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

项目总结 疼痛是与关节病相关的关键症状，即使对关节病变进行最佳控制，疼痛仍可持续 疾病改良型抗风湿药物(DMARDS)引起的炎症。止痛药和皮质类固醇是 通常用于补充DMARDS以短期缓解疼痛，但缺乏疾病修改特性和它们的 持续使用会带来不利风险。对能够实现持久控制的代理商的需求尚未得到满足 疼痛。虽然潜在的机制很复杂，但免疫细胞可以影响致敏和/或 支配关节结构并影响疼痛进程的感觉神经元的激活。的目标是 这一应用是为了测试利用免疫调节控制疼痛的可行性。该项目与以下方面有关 父母拨款，旨在验证关节内(IA)给药的新策略 免疫调节剂可通过促进自身免疫性关节炎的疾病缓解 增强疾病保护性调节性T细胞(Treg)。这项补充资料将扩大 父母拨款的现有目标，并将研究关节炎的T细胞-痛轴。目标1将评估时间 T细胞驱动的关节炎SKG小鼠模型的疼痛行为特征及相关药理学研究 对药物的反应性包括疼痛评估和组织病理学评估。AIM 2将使用SKG 系统地评估Treg稳定性在缓解疼痛中的作用。目标3将 比较Treg增强剂和标准护理对SKG小鼠疼痛进展的影响 免疫抑制DMARD。总体而言，这些研究将推进我们产生支持证据的目标 疼痛的T细胞集中免疫机制以及组织损伤和疼痛之间的双向相互作用 机械装置。

PROJECT SUMMARY Pain is a key symptom associated with joint arthropathies and can persist despite optimal control of inflammation by disease modifying anti-rheumatic drugs (DMARDs). Analgesic agents and corticosteroids are often used to supplement DMARDs for short-term pain relief but lack disease modifying properties and their sustained use carries adverse risks. There is an unmet need for agents that can achieve durable control of pain. While the underlying mechanisms are complex, immune cells can affect the sensitization and/or activation of sensory neurons that innervate joint structures and influence pain progression. The objective of this application is to test the feasibility of leveraging immunoregulation for pain control. The project is related to the parent grant, which seeks to validate a new strategy of intra-articular (IA) drug delivery of an immunomodulatory agent that could promote disease remission in autoimmune arthritis through the enhancement of disease-protective regulatory T cells (Treg). This supplement will expand the scope of the existing aims of the parent grant and will study the T cell-pain axis in arthritis. Aim 1 will evaluate the temporal profile of pain behaviors in the SKG mouse model of T cell driven arthritis and correlate pharmacologic responsiveness to the agent with pain assessments and histopathological evaluations. Aim 2 will use SKG Treg fate mapping mice to systematically assess the role of Treg stability in pain alleviation. Aim 3 will compare pain progression in SKG mice between the Treg enhancing agent and a standard-of-care immunosuppressive DMARD. Overall, these studies will advance our goal of generating supporting evidence for T cell-focused immune mechanisms of pain and bidirectional interaction between tissue damage and pain mechanisms.