Intra-Articular Drug Delivery Modulating Immune Cells in Inflammatory Joint Disease

项目总结 疾病修饰性抗风湿药物(DMARDS)极大地改善了炎性关节的治疗 但会引起全身性免疫抑制，增加严重感染和癌症的风险。这个 致病性炎症是自身免疫性关节炎的一个标志，在很大程度上可以归因于 调节免疫功能。迫切需要一种能够在不损害人体健康的情况下发挥作用的抗关节炎药物。 免疫系统，这也可以与目前的DMARDS相结合，用于那些努力实现 持久的缓解。为实现这一目标，赠款申请的目的是验证一项新战略 关节内(IA)给药可促进持久疾病缓解的免疫调节剂 在自身免疫性关节炎中不会引起全身性免疫抑制。我们的代理利用已有的 调节性T细胞(Treg)，被广泛认为是自身反应性T细胞的主要抑制因子，促进 具有调理疾病、抗炎的作用。认识到Treg经常没有被充分招募到 发炎的关节，表现出炎症诱导的不稳定和功能丧失的异常水平，我们的方法 实现关节Treg的局部扩张和稳定，减少炎症和全身性 在不引起全身性免疫抑制的情况下对关节炎小鼠受影响的关节进行疾病修改。这里, 我们将验证我们的方法作为炎症性关节炎的治疗选择。在目标1中，我们将优化我们的 使其持久地增强Treg调节炎症的大小和功能。在AIM 2、我们将系统地验证我们的代理的作用机制，并演示对 与疾病相关的Treg，而不抑制非特异性T细胞反应。在目标3中，我们将评估附加语 我们的方法具有广泛使用的一线DMARD来降低小鼠疾病严重性的潜力，显示出 部分DMARD反应性和评估该药在体外增强Treg的有效性 从接受DMARD治疗的关节炎患者中分离出来。总的来说，这些研究将推进我们的长期目标： 发展我们的方法来纠正影响自身免疫疾病的病原性免疫失调 关节和其他组织，因Treg功能不足而产生。

PROJECT SUMMARY Disease modifying anti-rheumatic drugs (DMARDs) have greatly improved the treatment of inflammatory joint disease but cause generalized immunosuppression and increase the risk of serious infections and cancer. The pathogenic inflammation, a hallmark of autoimmune arthritis, can largely be ascribed to a deficiency in regulatory immune function. There is a critical need for anti-arthritic agents that can operate without impairing the immune system, which could also be combined with current DMARDs in patients who struggle to achieve durable remission. Towards this goal, the objective of the grant application is to validate a new strategy of intra-articularly (IA) drug delivery of an immunomodulatory agent that could promote durable disease remission in autoimmune arthritis without causing generalized suppression of immunity. Our agent leverages pre-existing regulatory T cells (Treg), widely recognized as the primary suppressors of autoreactive T cells, to promote a disease modifying anti-inflammatory effect. Recognizing that Treg are often insufficiently recruited to the inflamed joints, display abnormal levels of inflammation-induced instability and loss of function, our approach achieves localized expansion and stabilization of joint Treg and results in reduced inflammation and systemic disease modification in affected joints of arthritic mice without causing generalized immunosuppression. Here, we will validate our approach as a therapeutic option for inflammatory arthritis. In Aim 1 we will optimize our approach such that it durably enhances the magnitude and function of Treg for modulating inflammation. In Aim 2, we will systematically validate the mechanism of action of our agent and demonstrate the enhancement of disease-relevant Treg without suppressing non-specific T cell responses. In Aim 3, we will assess the adjunctive potential of our approach with a widely used first-line DMARD to reduce disease severity in mice that show partial DMARD responsiveness and assess whether the agent is effective in the ex-vivo enhancement of Treg isolated from DMARD-treated arthritis patients. Overall, these studies will advance our long-term goal of developing our approach to correct pathogenic immune dysregulation in autoimmune disorders affecting the joint and other tissues, arising from insufficient Treg function.