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MS最终进展为严重残疾状态。因此，迫切需要新的途径来确定更有效的MS治疗方法。有趣的是，包括MS在内的自身免疫性疾病在怀孕期间得到了极大的改善，这是由于诱导了数百万年进化中选择的有效耐受机制来保护胎儿。因此，妊娠中的免疫调节是一个令人信服的范例，以模拟新的MS治疗。在拟议的项目中，我们将系统地研究如何在怀孕期间抑制MS，总体目标是描绘治疗的翻译途径。具体而言，我们将使用平行单细胞RNA测序、蛋白质表面标记物分析、T细胞受体和B细胞受体测序的组合，分析MS患者和健康个体在妊娠前、妊娠期间和妊娠后多个时间点的免疫细胞。我们将解剖所得的高维数据，以揭示最强的贡献，细胞类型和克隆型妊娠诱导改善MS。随后，我们将预测其驱动上游配体-受体相互作用，推测是理想的候选人治疗靶向。最后，我们将直接在人类免疫细胞中测试最有希望的靶候选物的扰动，以证明它们是可药物化的。总之，该项目有望确定强大的自然发生的免疫调节机制，适用于改变MS的病程，并为它们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.