Greenberg Benjamin M, Calabresi Peter A
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA.
Semin Neurol. 2008 Feb;28(1):121-7. doi: 10.1055/s-2007-1019133.
The success of presently available injectable immunomodulatory therapies in treating multiple sclerosis has led to heightened interest in finding even more efficacious and better tolerated therapies. Several oral agents have shown efficacy in phase-II clinical trials and are now entering phase-III pivotal trials. In addition, monoclonal antibodies targeting surface receptors on various cells of the peripheral immune system have also shown efficacy in early studies and will soon be entering phase III. All of these approaches target immune molecules that are not specific for multiple sclerosis (MS) and carry inherent risk of infection and systemic side effects. Novel immunotherapies in preclinical or phases I to IIa testing are attempting to more selectively target pathogenic effector cells and thereby block abnormal immune cell activation without compromising normal healthy immune responses. The induction of tolerance to self-proteins continues to be a goal of MS immunotherapy, but as yet has not been accomplished outside of the laboratory. There is increasing awareness of the need to understand and modulate nonclassical immune targets as well as central nervous system degenerative processes. The roles of vitamins, antimicrobials, and hormones continue to be studied. The mechanisms of neurodegeneration in MS are likely multifactorial and include direct damage by T cells and humoral immunity as well as oxidative stress, glutamate-mediated excitotoxicity, and neuronal and oligodendrocyte apoptosis. Neuroprotective drugs that were once only considered for classical degenerative diseases, such as amyotrophic lateral sclerosis and Parkinson's disease, are now being considered in MS.
目前可用的注射用免疫调节疗法在治疗多发性硬化症方面的成功，引发了人们对寻找更有效且耐受性更好的疗法的浓厚兴趣。几种口服药物在II期临床试验中已显示出疗效，目前正进入III期关键试验阶段。此外，针对外周免疫系统各种细胞表面受体的单克隆抗体在早期研究中也显示出疗效，并且很快将进入III期试验。所有这些方法所针对的免疫分子并非多发性硬化症（MS）所特有的，并且存在感染和全身性副作用的固有风险。处于临床前或I至IIa期试验阶段的新型免疫疗法正试图更有选择性地靶向致病性效应细胞，从而在不损害正常健康免疫反应的情况下阻断异常免疫细胞的激活。诱导对自身蛋白的耐受性仍然是MS免疫疗法的一个目标，但迄今为止在实验室之外尚未实现。人们越来越意识到需要了解和调节非经典免疫靶点以及中枢神经系统的退行性过程。维生素、抗菌药物和激素的作用仍在研究中。MS中的神经退行性变机制可能是多因素的，包括T细胞和体液免疫的直接损伤以及氧化应激、谷氨酸介导的兴奋性毒性，以及神经元和少突胶质细胞的凋亡。曾经仅被考虑用于经典退行性疾病（如肌萎缩侧索硬化症和帕金森病）的神经保护药物，现在也正在MS中进行研究。
