Systems-level analysis of therapeutic helminth-induced immune modulation in patients with rheumatoid arthritis

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Based on the hygiene hypothesis, the treatment of rheumatoid arthritis (RA) by intentional helminth infection with Trichuris suis ova (TSO) promises amelioration of the disease associated with less side effects as compared to currently approved therapies. The induction of the bodys own specific immunomodulatory pathways rather than the extrinsic suppression of the immune system by conventional medication, makes this new treatment concept particularly suitable for treatment of chronic inflammatory diseases such as RA, which require life-long medication and toleration of therapy.In order to gain insight in the mechanism of action of TSO therapy and to contribute to precision medicine in the treatment of RA, it is of great interest to study how immune features change during the response to TSO therapy, and how this relates to clinical parameters such as disease activity, response to therapy and serum levels of pathogenic antibodies or inflammatory cytokines.In this proposal, 40-dimensional single-cell mass cytometry (CyTOF) will be used to systematically study the composition and activation state of blood immune cells from RA patients undergoing targeted and timely controlled TSO treatment in a double-blinded, placebo-controlled clinical pilot trial. Our highly cutting-edge cytometric approach combined with clinical and serological data will give unprecedentedly detailed insights into the phenotype, functionality and TSO treatment response of white blood cells. Established unsupervised computational data analyses will be used to extract immune signatures of i) RA, ii) the immune systems response to helminth infection, and iii) clinical parameters such as disease activity or future therapy success. This study will, for the first time, provide systems-level insights into blood immune cell dysregulation in RA patients, and reveal the impact of TSO treatment on RA-associated immune cell abnormalities. Altogether, we expect our project to elucidate mechanism of action of helminth therapy in humans and contribute to the idea of precision medicine in chronic inflammatory diseases.