Principal Investigators Peter Grace, PhD, from MD Anderson Cancer Center, University of Texas, and Cobi Heijnen, PhD, from Rice University, were recently granted Investigator-Initiated Research Awards. Grace received funding totaling USD$3,064,079, and Heijnen received funding totaling USD$165,704.
Peripheral Neuropathy Advocacy
Grace and Heijnen’s awards were made possible through the Foundation for Peripheral Neuropathy’s (FPN) advocacy efforts with the Department of Defense’s CDMRP program. Advocacy and public policy work are important for advancing research into finding new treatments and, ultimately, cures for peripheral neuropathy. Led by FPN, new research studies underway are a direct result of the nationwide advocacy of the PN community.
In the third year for peripheral neuropathy (PN) eligibility, Grace and Heijen’s awards were two of three applications that received funding, totaling approximately USD$3.3 million for PN grants.
Study summary
Chronic pain conditions, like neuropathic pain, affect millions worldwide, with current treatments often ineffective and accompanied by unwanted side effects.
In this study, researchers are exploring a groundbreaking approach targeting local B cells and immunoglobulin G (IgG) to prevent and treat neuropathic pain. Preliminary data suggest that disrupting the B cell-IgG axis could be a game-changer in pain management.
The study aims to understand how B cells and IgG contribute to neuropathic pain and test novel therapies in mice and non-human primates. Researchers hope to alleviate pain without impairing systemic immune responses by locally depleting B cells or reducing IgG half-life. This innovative approach, leveraging FDA-approved treatments for other conditions, could offer new hope for those suffering from neuropathic pain, potentially revolutionizing pain management strategies in the future.
Specific Aims and Study Design
The study’s long-term objective is to harness the disease-modifying potential of neuroimmune signaling to treat neuropathic pain. The central hypothesis is that B cell-IgG signaling around the lumbar spinal cord and dorsal root ganglia (DRG) initiates and maintains neuropathic pain resulting from nerve trauma. They predict that such signaling can be locally silenced without impairing systemic adaptive immune responses.
The rationale for testing this hypothesis is that the researchers will identify completely new, safe, and pragmatic approaches to preventing and treating neuropathic pain after service members sustain traumatic nerve injuries in the theater of war. To accomplish the overall objective of this application, this qualified and multidisciplinary team will test the central hypothesis across the following specific aims:
Aim 1
Determine whether local depletion of B cells prevents and treats neuropathic pain. They will test the pronociceptive role of B cells residing around the lumbar spinal cord and DRG in mice and in non-human primates. Mice will receive a single intrathecal injection of an anti-CD20 mAb at the time of CCI (prevention) or on day 14 post injury (treatment). A comprehensive battery of tests will be used to assess evoked and ongoing/spontaneous pain behaviors. CCI will also be performed in rhesus macaques, and a single anti-CD20 mAb intrathecally administered at day 0 or 14 post CCI. Hypersensitivity to evoked stimuli and homecage behavior will be quantified (measuring ongoing pain and function). The effects of anti-CD20 mAb treatment on immune cell recruitment to the DRG and spinal cord meninges of both species will be quantified via flow cytometry and immunohistochemistry. All experiments will employ sham and IgG isotype controls.
Aim 2
Reveal how locally reducing IgG half-life alleviates neuropathic pain. IgG half-life is extended by recycling through neonatal Fc receptors (FcRn). Consequently, FcRn blockade has proven effective for the treatment of IgG-mediated disorders without leading to general immunosuppression. The team will test whether biologic or genetic disruption of FcRn prevents and treats neuropathic pain. Mice will receive repeated intrathecal injections of the FcRn blocker efgartigimod beginning at the time of CCI (prevention) or on day 14 post-injury (treatment). As an orthogonal approach, genetically mutated mice deficient in FcRn will also undergo CCI. Evoked and ongoing/spontaneous pain behaviors will be assessed. IgG deposition in the spinal cord and DRG will be quantified by immunohistochemistry. All experiments will employ sham, isotype, and/or wild-type controls.
Aim 3
Establish whether systemic antigen-specific B cell responses are retained with intrathecal anti-CD20 or FcRn blocking antibody treatments. To test whether intrathecal safely leaves systemic adaptive immune responses intact, mice will receive a single intrathecal dose of anti-CD20 or FcRn blocking antibodies (or isotype controls), followed by vaccination and boosts with tetanus toxoid. Serum IgM and IgG antibody titers will be quantified over time. Successful completion of this project will have major short- and long-term impact through application of completely new and safe immunotherapies to prevent and treat neuropathic pain. As these treatments (e.g., rituximab, ocrelizumab, efgartigimod) are already FDA-approved for other diseases, they could be rapidly repurposed.
Outcome
This research is conceptually innovative, because it will shift the paradigm of neuroimmune regulation of peripheral nerve injury by identifying a local B cell-IgG axis as a therapeutic target to prevent and treat neuropathic pain. Future studies will investigate other strategies to target B cell inhibitors in the central nervous system and to selectively degrade pathogenic autoantibodies.