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.
