From therapeutic mechanisms to unraveling the pathophysiology of MS

多发性硬化症(MS)是一种中枢神经系统(CNS)的炎症性脱髓鞘疾病，是导致年轻人残疾的主要原因。多发性硬化症的病因尚不清楚，但这种疾病在暴露于环境诱因的遗传易感个体中发展。多发性硬化症长期被支持的假说表明，在进入中枢神经系统的外周产生的自体反应性T细胞，在那里它们诱导炎症级联反应，导致先前正常的神经组织的损伤。然而，与实验性自身免疫性脑脊髓炎(EAE)动物模型相比，MS中既没有发现免疫反应的靶点(S)，也没有发现负责中枢神经系统损伤的免疫系统细胞。此外，一些针对EAE中枢组织破坏过程的MS治疗明显失败(如干扰素-γ、肿瘤坏死因子-α抑制剂等)，表明不同的机制可能导致MS与EAE的残疾发展。 由于动物系统允许广泛的实验操作自由，EAE已被广泛探索为MS的模型。另一方面，在人类研究的伦理约束下，唯一可能的实验操作是治疗的应用。因此，治疗性试验，特别是那些研究新型治疗剂的试验，代表着一个独特的机会，可以研究生物系统(在我们的情况下，特别是免疫系统)的哪些扰动是有益的，哪些对疾病过程是有害的。因此，我们的实验室专注于在应用新的免疫调节疗法之前和期间对MS患者免疫系统的复杂功能进行详细分析。这种方法使我们在过去获得了对人类免疫调节的重要洞察力。例如，在研究人源化抗CD25单抗(Daclizumab)治疗期间的免疫反应时，我们将CD56bright NK细胞定义为能够通过穿孔素脱颗粒杀死自体激活的T细胞的免疫调节细胞群。这一调节人群的治疗扩展与观察到的治疗多发性硬化症患者T细胞数量的减少相关，也与治疗受益的程度相关，如通过抑制脑MRI上对比剂增强的病变来衡量。 本项目的目标是仔细研究在研究者发起的MS的I/II期临床试验中，新型治疗药物的应用所引起的生物扰动，以确定中枢组织损伤的机制，以及那些有益的免疫调节和免疫介导的神经保护的机制。虽然在早期临床开发中只有一小部分治疗剂将证实治疗益处，但我们相信，从治疗失败中收集的信息对于将MS的病理生理学定义为从治疗成功中获得的信息同样有用。通过将生物系统中测量的变化(如T细胞或其他免疫细胞亚群的不同功能)与中枢神经系统破坏或修复的结构变化以及临床结果测量的功能数据相关联，我们可以了解在MS疾病过程中哪些生物过程是有益的，哪些是有害的。此外，了解应用疗法的哪些效果是其治疗益处的基础，将使我们能够定义具有指示性的生物标记物，理想情况下也可以预测全部治疗反应。最后，该项目的长期目标是充分了解不同亚型MS的中枢神经系统组织破坏的病理生理学机制，以开发更有效的、针对这种衰弱疾病的病理生理学靶向治疗方法。

Multiple Sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) and is a major cause of disability in young adults. The etiology of MS remains unclear, but the disease develops in genetically susceptible individuals exposed to environmental triggers. The long favored hypothesis in MS implicates autoreactive T cells generated in the periphery that access the CNS, where they induce an inflammatory cascade that results in the injury of previously normal neural tissues. However, in contrast to the animal model experimental autoimmune encephalomyelitis (EAE), neither the target(s) of the immune response nor the cells of the immune system responsible for CNS damage have been identified in MS. Furthermore, the apparent failure of some MS treatments targeting processes that underlie the development of CNS tissue destruction in EAE (e.g. IFN-gamma, TNF-alpha inhibitors and others) indicates that different mechanisms may cause the development of disability in MS versus EAE. EAE has been widely explored model of MS, due to the fact that animal systems allow extensive freedom of experimental manipulations. On the other hand the only experimental manipulation that is possible within the ethical constrains of human research is application of therapies. Therefore, therapeutic trials, especially those that investigate novel therapeutic agents, represent a unique opportunity to investigate which perturbations of the biological system (in our case especially of the immune system) are beneficial and which are deleterious for the disease process. As a result, our laboratory focuses on performing detailed analyses of the complex functions of the immune system in MS patients before and during application of novel immunomodulatory therapies. This approach allowed us in the past to gain important insight into immunoregulation in humans. E.g., while studying immune responses during treatment with a humanized monoclonal antibody against CD25 (daclizumab) we defined CD56bright NK cells as an immunoregulatory cell population that is capable of killing autologous activated T cells via perforin degranulation. The therapeutic expansion of this regulatory population correlated with the observed decrease in T cell numbers in treated MS patients and also correlated with the extent of therapeutic benefit, as measured by inhibition of contrast-enhancing lesions on brain MRI. The goal of this project is to carefully study the biological perturbations induced by the application of novel therapeutic agents in investigator-initiated Phase I/II clinical trials in MS in order to define mechanisms of CNS tissue injury, but also those mechanisms that underlie beneficial immunoregulation and immune-mediated neuroprotection. While only a minority of the therapeutic agents in early clinical development will confirm therapeutic benefit, we believe that the information collected from therapeutic failures is equally useful for defining pathophysiology of MS as information obtained from therapeutic successes. By correlating changes measured in the biological system (e.g. different functions of the T cells or other immune cell subsets) with structural changes of CNS destruction or repair, and with functional data as measured by clinical outcomes, we can understand which biological processes are beneficial and which are harmful in the MS disease process. Additionally, understanding which effects of applied therapies underlie their therapeutic benefit will allow us to define biomarkers that are indicative, and ideally also predictive of the full therapeutic response. Finally, the long-term goal of this project is to gain full understanding of the pathophysiological mechanisms that underlie CNS tissue destruction in different subtypes of MS, in order to develop more effective and pathophysiologically-targeted therapies for this debilitating disorder.