Novel immune therapy to promote functional recovery after traumatic brain injury

促进脑外伤后功能恢复的新型免疫疗法

• 批准号: 10363372
• 负责人: Xiaoming Hu
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363372
• 关键词: Acute; Adult; Allogenic; Anti-Inflammatory Agents; Antibodies; Attenuated; B-Lymphocytes; Binding Sites; Brain; Brain Diseases; Brain Injuries; Cell Count; Cell Therapy; Cells; Central Nervous System; Cerebrum; Chronic; Clinical; Coculture Techniques; Cognitive; Cognitive deficits; Communication; Complex; Data; Deterioration; Equilibrium; Exhibits; Fostering; Future; Health; IL2RA gene; Immune; Immune response; Immune system; Immunotherapy; Impairment; In Vitro; Infiltration; Inflammation; Inflammatory; Injections; Injury; Interleukin-2; Lesion; Macrophage; Microglia; Modeling; Morbidity - disease rate; Mus; Nervous System Physiology; Neurologic; Neurologic Deficit; Oligodendroglia; Outcome; Pathologic; Peripheral; Phase; Phenotype; Play; Recovery; Recovery of Function; Regulatory T-Lymphocyte; Reporting; Research; Role; Spleen; Stroke; System; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic Effect; Tissue Preservation; Tissues; Traumatic Brain Injury; Traumatic Brain Injury recovery; Veterans; brain repair; brain tissue; clinical application; clinical translation; controlled cortical impact; effective therapy; experimental study; gray matter; healing; immunoregulation; improved; in vitro testing; in vivo; in vivo evaluation; long term recovery; lymph nodes; mortality; nervous system disorder; neuroinflammation; neurological recovery; neuroprotection; neurotoxic; new therapeutic target; novel; novel therapeutics; permissiveness; prevent; protein complex; response; sex; therapeutic evaluation; white matter; Acute; Adult; Allogenic; Anti-Inflammatory Agents; Antibodies; Attenuated; B-Lymphocytes; Binding Sites; Brain; Brain Diseases; Brain Injuries; Cell Count; Cell Therapy; Cells; Central Nervous System; Cerebrum; Chronic; Clinical; Coculture Techniques; Cognitive; Cognitive deficits; Communication; Complex; Data; Deterioration; Equilibrium; Exhibits; Fostering; Future; Health; IL2RA gene; Immune; Immune response; Immune system; Immunotherapy; Impairment; In Vitro; Infiltration; Inflammation; Inflammatory; Injections; Injury; Interleukin-2; Lesion; Macrophage; Microglia; Modeling; Morbidity - disease rate; Mus; Nervous System Physiology; Neurologic; Neurologic Deficit; Oligodendroglia; Outcome; Pathologic; Peripheral; Phase; Phenotype; Play; Recovery; Recovery of Function; Regulatory T-Lymphocyte; Reporting; Research; Role; Spleen; Stroke; System; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic Effect; Tissue Preservation; Tissues; Traumatic Brain Injury; Traumatic Brain Injury recovery; Veterans; brain repair; brain tissue; clinical application; clinical translation; controlled cortical impact; effective therapy; experimental study; gray matter; healing; immunoregulation; improved; in vitro testing; in vivo; in vivo evaluation; long term recovery; lymph nodes; mortality; nervous system disorder; neuroinflammation; neurological recovery; neuroprotection; neurotoxic; new therapeutic target; novel; novel therapeutics; permissiveness; prevent; protein complex; response; sex; therapeutic evaluation; white matter

Traumatic brain injury (TBI) leads to high mortality and morbidity amongst veterans and civilians. There is an urgent unmet need for therapies to alleviate the long-term neurological deficits after TBI. Innate (microglia and macrophages) and adaptive (T and B lymphocytes) immune cells play critical roles in neuroinflammation, injury progression, and brain repair. Microglia/macrophages are highly plastic cells that execute both beneficial and detrimental functions after injury. Our previous studies highlight a shift of microglia/macrophages at the chronic stages of TBI toward a neurotoxic, pro-inflammatory phenotype that impairs tissue preservation and brain repair. Therefore, identification of mechanisms underlying anti-inflammatory/reparative microglia/macrophage responses may reveal novel therapeutic targets to foster a microenvironment permissive for brain repair and long-term recovery after TBI. CD4+CD25+ regulatory T cells (Tregs) are a specialized subpopulation of T cells known to alleviate inflammation. We reported that Tregs exerted neuroprotection by targeting inflammatory dysregulation in stroke. The effects of Tregs in TBI have not been appreciated until recently, and their mechanism of action is unknown. We recently in vitro study show that Tregs activated by brain injury stimulate microglial polarization toward an anti-inflammatory/reparative phenotype, which in turn promotes oligodendrocyte differentiation and maturation. Using the controlled cortical impact model of TBI, we have obtained in vivo data showing that: 1) Selective Treg depletion further deteriorates long-term sensorimotor and cognitive functional deficits and exacerbates brain lesions in both white matter and gray matter up to 21 days after TBI. 2) Treg-depleted mice display worse cerebral inflammation and more aggressive pro-inflammatory microglia/macrophage responses after TBI. 3) In contrast, boosting Tregs using an IL-2/IL-2 antibody complex (IL-2/IL-2Ab) significantly reduces brain injury and improves neurological functions after TBI. Given these new observations, the proposed studies will be the first to test the mechanistic hypothesis that Tregs improve brain repair and promote long-term recovery after TBI by polarizing microglia/macrophages toward an inflammation-resolving and reparative phenotype. Three Aims will be completed in a systematic fashion. Aim 1. Test if Tregs improve gray and white matter integrity and enhance long-term functional recovery after TBI. Aim 2. Test if Tregs shift microglia/macrophages toward an inflammation-resolving and tissue-reparative phenotype after TBI. Aim 3. Test if in vivo expansion of Tregs with IL-2/IL-2Ab treatment post-TBI reduces brain lesions and improves long-term neurological recovery. This study will be the first to mechanistically define the role of Tregs in regulating microglia/macrophage responses after TBI and to test the therapeutic potential of IL-2/IL-2Ab in TBI. If successful, these studies may reveal a new therapeutic horizon for TBI and other neurological disorders that involve persistent inflammation and diverse microglia/macrophages responses.

脑外伤（TBI）导致退伍军人和平民的死亡率和发病率很高。那里 是迫切需要疗法来减轻TBI后长期神经缺陷的需求。先天（小胶质细胞） 和巨噬细胞）和适应性（T和B淋巴细胞）免疫细胞在神经炎症中起关键作用， 损伤进展和脑修复。小胶质细胞/巨噬细胞是高度塑料细胞，两者都有益 受伤后的有害功能。我们以前的研究突出了小胶质细胞/巨噬细胞在 TBI朝着神经毒性，促炎的表型的慢性阶段损害组织保存和 脑修理。因此，鉴定抗炎/修复的基础机制 小胶质细胞/巨噬细胞反应可能会揭示新的治疗靶标，以促进微环境允许 用于大脑修复和TBI后的长期恢复。 CD4+ CD25+调节T细胞（Treg）是已知减轻的T细胞的专门亚群 炎。我们报告说，Tregs通过靶向中风中的炎症失调来施加神经保护作用。 直到最近，TREG在TBI中的影响才被欣赏，并且它们的作用机理尚不清楚。 我们最近在体外研究表明，脑损伤激活的Treg刺激了小胶质细化 抗炎/修复表型，进而促进少突胶质细胞分化和成熟。 使用TBI的受控皮质冲击模型，我们获得了体内数据，显示：1）选择性Treg 耗竭进一步恶化了长期的感觉运动和认知功能缺陷，并加剧了大脑 TBI后21天，白质和灰质的病变均在21天内。 2）贫血的小鼠表现出更恶化的脑 TBI后的炎症和更具侵略性的促炎小胶质细胞/巨噬细胞反应。 3）相反， 使用IL-2/IL-2抗体复合物（IL-2/IL-2AB）增强Treg，可显着减少脑损伤并改善 TBI后的神经功能。鉴于这些新观察，拟议的研究将是第一个测试 机械假说，即Tregs改善了大脑修复并促进TBI后长期恢复 偏振小胶质细胞/巨噬细胞朝向炎症和修复表型。 三个目标将以系统的方式完成。目标1。测试Tregs是否改善了灰色和白色物质 完整性并增强TBI后的长期功能恢复。 AIM 2。测试Tregs是否移动小胶质细胞/巨噬细胞 TBI后朝着炎症解决和组织re弥比的表型。目标3。测试体内扩展是否 TBI后进行IL-2/IL-2AB治疗的Tregs减少了脑部病变并改善了长期神经系统恢复。 这项研究将是第一个从机械上定义Treg在调节小胶质细胞/巨噬细胞中的作用的研究 TBI后的反应并测试IL-2/IL-2AB在TBI中的治疗潜力。如果成功，这些研究可能 揭示了涉及持续炎症的TBI和其他神经系统疾病的新治疗视野 以及各种小胶质细胞/巨噬细胞反应。