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Targeting CNS Neuroinflammation in Traumatic Brain Injury by Nasal Anti-CD3

通过鼻抗 CD3 靶向治疗创伤性脑损伤中的 CNS 神经炎症

基本信息

批准号：
10597247
负责人：
Saef Izzy
金额：
$ 23.07万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597247
关键词：
Ablation Acute Acute Brain Injuries Adaptive Immune System Aftercare American Animal Model Animals Anti-Inflammatory Agents Antibodies Area Attenuated Autoimmune Diseases Behavior Behavioral Biochemical Bioinformatics Biological Brain Brain Injuries C57BL/6 Mouse CD3 Antigens Cells Cervical lymph node group Chronic Chronic Phase Coculture Techniques Cognitive Cortical Contusions Data Disease Disease Progression FOXP3 gene Flow Cytometry Funding Goals Health Hippocampus Hour Human Immune response Immune system Immunologic Stimulation Immunology Immunotherapeutic agent Immunotherapy In Vitro Inflammation Inflammatory Inflammatory Response Injury Innate Immune Response Innate Immune System Interleukin-10 Interleukin-4 Ipsilateral Knowledge Learning Lesion Mechanics Mediating Mentors Microglia Modeling Molecular Monoclonal Antibodies Motor Multiple Sclerosis Mus Nature Neurologic Deficit Nose Outcome Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Phase Phenotype Play Regulation Regulatory T-Lymphocyte Rehabilitation therapy Research Research Personnel Role Short-Term Memory Signal Transduction Surveys T cell response T-Lymphocyte TBI treatment Tamoxifen Testing Therapeutic Effect Time Training Transforming Growth Factor beta Traumatic Brain Injury Traumatic Brain Injury recovery Travel United States National Institutes of Health Up-Regulation Work adaptive immune response adaptive immunity behavioral outcome brain cell career cell motility clinical application cognitive function controlled cortical impact cost cytokine disability effective therapy effector T cell experience experimental study glial activation immunoregulation improved in vivo insight interleukin-10 receptor migration mouse model neural neuroimmunology neuroinflammation neurological recovery neuropathology neurotoxic neurotoxicity novel novel therapeutics protective effect response transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY / ABSTRACT Traumatic brain injury (TBI) is a major health problem; 2.5 million Americans sustain TBI each year at a cost of 80 billion dollars annually. Few therapies reduce long-term cognitive sequelae of TBI, and there are only limited options for rehabilitation. Brain injury causes a primary structural injury followed by a secondary phase, which involves the activation of the innate and adaptive immune systems. Neuroinflammation with microglia’s involvement has been identified as a major contributor to the pathogenesis of TBI. However, there is still no effective immune therapy to modulate the microglial response post-injury. Nasal administration of anti-CD3 monoclonal antibody induces an anti-inflammatory immune response that down-regulates microglial activation in animal models of multiple sclerosis. The mechanism involves localization of nasal anti-CD3 to cervical lymph nodes where it induces IL-10-secreting (CD4+LAP+ and CD4+FoxP3+) regulatory T cells (Tregs) that migrate to the brain and inhibit microglial activation. Nasal anti-CD3 therapy is an unexplored area in TBI, and the mechanisms by which Tregs modulate microglia in TBI are largely unknown. Dr. Saef Izzy, a trained neurointensivist with a background in acute brain injury research, hypothesized that nasal anti-CD3 represents a unique, clinically applicable immunomodulatory approach for the treatment of TBI. Dr. Izzy worked closely with his primary mentor, Dr. Howard Weiner, to investigate the effects of nasal anti-CD3 on TBI outcomes in mice. His preliminary data showed that nasal anti-CD3 increases CD4+Tregs and IL 10 expression and reduces microglial activation in the brain 7 days after controlled cortical impact injury (CCI). It also improves behavioral outcomes at 1-month post-injury. In this K08 proposal, Dr. Izzy will determine the effects of nasal anti-CD3 on long-term histopathological and behavioral outcomes after CCI (Aim 1). He will survey the microglial, effector, and regulatory T cell responses after injury and study the effects of Tregs on microglial inflammatory response in vitro after CCI (Aim 2). He will investigate the effect of nasal anti-CD3 on IL-10/IL- 10R signaling in microglia using a C57BL6/J mouse harboring IL-10Rflox/floxTMEM119CreETR2, which does not express the IL-10 receptor on microglia after tamoxifen administration. He will also delineate the role(s) of other anti-inflammatory cytokines produced by Tregs by neutralizing TGF-β and IL-4 in vitro and in vivo and study their effects on behavior and microglial inflammatory response post-CCI (Aim 3). Dr. Izzy's career goal is to better understand how the adaptive immune response interfaces with the innate immune system after TBI. Successful completion of this proposal will provide insight into the mechanisms by which Tregs modulate the microglial response after TBI and the identification of novel immune-based therapeutics to improve patients’ outcomes. The proposed K08 application leverages Dr. Izzy’s mentor’s expertise in immunology, mouse models of acute brain injury, and bioinformatics to provide him with the additional knowledge and experience necessary to become an independent NIH-funded investigator and expert in the neuroimmunology of TBI.

项目摘要/摘要