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

• Applicant: Dr. Axel Schulz
• Subject Area: Rheumatology ; Immunology ; Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391151950

• Final Report Year: 2019

Final Report Abstract

Rheumatoid arthritis (RA) patients treated with a novel therapeutic approach using eggs of the intestinal, potentially immune modulatory helminth Trichuris suis (TSO) in a placebo-controlled clinical trial were studied at systems-level by mass cytometric (CyTOF) immune phenotyping to identify immune system aberrations associated with active RA and to investigate the therapeutic impact of a worm infection on the autoimmunityaltered immune system. For this purpose, we established an elaborated mass cytometric and computational analysis pipeline that included several technical advancements, such as antibody cocktail preservation and beta-2-microglobulin-based live cell barcoding, which were published by us in several papers. By analyzing time-resolved samples from 35 treated RA patients and 31 healthy controls with a 43-plex antibody panel, followed by a FlowSOM clustering approach, we were able to uncover a complex multivariate immune signature of active RA that was characterized by reduced memory and effector cells in T- and B-cell compartments and an overall diminished expression of the inflammatory chemokine receptor CXCR3 across different cell subsets. In contrast to placebo treatment, TSO infection induced changes in various immune cell subtypes within the first 13 weeks of treatment, the extent of which correlated with the early improvement of RA activity. The analysis of longitudinal data is still ongoing and the publication of the results is planned for the near future. Altogether, our study discovered important immune signatures in RA and the publication of essential procedures established for this study contributed to similar CyTOF-based studies in rheumatism research and beyond.

Publications

• Osmium-Labeled Microspheres for Bead-Based Assays in Mass Cytometry. J Immunol. 2019
  Budzinski L, Schulz AR, Baumgart S, Burns T, Rose T, Hirseland H, Mei HE
  (See online at https://doi.org/10.4049/jimmunol.1801640)
• Stabilizing Antibody Cocktails for Mass Cytometry. Cytometry A. 2019
  Schulz AR, Baumgart S, Schulze J, Urbicht M, Grützkau A, Mei HE
  (See online at https://doi.org/10.1002/cyto.a.23781)
• Surface Barcoding of Live PBMC for Multiplexed Mass Cytometry. Methods Mol Biol. 2019
  Schulz AR, Mei HE
  (See online at https://doi.org/10.1007/978-1-4939-9454-0_7)