Immune Modulation of T Cell Dysfunction in Tibia Fracture Model of Complex Regional Pain Syndrome 2260770

Abstract

Abstract Introduction Complex regional pain syndrome (CRPS) is a debilitating chronic pain disorder with no effective treatments. Increasingly, aberrant immune regulation has been recognized in the induction and maintenance of CRPS pathology. Less is known about the role of T cells in CRPS. More recently, resident memory T cells (Trm), which help define the response of local tissues, have been implicated in autoimmune diseases. We hypothesize that systemic T cell dysfunction in CRPS contributes to pathological Trm development leading to disease development and persistence. Targeting T cell dysfunction by repurposing FDA approved immune modulating therapies may provide a novel treatment strategy for CRPS. Methods Mouse tibia fracture model (TFM) of CRPS was generated and pain hypersensitivity was measured by von Frey and Hargreaves. Hind limb skin, lymph node, bone marrow, and PBMCs were collected at different time points. T cell populations were analyzed by flow cytometry. Drugs targeting T cell dysfunction were evaluated in fracture mice at 5 weeks post-fracture. Nur77-GFP reporter and TCR KO mice were used for measuring activation and pain behavior. RNA-seq and cytokine production assays were performed to assess drug efficacy and functional T cell phenotyping. Results TFM mice demonstrate increased presence of phenotypic Trm populations in the skin compared to control mice. Trm demonstrate increased CD103+ populations. Signaling markers associated with Trm development were upregulated in pathological Trm, which were autoreactive measured by activation in GFP reporter mice. Pharmacological blockade of JAK signaling reduced autoreactive Trm, pain and cytokine signaling. Experiments with TCR KO models and RNA-seq studies are ongoing. Conclusion CRPS currently has no approved therapies. Increases in pathological autoreactive skin Trm populations may provide a novel avenue for therapeutic intervention, where blockade of signaling for Trm development and maintenance could prove beneficial for attenuating pain in CRPS. Funding Source 4RF1NS130481-02 Topic Categories Basic Autoimmunity (BA)