Multiple Sclerosis (MS) is an immune-mediated neurological disorder, characterized by central nervous system (CNS) inflammation, oligodendrocyte loss, demyelination, and axonal degeneration. Although autoimmunity, inflammatory demyelination and neurodegeneration underlie MS, the initiating event has yet to be clarified. Effective disease modifying therapies need to both regulate the immune system and promote restoration of neuronal function, including remyelination. The challenge in developing an effective long-lived therapy for MS requires that three disease-associated targets be addressed: (1) self-tolerance must be re-established to specifically inhibit the underlying myelin-directed autoimmune pathogenic mechanisms; (2) neurons must be protected from inflammatory injury and degeneration; (3) myelin repair must be engendered by stimulating oligodendrocyte progenitors to remyelinate CNS neuronal axons. The combined use of chronic and relapsing remitting experimental autoimmune encephalomyelitis (C-EAE, R-EAE) (“outside-in”) as well as progressive diphtheria toxin A chain (DTA) and cuprizone autoimmune encephalitis (CAE) (“inside-out”) mouse models allow for the investigation and specific targeting of all three of these MS-associated disease parameters. The “outside-in” EAE models initiated by myelin-specific autoreactive CD4⁺ T cells allow for the evaluation of both myelin-specific tolerance in the absence or presence of neuroprotective and/or remyelinating agents. The “inside-out” mouse models of secondary inflammatory demyelination are triggered by toxin-induced oligodendrocyte loss or subtle myelin damage, which allows evaluation of novel therapeutics that could promote remyelination and neuroprotection in the CNS. Overall, utilizing these complementary pre-clinical MS models will open new avenues for developing therapeutic interventions, tackling MS from the “outside-in” and/or “inside-out”.

多发性硬化症（MS）是一种免疫介导的神经系统疾病，其特征在于中枢神经系统（CNS）炎症，少突胶质细胞丢失，脱髓鞘和轴突变性。尽管自身免疫，炎性脱髓鞘和神经退行性变是MS的基础，但起始事件尚未阐明。有效的疾病改良疗法既需要调节免疫系统，又需要促进神经元功能的恢复，包括髓鞘再生。开发有效的MS长期治疗方法所面临的挑战要求解决三个与疾病相关的靶标：（1）必须重新建立自我耐受性，以特异性抑制潜在的髓鞘定向自身免疫致病机制；（2）必须保护神经元免受炎性损伤和变性；（3）必须通过刺激少突胶质细胞祖细胞使髓鞘再生神经元轴突来进行髓磷脂修复。慢性和复发性缓解实验性自身免疫性脑脊髓炎（C-EAE，R-EAE）（“由内而外”）以及进行性白喉毒素A链（DTA）和铜酮自身免疫性脑炎（CAE）（“由内而外”）小鼠模型可用于研究和特异性靶向所有这三种与MS相关的疾病参数。由髓磷脂特异性自反应性CD4 ⁺启动的“由内而外” EAE模型在不存在或存在神经保护剂和/或髓鞘再生剂的情况下，T细胞可评估髓鞘特异性耐受性。毒素引起的少突胶质细胞损失或细微的髓磷脂损伤触发了“由内而外”的继发性炎性脱髓鞘小鼠模型，这使得可以评估可以促进中枢神经系统再髓鞘形成和神经保护的新型疗法。总体而言，利用这些互补的临床前MS模型将为开发治疗干预措施开辟新途径，从“由内而外”和/或“由内而外”应对MS。