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

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.

创伤性脑损伤（TBI）导致退伍军人和平民的高死亡率和发病率。那里 缓解 TBI 后长期神经功能缺损的治疗方法亟待满足。先天性（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、 损伤进展和脑修复。小胶质细胞/巨噬细胞是高度可塑性的细胞，可以执行有益的任务 以及受伤后的有害功能。我们之前的研究强调了小胶质细胞/巨噬细胞在 TBI 的慢性阶段发展为神经毒性、促炎表型，损害组织保存和 大脑修复。因此，识别抗炎/修复的潜在机制 小胶质细胞/巨噬细胞反应可能揭示新的治疗靶点，以培育微环境许可 用于 TBI 后的大脑修复和长期恢复。 CD4+CD25+调节性 T 细胞 (Treg) 是一种特殊的 T 细胞亚群，已知可以缓解 炎。我们报道了 Tregs 通过针对中风中的炎症失调发挥神经保护作用。 Tregs 在 TBI 中的作用直到最近才得到认识，其作用机制尚不清楚。 我们最近的体外研究表明，脑损伤激活的 Tregs 会刺激小胶质细胞极化，使其向 抗炎/修复表型，进而促进少突胶质细胞分化和成熟。 利用 TBI 的受控皮质影响模型，我们获得的体内数据表明：1）选择性 Treg 耗竭会进一步恶化长期感觉运动和认知功能缺陷，并加剧大脑 TBI 后 21 天，白质和灰质均出现损伤。 2）Treg细胞缺失的小鼠表现出更差的大脑功能 TBI 后炎症和更积极的促炎小胶质细胞/巨噬细胞反应。 3）相比之下， 使用 IL-2/IL-2 抗体复合物 (IL-2/IL-2Ab) 增强 Tregs 显着减少脑损伤并改善 TBI 后的神经功能。鉴于这些新的观察结果，拟议的研究将是第一个测试 机制假设认为 Tregs 通过以下方式改善大脑修复并促进 TBI 后的长期恢复： 使小胶质细胞/巨噬细胞极化至炎症消解和修复表型。 系统完成“三个目标”。目标 1. 测试 Tregs 是否改善灰质和白质 完整性并增强 TBI 后的长期功能恢复。目标 2. 测试 Tregs 是否会改变小胶质细胞/巨噬细胞 TBI 后炎症消退和组织修复表型。目标 3. 测试是否体内扩增 TBI 后使用 IL-2/IL-2Ab 治疗的 Tregs 可减少脑损伤并改善长期神经功能恢复。 这项研究将是第一个从机制上定义 Tregs 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。如果成功的话，这些研究可能 揭示 TBI 和其他涉及持续炎症的神经系统疾病的新治疗前景 和不同的小胶质细胞/巨噬细胞反应。