MOG特异性汽车Tregs：一种治疗多发性硬化症的新方法
MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis
影响因子:10.10000
分区:医学1区 Top / 免疫学1区 神经科学1区
发表日期:2024 Oct 20
作者:
Jihane Frikeche, Marion David, Xavier Mouska, Damien Treguer, Yue Cui, Sandrine Rouquier, Enora Lecorgne, Emma Proics, Papa Babacar Fall, Audrey Lafon, Gregory Lara, Alexandra Menardi, David Fenard, Tobias Abel, Julie Gertner-Dardenne, Maurus de la Rosa, Celine Dumont
摘要
多发性硬化症（MS）是一种自身免疫性疾病，影响中枢神经系统（CNS），免疫系统攻击导致神经元死亡的髓鞘。虽然可以治疗几种疾病改良疗法，但这些疗法并非普遍有效，也不停止疾病进展。更个性化的长期治疗方案针对疾病的特定方面，例如减少复发频率，延迟残疾积累以及解决影响日常功能的症状，以及可以促进神经保护和修复的疗法。嵌合抗原受体（CAR）TCELL疗法通过静脉内（IV）彻底改变了癌症治疗，该癌症治疗以汽车提供的高特异性给定剂量的T细胞。使用抑制性调节T细胞（Tregs）诱导长期耐受性的自体CAR T细胞疗法将是患者的理想疗法。因此，我们通过将汽车引入Treg来治疗MS患者来扩展CAR-T细胞的应用。我们为MS患者开发了一种髓磷脂少突胶质细胞糖蛋白（MOG）特异性CAR Treg细胞疗法。 MOG在髓磷脂鞘的外膜上表达，神经周围的形式是绝缘层，使其成为汽车Treg疗法的理想靶标。我们的主要候选人是第二代汽车，由从大型人类图书馆筛选的反MOG SCFV组成。在体外，我们证明了CAR依赖性功能，并使用被动EAE小鼠模型显示了体内功效。此外，Mog-Car Tregs具有非常低的补体信号传导，所需的信噪比会导致高度有效的汽车。总而言之，我们的数据表明，Mog-Car Treg是一种有希望的MS治疗选择，有可能诱导患者持久的耐受性。
Abstract
Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients.