Using CD4+ T cells as a candidate therapy to slow disease progression in ALS

使用 CD4 T 细胞作为减缓 ALS 疾病进展的候选疗法

• 批准号: 7774428
• 负责人: Stanley H. Appel
• 金额: $ 23.1万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7774428
• 关键词: Amyotrophic Lateral Sclerosis; Animal Model; Attenuated; Beer; Blood; Blood specimen; Bone Marrow Transplantation; Breeding; CD4 Positive T Lymphocytes; Cell Therapy; Cells; Chronic; Clinic; Clinical; Data; Disease; Disease Progression; Eragrostis; Gliosis; Goals; Human; Immune system; Inflammation; Inflammatory; Inherited; Injury; Investigation; Lead; Life Expectancy; Lymphocyte; Mediating; Modeling; Monitor; Motor Neurons; Mus; Mutation; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neuromuscular Diseases; Neuronal Injury; Neurons; North America; Onset of illness; Patients; Phase; Play; Population; Quality of life; Regulatory T-Lymphocyte; Research Design; Role; Superoxide Dismutase; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Time; Transgenic Animals; Transgenic Mice; Wild Type Mouse; clinically relevant; cytokine; cytotoxicity; effective therapy; functional loss; improved; lymph nodes; medical attention; mutant; neuroinflammation; neuropathology; neuroprotection; neurotoxicity; public health relevance; reconstitution; volunteer

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a devastating chronic neurodegenerative disease with minimally effective therapy. Our own efforts to develop meaningful therapies have focused upon neuroinflammation and the roles of the innate and adaptive immune systems in ALS patients. ALS neuropathology is marked by gliosis and infiltrating T-cells both in ALS patients and in mSOD1 transgenic animal models of inherited ALS. Although earlier studies were ambiguous as to whether this inflammation contributed to neuronal protection, neuronal injury, or was merely a late consequence of injury, it has recently become apparent that CD4+ T cells play an endogenous neuroprotective role in ALS. In mSOD1 mice bred with mice lacking functional T cells, or CD4+ T cells, motoneuron disease was accelerated, accompanied by increased levels of pro-inflammatory cytokines. Bone marrow transplants reconstituted these mice with functional T cells leading to prolonged survival and suppressed neurotoxicity. Another study using mSOD1 transgenic mice bred with different T cell deficient mice reached a similar conclusion, namely that T cells have the abilities to improve neurological function and life expectancy in mSOD1 mice. Our preliminary data suggest that mSOD1/RAG2-/- mice passively transferred with CD4+ T cells are neuroprotective but that CD4+ T cells obtained from mSOD1 mice are more beneficial than CD4+ T cells obtained from wild-type mice. These data establish that the ALS patient's own CD4+ T cells may be used for therapy and may provide the opportunity for therapeutic intervention in ALS. Thus, we hypothesize that CD4+ T cells, or subpopulations of CD4+ T cells, are a clinically relevant and beneficial therapy in mSOD1 mice, and may provide clinical benefit in ALS. The 1st specific aim will determine the clinical benefits of passively transferring mouse CD4+ T cells, or subpopulations of CD4+ T cell, into mSOD1 mice. This aim will also determine whether ex vivo expanded CD4+ T cells (such as Treg and Th2 lymphocytes) further enhance survival. Thus, this specific aim will provide proof-of-principle that CD4+ T cells, or subpopulations of CD4+ T cells, are therapeutic candidates for ALS. The 2nd specific aim will determine the clinical benefits of passively transferring ex vivo expanded human CD4+ T cells obtained from ALS patients into immunodeficient mSOD1 mice. This specific aim will provide proof-of-principle that the ALS patient's own CD4+ T cells may be used for therapy. Since ALS patients seek medical attention only after disease onset, therapies directed at slowing disease progression are vitally needed. Therefore, the proposed studies are designed to develop proof-of-principle data on the efficacy of CD4+ T cells, or subpopulations of CD4+ T cells, as a candidate therapy to slow or arrest disease progression. This translational project will lead directly to subsequent projects using CD4+ T cells as a therapy to slow disease progression in ALS patients. PUBLIC HEALTH RELEVANCE: ALS is a horrific, devastating neurodegenerative disease in which patients watch themselves deteriorate over a very short period of time; and despite extensive basic investigations, there is minimal effective therapy Our own efforts to develop meaningful therapies have focused upon the roles of the innate and adaptive immune systems. Recently, T cells have been shown to have the ability to improve neurological function and life expectancy in ALS models. Since T cells are readily accessible in ALS patients, defining the specific populations mediating neuroprotection in the ALS models is translatable into our ultimate goal of using T cell therapies in ALS patients to slow disease progression and improve their quality of life.

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是一种破坏性的慢性神经退行性疾病，治疗效果最低。我们自己开发有意义的治疗方法的努力集中在神经炎症和先天免疫系统和适应性免疫系统在ALS患者中的作用。在ALS患者和遗传性ALS的mSOD1转基因动物模型中，ALS神经病理学都以胶质瘤和浸润t细胞为特征。尽管早期的研究对于这种炎症是否有助于神经元保护、神经元损伤，或者仅仅是损伤的晚期后果尚不明确，但最近发现CD4+ T细胞在ALS中发挥内源性神经保护作用。在与缺乏功能性T细胞或CD4+ T细胞的小鼠繁殖的mSOD1小鼠中，运动神经元疾病加速，并伴有促炎细胞因子水平升高。骨髓移植重建了这些具有功能T细胞的小鼠，从而延长了存活时间并抑制了神经毒性。另一项利用mSOD1转基因小鼠与不同T细胞缺陷小鼠杂交的研究也得出了类似的结论，即T细胞具有改善mSOD1小鼠神经功能和预期寿命的能力。我们的初步数据表明，被动转移CD4+ T细胞的mSOD1/RAG2-/-小鼠具有神经保护作用，但从mSOD1小鼠获得的CD4+ T细胞比从野生型小鼠获得的CD4+ T细胞更有益。这些数据表明，ALS患者自身的CD4+ T细胞可能用于治疗，并可能为ALS的治疗干预提供机会。因此，我们假设CD4+ T细胞或CD4+ T细胞亚群在mSOD1小鼠中是一种临床相关且有益的治疗方法，并且可能对ALS提供临床益处。第一个具体目标是确定将小鼠CD4+ T细胞或CD4+ T细胞亚群被动转移到mSOD1小鼠中的临床益处。该目的还将确定体外扩增的CD4+ T细胞（如Treg和Th2淋巴细胞）是否能进一步提高生存率。因此，这一特定的目标将提供CD4+ T细胞或CD4+ T细胞亚群是ALS治疗候选者的原理证明。第二个具体目标是确定将ALS患者体外扩增的人CD4+ T细胞被动转移到免疫缺陷的mSOD1小鼠中的临床益处。这一特定的目标将为ALS患者自身的CD4+ T细胞可能用于治疗提供原理证明。由于ALS患者只在发病后才寻求医疗护理，因此迫切需要针对减缓疾病进展的治疗。因此，拟议的研究旨在开发CD4+ T细胞或CD4+ T细胞亚群作为减缓或阻止疾病进展的候选治疗方法的有效性的原理证明数据。这个转化项目将直接导致后续使用CD4+ T细胞作为减缓ALS患者疾病进展的治疗方法的项目。