From therapeutic mechanisms to unraveling the pathophysiology of MS

从治疗机制到揭示多发性硬化症的病理生理学

• 批准号: 7735343
• 负责人: Bibiana Bielekova
• 金额: $ 132.48万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7735343
• 关键词: Adverse effects; Animal Model; Animals; Autologous; Biological; Biological Markers; Biological Process; Brain; Cell Count; Cells; Clinical; Clinical Trials; Complex; Daclizumab; Data; Development; Disease; Encephalomyelitis; Enhancing Lesion; Etiology; Experimental Autoimmune Encephalomyelitis; Experimental Models; Failure; Freedom; Functional disorder; Goals; Hand; Human; IL2RA gene; Immune; Immune response; Immune system; Individual; Inflammatory; Injury; Interferon Type II; Laboratories; Magnetic Resonance Imaging; Measures; Mediating; Minority; Modeling; Multiple Sclerosis; Natural Killer Cells; Nervous System Trauma; Neuraxis; Outcome; Patients; Phase; Population; Process; Research; Research Personnel; System; T-Lymphocyte; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapy Clinical Trials; Tissues; autoreactive T cell; central nervous system demyelinating disorder; disability; humanized monoclonal antibodies; immunoregulation; insight; killings; neuroprotection; novel; novel therapeutics; perforin; relating to nervous system; repaired; response; success; tumor necrosis factor-alpha inhibitor; young adult

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.

多发性硬化（MS）是中枢神经系统（CNS）的炎性脱髓鞘疾病，并且是年轻成人残疾的主要原因。 MS的病因尚不清楚，但该疾病在暴露于环境触发因素的遗传易感个体中发展。 MS中长期受欢迎的假设涉及在进入CNS的外周中产生的自身反应性T细胞，在那里它们诱导导致先前正常神经组织损伤的炎症级联反应。 然而，与动物模型实验性自身免疫性脑脊髓炎（EAE）相反，在MS中既没有鉴定出免疫应答的靶标，也没有鉴定出负责CNS损伤的免疫系统的细胞。（例如IFN-γ、TNF-α抑制剂等）表明不同的机制可能会导致MS与EAE的残疾发展。 由于动物系统允许实验操作的广泛自由，EAE已被广泛探索的MS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应用治疗。因此，治疗试验，特别是那些研究新型治疗药物的试验，代表了一个独特的机会，可以研究生物系统（在我们的情况下，特别是免疫系统）的哪些扰动对疾病过程是有益的，哪些是有害的。因此，我们的实验室专注于在应用新型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见解。例如，在一个示例中，在研究用抗CD 25的人源化单克隆抗体（达克珠单抗）治疗期间的免疫应答时，我们将CD 56 bright NK细胞定义为能够通过穿孔素脱粒杀死自体活化T细胞的免疫调节细胞群。该调节人群的治疗扩展与治疗的MS患者中观察到的T细胞数量减少相关，并且还与治疗益处的程度相关，如通过抑制脑MRI上的对比增强病变所测量的。 本项目的目标是仔细研究在MS中的代谢物启动的I/II期临床试验中应用新型治疗药物引起的生物学扰动，以确定CNS组织损伤的机制，以及那些作为有益免疫调节和免疫介导的神经保护的基础的机制。虽然在早期临床开发中只有少数治疗药物将证实治疗获益，但我们认为，从治疗失败中收集的信息对于定义MS的病理生理学与从治疗成功中获得的信息同样有用。通过将在生物系统中测量的变化（例如T细胞或其他免疫细胞亚群的不同功能）与CNS破坏或修复的结构变化以及与通过临床结果测量的功能数据相关联，我们可以理解在MS疾病过程中哪些生物过程是有益的，哪些是有害的。此外，了解所应用的疗法的哪些效应是其治疗益处的基础将使我们能够定义指示性的生物标志物，并且理想地还预测完全治疗反应。最后，该项目的长期目标是充分了解MS不同亚型中CNS组织破坏的病理生理机制，以便为这种使人衰弱的疾病开发更有效的病理生理靶向疗法。