Novel immune therapy to promote functional recovery after traumatic brain injury

创伤性脑损伤在退伍军人和平民中具有很高的死亡率和发病率。那里 是一种迫切的未得到满足的治疗需求，以缓解脑外伤后的长期神经功能障碍。先天(小胶质细胞 免疫细胞)和适应性免疫细胞(T和B淋巴细胞)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，执行这两种有益的 和损伤后的有害功能。我们之前的研究强调了小胶质细胞/巨噬细胞在 颅脑损伤的慢性期向神经毒性、促炎表型转变，损害组织保存和 大脑修复。因此，确定潜在的抗炎/修复机制 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 用于脑损伤后的脑修复和长期康复。 CD4+CD25+调节性T细胞(Tregs)是一种特殊的T细胞亚群 发炎。我们报道，Tregs通过靶向卒中的炎性失调来发挥神经保护作用。 Tregs在脑外伤中的作用直到最近才被认识，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刺激小胶质细胞极化为 抗炎/修复表型，进而促进少突胶质细胞分化和成熟。 利用脑外伤受控皮质撞击模型，我们获得了体内数据，结果表明：1)选择性Treg 耗竭会进一步恶化长期的感觉运动和认知功能障碍，并加剧大脑 脑损伤后21天，脑白质和灰质均有损害。2)Treg耗竭小鼠的大脑表现更差 脑外伤后炎症和更具侵袭性的促炎小胶质细胞/巨噬细胞反应。3)相反， 使用IL-2/IL-2抗体复合体(IL-2/IL-2Ab)增强Tregs显著减少脑损伤并改善 颅脑损伤后神经功能恢复情况。鉴于这些新的观察结果，拟议的研究将是第一个测试 Tregs改善脑损伤后脑修复和促进长期康复的机制假说 使小胶质细胞/巨噬细胞极化为消炎和修复表型。 三个目标将有系统地完成。目标1.测试Tregs是否能改善灰质和白质 改善颅脑损伤后的完整性，促进远期功能恢复。目的2.测试Tregs是否移动小胶质细胞/巨噬细胞 脑外伤后的炎症消退和组织修复表型。目的3.测试是否在体内扩增 颅脑损伤后应用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。 这项研究将首次从机械上确定Tregs在调节小胶质细胞/巨噬细胞中的作用 并检测IL-2/IL-2Ab在颅脑损伤中的治疗潜力。如果成功，这些研究可能会 为脑外伤和其他涉及持续性炎症的神经疾病揭示了新的治疗视野 和不同的小胶质细胞/巨噬细胞反应。

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.