New avenues of multiple sclerosis treatment inspired by pregnancy

多发性硬化症(MS)是一种中枢神经系统的自身免疫性疾病，影响着全球数百万年轻人。尽管有几种治疗选择，但没有一种被证明能够阻止多发性硬化症最终发展到严重残疾的状态。因此，迫切需要新的途径来寻找更有效的治疗多发性硬化症的方法。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，这是因为经过数百万年的进化选择了有效的耐受机制来保护胎儿。因此，妊娠中的免疫调节是模拟新的多发性硬化症治疗方法的一个引人注目的范例。在拟议的项目中，我们将系统地研究妊娠期间多发性硬化症是如何被抑制的，首要目标是勾勒出转化为治疗的途径。具体地说，我们将结合并行单细胞RNA测序、蛋白质表面标志物分析、T细胞受体测序和B细胞受体测序，从怀孕前、怀孕期间和怀孕后的多个时间点分析多发性硬化症患者和健康人的免疫细胞。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上游配体-受体的相互作用，被认为是治疗靶向的理想候选。最后，我们将直接在人类免疫细胞中测试最有希望的候选靶点的扰动，以努力证明它们是可下药的。总之，该项目承诺识别强大的自然发生的免疫调节机制，这些机制适用于修改MS的病程，并为将其直接转化为药物开发铺平道路。

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.