New avenues of multiple sclerosis treatment inspired by pregnancy

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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.