Regulatory T cell as a restorative therapy for ischemic stroke

调节性 T 细胞作为缺血性中风的恢复疗法

• 批准号: 9619010
• 负责人: Dandan Sun
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9619010
• 关键词: Acute; Adoptive Transfer; Aftercare; Animals; Antibodies; Blood Circulation; Brain; Brain Injuries; Cell Differentiation process; Cell Maturation; Cell Proliferation; Cells; Cerebral Ischemia; Cessation of life; Clinical; Clinical Trials; Complex; Data; Environment; Failure; Generations; IL2RA gene; Immune response; Immunotherapy; Impairment; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injections; Interleukin-10; Interleukin-2; Ischemia; Ischemic Stroke; Knockout Mice; Lesion; Measures; Microglia; Middle Cerebral Artery Occlusion; Myelin; Myelin Sheath; Neurological outcome; Oligodendroglia; Outcome; Phenotype; Prevention; Production; Recovery; Recovery of Function; Regulatory T-Lymphocyte; Reperfusion Therapy; Research; Role; Sensorimotor functions; Stroke; Structure; T-Lymphocyte; Testing; Therapeutic Studies; Tissues; Treg therapy; aged; behavior test; cytokine; disability; functional disability; functional outcomes; gray matter; immunoregulation; improved; in vivo; inflammatory marker; injury and repair; injury recovery; macrophage; neurological recovery; neuroprotection; neurovascular; novel; novel strategies; oligodendrocyte precursor; post stroke; precursor cell; preservation; public health relevance; repaired; restoration; stroke model; stroke recovery; tissue repair; white matter; white matter injury; young adult

 DESCRIPTION (provided by applicant): White matter (WM) lesions, characterized by the loss of myelin and myelin-producing oligodendrocytes (OLs), are a major cause of functional disability after stroke but have not been widely appreciated in therapeutic studies until recently. Here we propose to rectify this gap in the field by focusing on WM integrity and its modulation by immune responses in the ischemic brain. Activated microglia/macrophages of distinct phenotypes are known to determine OL cell fate and WM integrity after brain injuries. Specifically, the "alternatively activated" M2 phenotype is essential for WM preservation and repair because M2 cells resolve local inflammation, clear broken myelin sheaths, and provide trophic factors that promote WM repair. CD4+CD25+ regulatory T cells (Tregs) are a specialized subpopulation of T cells that negatively regulate immune responses. Our recent study demonstrated that adoptive Treg therapy exerted early neuroprotection by targeting inflammatory dysregulation and neurovascular disruption after stroke. However, it is not known whether Tregs also have a beneficial effect on WM integrity. Recently, we discovered that Treg-conditioned media stimulates microglial polarization toward the M2 phenotype, and M2 microglia enhance OL survival and promote OPC differentiation in vitro. These exciting results suggest that Tregs can preserve WM integrity. We obtained further promising data showing that 1) Treg transfer at 2h of reperfusion reduced the extent of WM injury and improved sensorimotor functions for at least 28d after transient middle cerebral artery occlusion (tMCAO); 2) Post-stroke Treg treatment resulted in a long-lasting elevation of IL-10, a major Treg-derived cytokine that is important for WM repair; 3) Treg treatment promoted M2 polarization of microglia/macrophages in both WM and gray matter after tMCAO. Furthermore, we have successfully induced a robust increase of Tregs in the circulation after stroke by systemic injection of interleukin (IL)-2/IL-2 antibody complex (IL-2/IL- 2Ab), an established approach to expand Tregs in vivo. We demonstrated that IL-2/IL-2Ab-induced Treg expansion reduces myelin loss 7d after tMCAO and improves sensorimotor functions. The current proposal will further explore the effects of Tregs on WM injury and repair after stroke and develop in vivo Treg expansion as a novel strategy to promote WM integrity and enhance post-stroke recovery. The central hypothesis to be tested is that Tregs promote WM integrity and long-term recovery after stroke by polarizing microglia/macrophages toward the M2 phenotype in an IL-10 dependent manner. Three specific aims are proposed: Aim 1. Test the hypothesis that Treg treatment after stroke improves long-term functional recovery and promotes WM integrity. Aim 2. Test the hypothesis that Treg-derived IL-10 shifts microglia/macrophage polarization towards the M2 phenotype, thereby promoting WM integrity after stroke. Aim 3. Test the hypothesis that in vivo expansion of Tregs with post-stroke IL-2/IL-2Ab treatment is effective in reducing long-term WM injury and improving neurological recovery after stroke.