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

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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.