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.

项目概要/摘要创伤性脑损伤 (TBI) 是一个主要的健康问题；每年有 250 万美国人遭受创伤性脑损伤，造成的损失为每年花费 800 亿美元，很少有治疗方法可以减少 TBI 的长期认知后遗症，而且只有几种治疗方法。脑损伤的康复选择有限，会导致原发性结构损伤，然后是继发性损伤。这涉及小胶质细胞的先天性和适应性免疫系统的激活。参与已被确定为 TBI 发病机制的一个主要因素，但目前尚无定论。鼻腔给予抗 CD3 药物可有效调节小胶质细胞反应。单克隆抗体诱导抗炎免疫反应，下调小胶质细胞活化在多发性硬化症动物模型中，其机制涉及鼻腔抗 CD3 定位至颈部淋巴。诱导 IL-10 分泌（CD4+LAP+ 和 CD4+FoxP3+）调节性 T 细胞 (Treg) 迁移的节点鼻抗 CD3 疗法是 TBI 中尚未探索的领域。 Saef Izzy 博士是一位训练有素的医生，Treg 调节 TBI 中小胶质细胞的机制在很大程度上尚不清楚。具有急性脑损伤研究背景的神经重症医师，领导鼻抗 CD3 代表 Izzy 博士密切合作，采用一种独特的、临床适用的免疫调节方法来治疗 TBI。与他的主要导师 Howard Weiner 博士一起研究鼻抗 CD3 对 TBI 结局的影响他的初步数据表明，鼻抗 CD3 会增加 CD4+Treg 和 IL 10 的表达，并且受控皮质冲击损伤 (CCI) 7 天后，大脑中的小胶质细胞激活减少，它也有所改善。受伤后 1 个月的行为结果在本 K08 提案中，Izzy 博士将确定鼻腔的影响。抗 CD3 对 CCI 后长期组织病理学和行为结果的影响（目标 1）。损伤后小胶质细胞、效应细胞和调节性 T 细胞的反应，并研究 Tregs 对小胶质细胞的影响 CCI 后的体外炎症反应（目标 2）他将研究鼻抗 CD3 对 IL-10/IL- 的影响。使用携带 IL-10Rflox/floxTMEM119CreETR2 的 C57BL6/J 小鼠观察小胶质细胞中的 10R 信号传导，该小鼠不他莫昔芬给药后在小胶质细胞上表达 IL-10 受体，他还将描述其作用。 Tregs 通过在体外和体内中和 TGF-β 和 IL-4 产生的其他抗炎细胞因子，研究它们对 CCI 后行为和小胶质细胞炎症反应的影响（目标 3）。更好地了解 TBI 后适应性免疫反应如何与先天免疫系统相互作用。该提案的成功完成将深入了解 Tregs 调节 TBI 后的小胶质细胞反应以及识别新型免疫疗法以改善患者的拟议的 K08 应用利用了 Izzy 博士导师在免疫学、小鼠方面的专业知识。急性脑损伤模型和生物信息学为他提供了额外的知识和经验成为一名由 NIH 资助的独立研究者和 TBI 神经免疫学专家是必要的。