title: Myeloperoxidase Peptide-Based Nasal Tolerance in Experimental ANCA-Associated GN.
abstract: Less toxic treatment options for patients with myeloperoxidase (MPO)-ANCA-associated GN are needed. Using an established murine model of focal necrotizing GN mediated by autoimmunity to MPO (autoimmune anti-MPO GN), we assessed the capacity for nasal tolerance induced by nasal insufflation of the immunodominant nephritogenic MPO peptide (MPO409-428) to attenuate this disease. Compared with mice that received an irrelevant immunodominant ovalbumin (OVA) peptide, OVA323-339, mice that received MPO409-428 were protected from the development of humoral and cell-mediated autoimmunity to full-length MPO and the development of GN. In mice with established anti-MPO autoimmunity, nasal insufflation of MPO409-428 as a therapeutic attenuated anti-MPO GN. To investigate the nature of this induced tolerance, we isolated CD4(+) T cells from the upper airway draining lymph nodes of both OVA323-339- and MPO409-428-tolerized mice. Adoptive transfer of CD4(+) T cells from MPO409-428- but not OVA323-339-tolerized mice to animals with established anti-MPO autoimmunity attenuated the subsequent development of GN, confirming that the immunosuppression induced by these T cells is antigen specific. Ex vivo studies showed that nasal tolerance to MPO is mediated by both conventional and induced T regulatory cells. The strong homology between the pathogenic human MPO B cell epitope recognized by ANCA in patients with acute vasculitis and the nephritogenic murine T cell MPO epitope emphasizes the clinical relevance of this study.
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; and.
authors.forename: Poh-Yi
authors.initials: PY
authors.lastname: Gan
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; and.
authors.forename: Diana S Y
authors.initials: DS
authors.lastname: Tan
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; and.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Ooi
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; and.
authors.forename: Maliha A
authors.initials: MA
authors.lastname: Alikhan
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; and Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; and Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia Stephen.holdsworth@monash.edu.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
mesh_terms: D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic; D005921:Glomerulonephritis / Q000201:enzymology* / Q000276:immunology*; D007108:Immune Tolerance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009666:Nose / Q000276:immunology*; D010455:Peptides; D009195:Peroxidase
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D010455:Peptides; D009195:Peroxidase
keywords: ANCA; GN; tolerance