炎(RA)是一种以滑膜为特征的慢性关节衰弱疾病 促炎细胞因子、骨质破坏和血管生成。在正在进行的项目中，我们提出了证据表明，当通过腺病毒载体方法在1)大鼠佐剂性关节炎(AIA)、RA模型和2)人类RA滑膜组织(ST)外植体培养中给予“抗炎”细胞因子IL-4或IL-13时，它们是有效的治疗药物。在大鼠AIA中，这些细胞因子导致的关节炎程度较轻，滑膜促炎性单因子减少，ST血管数量减少。类似地，在RA ST外植体模型中，IL-4或IL-13处理导致促炎细胞因子的产生减少。在目前的提案中，我们计划在初步观察的基础上再接再厉。具体地说，我们将检验IL-4或IL-13是否导致1)血管生成减少，2)趋化因子和趋化因子受体表达减少，3)骨和软骨破坏的标记物减少。为了开始了解IL-4和IL-13的作用机制，我们将确定IL-4和IL-13介导其对大鼠AIA关节、人单核细胞和RA滑液单核细胞的作用的细胞信号通路。为了进一步研究这些细胞因子在人类系统中的相关性，我们将使用RA ST外植体来确定病毒传递的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的标志。最后，我们将使用RA ST-严重联合免疫缺陷(SCID)嵌合体来确定病毒传递的IL-4或IL-13对RA ST炎症和血管生成的影响。几年前，细胞因子对类风湿关节炎的治疗还只是一个希望。目前，这是一个现实的病人护理。本研究提出的实验应表明IL-4和IL-13作为治疗类风湿关节炎的新疗法的可行性，并探索它们在类风湿关节炎中的作用机制。

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.