Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis

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 patient...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the American Society of Nephrology 2016-05, Vol.27 (5), p.1321-1333
Main Authors: Gan, Poh-Yi, O'Sullivan, Kim M, Ooi, Joshua D, Alikhan, Maliha A, Odobasic, Dragana, Summers, Shaun A, Kitching, A Richard, Holdsworth, Stephen R
Format: Article
Language:English
Subjects:
Aged
Animals
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - drug therapy
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - immunology
Autoimmune Diseases - drug therapy
Autoimmune Diseases - immunology
Basic Research
Cromolyn Sodium - pharmacology
Cromolyn Sodium - therapeutic use
Female
Glomerulonephritis - drug therapy
Glomerulonephritis - immunology
Humans
Male
Mast Cells - drug effects
Mast Cells - immunology
Mice
Peroxidase - immunology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1046-6673
1533-3450
DOI:10.1681/asn.2014090906