HLA-B27-homodimer-specific antibody modulates the expansion of pro-inflammatory T-cells in HLA-B27 transgenic rats

Antoniou, A.N. et al. (2015) HLA-B27-homodimer-specific antibody modulates the expansion of pro-inflammatory T-cells in HLA-B27 transgenic rats. PLoS ONE, 10(6), e0130811. (doi:10.1371/journal.pone.0130811) (PMID:26125554) (PMCID:PMC4488392)

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Abstract

Objectives: 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. Conclusion: 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Milling, Professor Simon
Authors: Antoniou, A.N., Marroquin Belaunzaran, O., Kleber, S., Schauer, S., Hausmann, M., Nicholls, F., Van den Broek, M., Payeli, S., Ciurea, A., Milling, S., Stenner, F., Shaw, J., Kollnberger, S., Bowness, P., Petrausch, U., and Renner, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in PLoS One 10(6):e0130811
Publisher Policy:Reproduced under a Creative Commons License

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