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 是缓解TBI后长期神经功能缺损的治疗的迫切未满足的需求。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中起关键作用， 损伤进展和大脑修复小胶质细胞/巨噬细胞是高度可塑性的细胞， 和损伤后的有害功能。我们以前的研究强调了小胶质细胞/巨噬细胞的转移， TBI的慢性阶段朝向神经毒性、促炎表型，其损害组织保存， 大脑修复因此，确定抗炎/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，以促进微环境允许 用于脑损伤后的大脑修复和长期恢复。 CD 4 + CD 25+调节性T细胞（TCR 4）是已知缓解CD 4 + CD 25 + T细胞的特化T细胞亚群。 炎症我们报道了TdR通过靶向卒中中的炎症失调发挥神经保护作用。 TBI中TdR的作用直到最近才被认识到，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TGFAP刺激小胶质细胞极化， 抗炎/修复表型，这反过来又促进少突胶质细胞分化和成熟。 使用TBI的受控皮质撞击模型，我们已经获得了体内数据，显示：1）选择性Treg 消耗进一步恶化了长期感觉运动和认知功能缺陷， TBI后21天内，白色物质和灰质中均出现病变。2)Treg缺失的小鼠表现出更差的大脑功能 炎症和TBI后更积极的促炎性小胶质细胞/巨噬细胞反应。3)与此相反， 使用IL-2/IL-2抗体复合物（IL-2/IL-2Ab）加强TCRP显著减少脑损伤并改善 TBI后的神经功能考虑到这些新的观察结果，拟议中的研究将是第一个测试 机械假说认为TTRIP通过以下方式改善脑损伤后的脑修复并促进长期恢复： 使小胶质细胞/巨噬细胞向炎症消退和修复表型极化。 三个目标将以系统的方式完成。目标1.测试TTRY是否改善灰色和白色物质 完整性和增强TBI后长期功能恢复。目标2.测试Tissue移位小胶质细胞/巨噬细胞 TBI后炎症消退和组织修复表型。目标3.测试是否在体内扩增 TBI后IL-2/IL-2Ab治疗可减少脑损伤并改善长期神经恢复。 这项研究将是第一个从机制上确定TGFAP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。