New avenues of multiple sclerosis treatment inspired by pregnancy

受怀孕启发的多发性硬化症治疗新途径

• 批准号: 456055988
• 负责人: Dr. Max Kaufmann
• 金额: --
• 依托单位: Institut für Neuroimmunologie und Multiple Sklerose (INIMS)
• 依托单位国家: 德国
• 项目类别: WBP Position
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/456055988?language=en
• 关键词: New; avenues; multiple; sclerosis; treatment

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that affects millions of young individuals world-wide. Despite the availability of several therapeutic options, none has proven capable to prevent the eventual progression of MS to a state of severe disability. Thus, new avenues are desperately needed to identify more effective therapeutics for MS. Intriguingly, autoimmune diseases including MS are strongly ameliorated during pregnancy due to the induction of potent tolerance mechanisms selected over millions of years of evolution to protect the fetus. Immune modulation in pregnancy is therefore a compelling paradigm to model novel MS therapeutics. In the proposed project we will systematically study how MS is suppressed during pregnancy with the overarching goal to delineate routes of translation towards therapy. Specifically, we will analyse immune cells of MS patients and healthy individuals from multiple time points before, during and after pregnancy using a combination of parallel single cell RNA-sequencing, protein surface marker profiling, T cell receptor and B cell receptor sequencing. We will dissect the resulting high dimensional data to uncover the strongest contributions of cell types and clonotypes to the pregnancy-induced amelioration of MS. Subsequently, we will predict their driving upstream ligand-receptor interactions presumed to be ideal candidates for therapeutic targeting. Finally, we will test perturbations of the most promising target candidates directly in human immune cells striving to demonstrate that they are druggable. Together, this project promises to identify powerful naturally occurring mechanisms of immune modulation that are applicable to modify the disease course of MS and to pave the way for their direct translation into drug development.

多发性硬化症（MS）是一种中枢神经系统自身免疫性疾病，影响着全世界数以百万计的年轻人。尽管有几种治疗方法可供选择，但没有一种被证明能够防止MS最终发展为严重残疾状态。因此，迫切需要新的途径来确定更有效的多发性硬化症治疗方法。有趣的是，包括多发性硬化症在内的自身免疫性疾病在怀孕期间得到了强烈的改善，这是由于在数百万年的进化中选择了有效的耐受性机制来保护胎儿。因此，怀孕期间的免疫调节是一个令人信服的范例，以模拟新的MS治疗方法。在拟议的项目中，我们将系统地研究MS在怀孕期间是如何被抑制的，总体目标是描述转化为治疗的途径。具体来说，我们将使用平行单细胞rna测序、蛋白质表面标记分析、T细胞受体和B细胞受体测序的组合，分析MS患者和健康个体在怀孕前、怀孕期间和怀孕后多个时间点的免疫细胞。我们将分析由此产生的高维数据，以揭示细胞类型和克隆类型对妊娠诱导的ms改善的最大贡献。随后，我们将预测它们驱动的上游配体-受体相互作用，被认为是治疗靶向的理想候选者。最后，我们将测试最有希望的目标候选人的扰动直接在人类免疫细胞努力证明他们是可药物。总之，该项目有望确定适用于改变多发性硬化症病程的强大的自然发生的免疫调节机制，并为其直接转化为药物开发铺平道路。