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

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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.