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）：肌萎缩性侧索硬化症（ALS）是一种具有最小有效疗法的破坏性慢性神经退行性疾病。我们自己开发有意义的疗法的努力集中在神经炎症以及先天和适应性免疫系统在ALS患者中的作用。 ALS神经病理学的特征是ALS患者和MSOD1遗传ALS的MSOD1转基因动物模型的神经胶质病和T细胞浸润。尽管较早的研究对这种炎症是有助于神经元保护，神经元损伤还是仅仅是损伤的后果，但最近显然已经显而易见的是，CD4+ T细胞在ALS中起内源性神经保护作用。在缺乏功能性T细胞或CD4+ T细胞的小鼠的MSOD1小鼠中，运动神经元疾病加速，伴随着促炎性细胞因子的水平升高。骨髓移植物用功能性T细胞重新构造了这些小鼠，导致生存率延长并抑制神经毒性。另一项使用与不同T细胞缺乏小鼠的MSOD1转基因小鼠的研究得出了类似的结论，即T细胞具有改善MSOD1小鼠的神经功能和预期寿命的能力。我们的初步数据表明，用CD4+ T细胞被动转移的MSOD1/RAG2 - / - 小鼠是神经保护性的，但是从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患者自己的CD4+ T细胞可用于治疗，并可能为ALS治疗干预提供机会。因此，我们假设CD4+ T细胞或CD4+ T细胞的亚群是MSOD1小鼠的临床相关且有益的治疗，并且可能在ALS中提供临床益处。第一个特定的目标将确定被动转移小鼠CD4+ T细胞或CD4+ T细胞亚群的临床益处。该目的还将确定离体扩展的CD4+ T细胞（例如Treg和Th2淋巴细胞）是否进一步增强了存活率。因此，该特定目的将提供原理证明CD4+ T细胞或CD4+ T细胞的亚群是ALS的治疗候选者。第二个特定目标将确定从ALS患者获得的免疫转移的人CD4+ T细胞被动转移到免疫缺陷型MSOD1小鼠中的临床益处。该特定目的将提供原则上的证明，即ALS患者自己的CD4+ T细胞可用于治疗。由于ALS患者仅在疾病发作后才寻求医疗护理，因此至关重要的是针对疾病进展减缓的疗法。因此，拟议的研究旨在开发有关CD4+ T细胞有效性或CD4+ T细胞亚群的原则证明数据，以作为减慢或阻止疾病进展的候选疗法。这个翻译项目将直接导致随后的项目使用CD4+ T细胞作为降低ALS患者疾病进展的疗法。 公共卫生相关性：ALS是一种可怕的，毁灭性的神经退行性疾病，患者观看自己在很短的时间内会恶化；尽管进行了广泛的基础研究，但我们自己为开发有意义的疗法的努力的有效疗法最少，集中在先天和适应性免疫系统的作用上。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。由于在ALS患者中很容易访问T细胞，因此在ALS模型中定义介导神经保护的特定种群可以转化为我们在ALS患者中使用T细胞疗法来减慢疾病进展并改善其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