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.

多发性硬化症（MS）是中枢神经系统（CNS）的炎症性脱髓鞘疾病，是年轻人残疾的主要原因。 MS的病因尚不清楚，但是该疾病在暴露于环境触发因素的遗传易感人群中发展。 长期以来，MS中长期以来的假设暗示了进入中枢神经系统的外围产生的自动反应性T细胞，它们会诱导炎症性级联反应，从而导致先前正常神经组织的损伤。 但是，与动物模型实验性自身免疫性脑脊髓炎（EAE）相反，在MS中均未确定免疫反应的靶标或负责CNS损伤的免疫系统的细胞。此外，某些MS处理的靶向过程的明显失败是基于EAE中枢神经系统组织破坏发展的基础（例如IFN-Gamma，TNF-Alpha抑制剂和其他抑制剂），这表明不同机制可能导致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，因此已广泛探索了MS的模型。另一方面，在人类研究的伦理约束中，唯一可能的实验操作是治疗的应用。因此，治疗试验，尤其是研究新型治疗剂的试验，是一个独特的机会，可以调查生物系统的哪种扰动（在我们的情况下，尤其是免疫系统的扰动）是有益的，并且在疾病过程中是有害的。结果，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患者中免疫系统复杂功能进行详细分析。这种方法使我们过去能够对人类免疫调节的重要见解。例如，在研究用人源化的单克隆抗体对CD25（Daclizumab）治疗期间的免疫反应时，我们将CD56Bright NK细胞定义为一种免疫调节细胞群，能够通过perforin脱粒杀死自体激活的T细胞。该调节群体的治疗扩张与已观察到的MS患者的T细胞数量的减少相关，并且与治疗益处的程度相关，这是通过抑制对脑MRI的对比增强病变来衡量的。 该项目的目的是仔细研究新型治疗剂在MS中的I/II期临床试验中应用新型治疗剂引起的生物扰动，以定义CNS组织损伤的机制，以及这些机制，这些机制是基于有益的免疫调节和免疫介导的神经保护的机制。尽管在早期临床开发中只有少数治疗剂可以证实治疗益处，但我们认为，从治疗失败中收集的信息对于从治疗成功中获得的信息定义MS的病理生理学同样有用。通过将生物系统中测得的变化（例如，T细胞或其他免疫细胞子集的不同功能）与中枢神经系统破坏或修复的结构变化以及通过临床结果衡量的功能数据相关联，我们可以了解哪些生物学过程是有益的，哪些在MS疾病过程中是有害的。另外，了解其治疗益处是应用疗法的哪些影响将使我们能够定义指示性的生物标志物，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对MS不同亚型的CNS组织破坏的病理生理机制充分了解，以便为这种令人衰弱的疾病开发更有效和病理生理学的疗法。