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

描述(申请人提供)：肌萎缩侧索硬化症(ALS)是一种毁灭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ALS患者的先天性和获得性免疫系统的作用上。在ALS患者和遗传性ALS的mSOD1转基因动物模型中，ALS的神经病理特征都是胶质细胞增生和T细胞浸润性。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，但最近已经变得明显的是，CD4+T细胞在ALS中发挥着内源性神经保护作用。在缺乏功能性T细胞或CD4+T细胞的mSOD1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。骨髓移植使这些小鼠重新获得了具有功能的T细胞，从而延长了存活时间，并抑制了神经毒性。另一项使用不同T细胞缺陷小鼠培育的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细胞可以用于治疗，并可能为ALS的治疗干预提供机会。因此，我们假设CD4+T细胞或亚群的CD4+T细胞对mSOD1小鼠是一种临床相关和有益的治疗方法，并可能在ALS中提供临床益处。第一个具体目标将确定被动地将小鼠CD4+T细胞或CD4+T细胞亚群转移到mSOD1小鼠中的临床益处。这一目标也将决定体外扩增的CD4+T细胞(如Treg和Th2淋巴细胞)是否会进一步提高存活率。因此，这个特定的目标将提供原理证明，即CD4+T细胞或CD4+T细胞亚群是ALS的治疗候选细胞。第二个特定目标将确定被动地将从ALS患者获得的体外扩增的人CD4+T细胞转移到免疫缺陷的mSOD1小鼠中的临床益处。这一特定目的将提供ALS患者自身的CD4+T细胞可用于治疗的原则证明。由于肌萎缩侧索硬化症患者只有在发病后才寻求医疗护理，因此非常需要针对减缓疾病进展的治疗。因此，建议的研究旨在开发关于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疗法的有效性的原则证明数据。这个翻译项目将直接导致后续的项目，使用CD4+T细胞作为治疗方法来减缓ALS患者的疾病进展。 与公共卫生相关：肌萎缩侧索硬化症是一种可怕的、毁灭性的神经退行性疾病，患者看着自己在很短的时间内恶化；尽管进行了广泛的基础研究，但有效的治疗方法很少，我们自己努力开发有意义的治疗方法的重点是先天性和获得性免疫系统的作用。最近，在ALS模型中，T细胞被证明具有改善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，因此在ALS模型中定义介导神经保护的特定人群可以转化为我们的最终目标，即在ALS患者中使用T细胞疗法来减缓疾病进展并提高他们的生活质量。

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.