Immunization against poly-N-acetylglucosamine reduces neutrophil activation and GVHD while sparing microbial diversity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 41; pp. 20700 - 20706
• Main Authors: Hülsdünker, Jan, Thomas, Oliver S., Haring, Eileen, Unger, Susanne, Núñez, Nicolás Gonzalo, Tugues, Sonia, Gao, Zhan, Duquesne, Sandra, Cywes-Bentley, Colette, Oyardi, Ozlem, Kirschnek, Susanne, Schmitt-Graeff, Annette, Pabst, Oliver, Koenecke, Christian, Duyster, Justus, Apostolova, Petya, Blaser, Martin J., Becher, Burkhard, Pier, Gerald B., Häcker, Georg, Zeiser, Robert
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08.10.2019
• Subjects: Animals; Antibiotics; Antibodies; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - immunology; Antiinfectives and antibacterials; Antimicrobial activity; Antimicrobial agents; Bacteria; Bacteria - classification; Bacteria - drug effects; Bacteria - immunology; Biological Sciences; Cell activation; DNA sequencing; Female; Graft vs Host Disease - immunology; Graft vs Host Disease - pathology; Graft vs Host Disease - prevention & control; Graft-versus-host reaction; Ileum; Immune system; Immunization; Immunization (passive); Immunization, Passive - methods; Intestine; Intestines - drug effects; Intestines - immunology; Leukocytes (granulocytic); Leukocytes (neutrophilic); Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microbiota; Microorganisms; Monoclonal antibodies; Mucosa; N-Acetylglucosamine; Neutrophil Activation - drug effects; Neutrophil Activation - immunology; Neutrophils; Neutrophils - drug effects; Neutrophils - immunology; Pathogens; Peroxidase; Polysaccharides; Polysaccharides, Bacterial - antagonists & inhibitors; Polysaccharides, Bacterial - immunology; Ribosomal DNA; Sepsis; Transplantation; Vaccination; Vaccines; microbiome; GVHD; neutrophil granulocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1908549116

Microbial invasion into the intestinal mucosa after allogeneic hematopoietic cell transplantation (allo-HCT) triggers neutrophil activation and requires antibiotic interventions to prevent sepsis. However, antibiotics lead to a loss of microbiota diversity, which is connected to a higher incidence of acute graft-versus-host disease (aGVHD). Antimicrobial therapies that eliminate invading bacteria and reduce neutrophil-mediated damage without reducing the diversity of the microbiota are therefore highly desirable. A potential solution would be the use of antimicrobial antibodies that target invading pathogens, ultimately leading to their elimination by innate immune cells. In a mouse model of aGVHD, we investigated the potency of active and passive immunization against the conserved microbial surface polysaccharide poly-N-acetylglucosamine (PNAG) that is expressed on numerous pathogens. Treatment with monoclonal or polyclonal antibodies to PNAG (anti-PNAG) or vaccination against PNAG reduced aGVHD-related mortality. Anti-PNAG treatment did not change the intestinal microbial diversity as determined by 16S ribosomal DNA sequencing. Anti-PNAG treatment reduced myeloperoxidase activation and proliferation of neutrophil granulocytes (neutrophils) in the ileum of mice developing GVHD. In vitro, anti-PNAG treatment showed high antimicrobial activity. The functional role of neutrophils was confirmed by using neutrophil-deficient LysMcre Mcl1fl/fl mice that had no survival advantage under anti-PNAG treatment. In summary, the control of invading bacteria by anti-PNAG treatment could be a novel approach to reduce the uncontrolled neutrophil activation that promotes early GVHD and opens a new avenue to interfere with aGVHD without affecting commensal intestinal microbial diversity.