Modern drugs in use for multiple sclerosis patients have shown immense beneficial effects on relapse rate, disease progression and MRI-activity. However, recent increase of progressive multifocal leukoencephalopathy related with some of them is not unders

用于治疗多发性硬化症患者的现代药物对复发率、疾病进展和 MRI 活性显示出巨大的有益作用。

• 批准号: 194656860
• 负责人: Professor Dr. Aiden Haghikia
• 金额: --
• 依托单位: Weatherall Institute of Molecular Medicine
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/194656860?language=en
• 关键词: Modern; drugs; use; multiple; sclerosis

Recent progress in the understanding of relevant pathomechanisms of multiple sclerosis (MS) has led to the development of highly specific therapeutic approaches. However, some of these therapeutics have led to severe virologic infections of the brain, e.g. progressive multifocal leukoencephalopathy (PML). The occurrence and key pathomechanisms of PML - an opportunistic JC viral mediated and typically fatal CNS-infection - under monoclonal antiibodies (mAb), e.g. natalizumab, rituximab and efalizumab in otherwise immunocompetent MS (but also psoriasis- and arthritis-) patients remain cryptic. So far, PML was typically associated with severely immunocompromised patients, e.g. HIV or leukemic diseases. In a pilot study, we have established a sensitive immunoassay by quantifying cellular energetics of immune effector cells in response to stimulation as a functional parameter of cellular immunity in over 500 MS patients under various therapies and in 20 recent cases of mAb- and HIV-related PML. To achieve a higher degree of specificity, and concerning the pathogenesis of PML, to identify possible host predisposition, the project as planned in Prof. Fuggers group at the University of Oxford is aiming at immunogenetic (HLA type of PML patients) and immunologic (ability of CD4+/CD8+-cells to response to antigen specific stimulation by the immunodominant JCV epitope(s)) factors leading to the unexpected occurrence of PML in MS patients. By results gained from this study, we await a better understanding of JC viral infection of the CNS which will enable the development of a predictive marker identifying patients at risk for PML.

最近对多发性硬化症（MS）相关病理机制的理解取得了进展，导致了高度特异性治疗方法的发展。然而，其中一些疗法已导致严重的大脑病毒感染，例如进行性多灶性白质脑病（PML）。 PML（一种机会性 JC 病毒介导的、通常致命的 CNS 感染）在单克隆抗体 (mAb) 的作用下的发生和关键病理机制，例如那他珠单抗、利妥昔单抗和依法珠单抗在其他免疫功能正常的多发性硬化症（以及牛皮癣和关节炎）患者中的作用仍然神秘。到目前为止，PML 通常与严重免疫功能低下的患者有关，例如艾滋病毒或白血病。在一项试点研究中，我们通过量化免疫效应细胞响应刺激的细胞能量作为细胞免疫的功能参数，建立了一种灵敏的免疫测定方法，该方法对超过 500 名接受各种治疗的 MS 患者以及最近 20 例 mAb 和 HIV 相关 PML 病例进行了分析。为了实现更高程度的特异性，并就 PML 的发病机制，确定可能的宿主易感性，牛津大学 Fuggers 教授小组计划的项目旨在研究免疫遗传（PML 患者的 HLA 类型）和免疫学（CD4+/CD8+-细胞对免疫显性 JCV 表位对抗原特异性刺激作出反应的能力）因素，从而导致意外的发生。 MS 患者发生 PML。通过这项研究获得的结果，我们等待对 CNS 的 JC 病毒感染有更好的了解，这将有助于开发出识别有 PML 风险的患者的预测标记。