Targeting Regulatory T Cells to Treat Chronic Migraine and Post-Traumatic Headache
Abstract
This application responds to the FY20 PRMRP Topic Area Chronic Migraine and Post-Traumatic Headache. Our objective is to validate regulatory T (Treg) cell as a novel cellular target for persistent headache and memory deficit in chronic migraine and post-traumatic headache. More than 4 million people suffer from chronic migraine, with at least 15 migraine days every month. Nearly 1.4 million people experience post-traumatic headache resulting from mild traumatic brain injuries every year. The prevalence of chronic migraine and post-traumatic headache is even higher in military personnel and Veterans due to the stress and the traumatic brain injuries they experience in the line of duty. Many Soldiers with mild traumatic brain injury report chronic daily headache as well as other disorders such as cognitive deficits, emotional difficulties, and behavioral disturbances. The debilitating headache and accompanying disorders severely affect the return to active duty or a fully functional civilian life. Despite the high prevalence, chronic migraine and post-traumatic headache remain poorly understood and inadequately treated. Many patients are either not responsive to the current drugs or intolerant to their side effects. Moreover, overuse of anti-migraine drugs and opioids increase headache frequency and exacerbate the condition. There is an urgent need to develop novel therapy for chronic migraine and post-traumatic headache and co-occurring disorders. Regulatory T (Treg) cell is a special type of immune cell that can suppress the function of other immune cells. In some migraine patients, the number and function of Treg cells in the blood is significantly reduced, suggesting that Treg deficiency plays a role in migraine pathophysiology. In a mouse model of chronic migraine, we also observed a lower abundance of Treg cells versus other immune cells in the trigeminal ganglia, where headache-generating primary afferent neurons are localized. When we treated mice with low-dose interleukin-2 (ld-IL2) to preferentially expand and activate Treg cells, we found that ld-IL2 completely reversed chronic migraine- and post-traumatic headache-related behavioral and neuronal changes in both male and female mice. Importantly, ld-IL2 treatment did not alter basal nociceptive responses, and repeated usage did not develop drug tolerance. Moreover, ld-IL2 also prevented mild traumatic brain injury-induced memory impairment in mice. Collectively, these results suggest that Treg is a novel cellular target to treat chronic migraine and post-traumatic headache and the accompanying cognitive deficit. In this application, we propose to elucidate the mechanisms through which Treg cells contribute to the recurring headache and cognitive impairment in chronic migraine and post-traumatic headache. We also aim to validate Treg as a novel therapeutic target. To ensure the clinical relevance of our results, we will measure both reflexive behaviors and voluntary responses in male and female mice. We will also measure cellular changes in tissues that are involved in headache generation. First, we will investigate whether mild traumatic brain injury lowers the abundance of Treg cells versus other immune cells in the trigeminal ganglia, similar to what we observed in mice under chronic migraine-like state. We will also selectively deplete Treg cells in mice and test whether this exacerbates chronic migraine- and post-traumatic headache-related behaviors and cellular changes. These experiments will reveal whether Treg cells regulate the development and/or maintenance of recurring headache under disease states. Secondly, our preliminary study suggests that Treg cells reverse chronic migraine and post-traumatic headache through both transforming growth factor beta and interleukin-10 signaling pathways at peripheral tissues. Here, we will use conditional knockout mice to investigate whether ld-IL2/Treg reverses chronic migraine through activation of thes
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110597
Entities
People
- Yu-qing Cao
Organizations
- United States Army
- Washington University in St. Louis