title: Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis.
abstract: Observations in experimental murine myeloperoxidase (MPO)-ANCA-associated vasculitis (AAV) show mast cells degranulate, thus enhancing injury as well as producing immunomodulatory IL-10. Here we report that, compared with biopsy specimens from control patients, renal biopsy specimens from 44 patients with acute AAV had more mast cells in the interstitium, which correlated with the severity of tubulointerstitial injury. Furthermore, most of the mast cells were degranulated and spindle-shaped in patients with acute AAV, indicating an activated phenotype. We hypothesized that the mast cell stabilizer disodium cromoglycate would attenuate mast cell degranulation without affecting IL-10 production. We induced anti-MPO GN by immunizing mice with MPO and a low dose of anti-glomerular basement membrane antibody. When administered before or after induction of MPO autoimmunity in these mice, disodium cromoglycate attenuated mast cell degranulation, development of autoimmunity, and development of GN, without diminishing IL-10 production. In contrast, administration of disodium cromoglycate to mast cell-deficient mice had no effect on the development of MPO autoimmunity or GN. MPO-specific CD4(+) effector T cell proliferation was enhanced by co-culture with mast cells, but in the presence of disodium cromoglycate, proliferation was inhibited and IL-10 production was enhanced. These results indicate that disodium cromoglycate blocks injurious mast cell degranulation specifically without affecting the immunomodulatory role of these cells. Thus as a therapeutic, disodium cromoglycate may substantially enhance the regulatory role of mast cells in MPO-AAV.
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, VIC, Australia; and.
authors.forename: Poh-Yi
authors.initials: PY
authors.lastname: Gan
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, VIC, Australia; and.
authors.forename: Kim M
authors.initials: KM
authors.lastname: O'Sullivan
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, VIC, Australia; and.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Ooi
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, VIC, Australia; and.
authors.forename: Maliha A
authors.initials: MA
authors.lastname: Alikhan
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, VIC, Australia; and.
authors.forename: Dragana
authors.initials: D
authors.lastname: Odobasic
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, VIC, Australia; and.
authors.forename: Shaun A
authors.initials: SA
authors.lastname: Summers
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, VIC, Australia; and Department of Nephrology, Monash Health, 246 Clayton Road, Clayton, VIC 3168, Australia.
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, VIC, Australia; and Department of Nephrology, Monash Health, 246 Clayton Road, Clayton, VIC 3168, Australia Stephen.holdsworth@monash.edu.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
mesh_terms: D000368:Aged; D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000188:drug therapy* / Q000276:immunology*; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology*; D004205:Cromolyn Sodium / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D009195:Peroxidase / Q000276:immunology*
chemical_list: D009195:Peroxidase; D004205:Cromolyn Sodium