title: HLA-B27-Homodimer-Specific Antibody Modulates the Expansion of Pro-Inflammatory T-Cells in HLA-B27 Transgenic Rats.
abstract: OBJECTIVE
  HLA-B27 is a common genetic risk factor for the development of Spondyloarthritides (SpA). HLA-B27 can misfold to form cell-surface heavy chain homodimers (B272) and induce pro-inflammatory responses that may lead to SpA pathogenesis. The presence of B272 can be detected on leukocytes of HLA-B27+ Ankylosing spondylitis (AS) patients and HLA-B27 transgenic rats. We characterized a novel B272-specific monoclonal antibody to study its therapeutic use in HLA-B27 associated disorders.
  
  
  METHODS
  The monoclonal HD5 antibody was selected from a phage library to target cell-surface B272 homodimers and characterized for affinity, specificity and ligand binding. The immune modulating effect of HD5 was tested in HLA-B27 transgenic rats. Onset and progression of disease profiles were monitored during therapy. Cell-surface B272 and expansion of pro-inflammatory cells from blood, spleen and draining lymph nodes were assessed by flow cytometry.
  
  
  RESULTS
  HD5 bound B272 with high specificity and affinity (Kd = 0.32 nM). HD5 blocked cell-surface interaction of B272 with immune regulatory receptors KIR3DL2, LILRB2 and Pirb. In addition, HD5 modulated the production of TNF from CD4+ T-cells by limiting B272 interactions in vitro. In an HLA-B27 transgenic rat model repetitive dosing of HD5 reduced the expansion of pro-inflammatory CD4+ T-cells, and decreased the levels of soluble TNF and number of cell-surface B272 molecules.
  
  
  CONCLUSIONS
  HD5 predominantly inhibits early TNF production and expansion of pro-inflammatory CD4+ T-cells in HLA-B27 transgenic rats. Monoclonal antibodies targeting cell-surface B272 propose a new concept for the modulation of inflammatory responses in HLA-B27 related disorders.
authors.affiliation: Division of Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Osiris
authors.initials: O
authors.lastname: Marroquin Belaunzaran
authors.affiliation: Division of Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Sascha
authors.initials: S
authors.lastname: Kleber
authors.affiliation: Functional Genomics Center Zurich, Swiss Federal Institute of Technology Zurich / University of Zurich, Zurich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schauer
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Hausmann
authors.affiliation: Central Biological Laboratory, University of Zurich, Zurich, Switzerland.
authors.forename: Flora
authors.initials: F
authors.lastname: Nicholls
authors.affiliation: Division of Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Maries
authors.initials: M
authors.lastname: Van den Broek
authors.affiliation: Division of Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Sravan
authors.initials: S
authors.lastname: Payeli
authors.affiliation: Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Ciurea
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Milling
authors.affiliation: Department of Oncology, University Hospital Basel, Basel, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Stenner
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, United Kingdom.
authors.forename: Jackie
authors.initials: J
authors.lastname: Shaw
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Kollnberger
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Bowness
authors.affiliation: Division of Oncology, University Hospital Zurich, Zurich, Switzerland; Department of Clinical Immunology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Ulf
authors.initials: U
authors.lastname: Petrausch
authors.affiliation: Division of Oncology, University Hospital Zurich, Zurich, Switzerland; Department of Oncology, University Hospital Basel, Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Renner
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D015796:HLA-B27 Antigen / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D025241:Spondylarthritis / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015796:HLA-B27 Antigen