# Immune modulating therapies to treat complex regional pain syndrome

> **NIH NIH RF1** · DREXEL UNIVERSITY · 2022 · $2,018,200

## Abstract

Abstract
Complex regional pain syndrome (CRPS) is a chronic pain disorder of unknown etiology that can affect one or
more extremities. Difficulty in treating CRPS stems from incomplete understanding of the underlying
mechanisms. Despite different clinical presentations, clear evidence for altered processing of sensory stimuli
leading to allodynia, hyperalgesia, and hyperaesthesia has been demonstrated in CRPS. Aberrant immune
function is reported to contribute to CRPS pathology. Autoinflammatory and autoimmune mechanisms in the skin
of the affected limb, and systemically in circulation, reportedly contribute to increased pain hypersensitivity.
Systemically, CRPS patients have increased proinflammatory monocytes, and altered circulating memory T cells
(Tcircm). An expansion of long-lived central memory CD8+ and CD4+ T cells with increased proinflammatory
signaling is reported in CRPS patients. However, current studies on Tcircm do not account for local tissue-resident
memory T cells (Trm) which have been implicated in several autoimmune disorders. Cluster of differentiation 69
(CD69) is a type II C-lectin membrane receptor that is rapidly induced upon T cell activation, enabling their
accumulation in nonlymphoid tissues like skin. CD69 antagonizes the cell-surface expression of G-protein–
coupled sphingosine-1-phosphate receptor-1 and 5 (S1PR1/5). By inhibiting the expression of S1PR1/5, CD69
impairs egress and promotes T cell residency. We have identified dysregulation of circulating miRNA signatures
common to both CRPS patients and mouse tibia fracture model (TFM) of CRPS that can regulate Tcircm.
Interestingly several miRNAs, including a miRNA directly associated with positive outcomes for CRPS patients,
can target genes critical to Trm development. This led us to evaluate Tcircm and Trm dysfunction in TFM mice, where
preliminary data demonstrate formation of pathological Trm in TFM mice. We hypothesize that dysregulation of T
cells in CRPS converges on targets crucial for both Tcircm homeostasis and Trm formation. We will test whether
pathological Tcircm and Trm contribute to CRPS pathology, and if therapies that cooperatively target both
populations can serve as a novel therapeutic strategy. By following Tcircm and Trm, we will elucidate mechanisms
of T cell dysfunction and investigate novel immune modulating therapies for treating CRPS.

## Key facts

- **NIH application ID:** 10583271
- **Project number:** 1RF1NS130481-01
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Seena Ajit
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,018,200
- **Award type:** 1
- **Project period:** 2022-09-30 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10583271

## Citation

> US National Institutes of Health, RePORTER application 10583271, Immune modulating therapies to treat complex regional pain syndrome (1RF1NS130481-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10583271. Licensed CC0.

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