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: 8022831
• 负责人: Stanley H. Appel
• 金额: $ 19.25万
• 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 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8022831
• 关键词: Amyotrophic Lateral Sclerosis; Animal Model; Attenuated; Blood; Blood specimen; Bone Marrow Transplantation; Breeding; CD3 Antigens; CD4 Positive T Lymphocytes; Cell Therapy; Cells; Chronic; Clinic; Clinical; Data; Disease; Disease Progression; Eragrostis; Gliosis; Goals; Human; IL2RA gene; Immune system; Inflammation; Inflammatory; Inherited; Injury; Interleukin-12; Interleukin-2; Interleukin-4; 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）：肌萎缩侧索硬化症（ALS）是一种破坏性慢性神经退行性疾病，治疗效果极低。我们自己开发有意义的治疗方法的努力集中在神经炎症以及ALS患者先天和适应性免疫系统的作用上。在ALS患者和遗传性ALS的mSOD 1转基因动物模型中，ALS神经病理学的特征都是神经胶质增生和浸润T细胞。虽然早期的研究对于这种炎症是否有助于神经元保护、神经元损伤或仅仅是损伤的晚期后果是模糊的，但最近已经变得明显的是，CD 4 + 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CD 4 + T细胞的小鼠一起繁殖的mSOD 1小鼠中，运动神经元疾病加速，伴随着促炎细胞因子水平的增加。骨髓移植重建这些小鼠与功能性T细胞导致延长生存和抑制神经毒性。另一项使用mSOD 1转基因小鼠与不同T细胞缺陷小鼠繁殖的研究得出了类似的结论，即T细胞具有改善mSOD 1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CD 4 + T细胞的mSOD 1/RAG 2-/-小鼠具有神经保护作用，但从mSOD 1小鼠获得的CD 4 + T细胞比从野生型小鼠获得的CD 4 + T细胞更有益。这些数据表明ALS患者自身的CD 4 + T细胞可用于治疗，并可为ALS的治疗干预提供机会。因此，我们假设CD 4 + T细胞或CD 4 + T细胞亚群在mSOD 1小鼠中是一种临床相关和有益的治疗，并可能在ALS中提供临床益处。第一个具体目标将确定将小鼠CD 4 + T细胞或CD 4 + T细胞亚群被动转移到mSOD 1小鼠中的临床获益。该目的还将确定离体扩增的CD 4 + T细胞（如Treg和Th 2淋巴细胞）是否进一步增强存活。因此，这一特定目标将提供CD 4 + T细胞或CD 4 + T细胞亚群是ALS的治疗候选者的原理证明。第二个具体目标将确定将从ALS患者获得的离体扩增的人CD 4 + T细胞被动转移到免疫缺陷mSOD 1小鼠中的临床益处。这一特定目标将提供ALS患者自身的CD 4 + T细胞可用于治疗的原理证明。由于ALS患者仅在疾病发作后才寻求医疗照顾，因此迫切需要针对减缓疾病进展的治疗。因此，拟定的研究旨在开发关于CD 4 + T细胞或CD 4 + T细胞亚群作为减缓或阻止疾病进展的候选疗法的疗效的原理验证数据。这一转化项目将直接导致后续项目使用CD 4 + T细胞作为减缓ALS患者疾病进展的疗法。 公共卫生关系：ALS是一种可怕的，毁灭性的神经退行性疾病，患者在很短的时间内看到自己恶化;尽管进行了广泛的基础研究，但有效的治疗方法很少。最近，T细胞已被证明具有改善ALS模型中神经功能和预期寿命的能力。由于ALS患者很容易获得T细胞，因此定义ALS模型中介导神经保护的特定群体可以转化为我们在ALS患者中使用T细胞疗法来减缓疾病进展并改善他们的生活质量的最终目标。

项目成果

Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS.

• DOI: 10.1016/j.expneurol.2012.06.011
• 发表时间: 2012-09
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Liao, Bing;Zhao, Weihua;Beers, David R.;Henkel, Jenny S.;Appel, Stanley H.
• 通讯作者: Appel, Stanley H.

Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms.

• DOI: 10.1016/j.nbd.2012.07.008
• 发表时间: 2012-12
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Zhao W;Beers DR;Liao B;Henkel JS;Appel SH
• 通讯作者: Appel SH