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Title: | Mast cell stabilization ameliorates autoimmune anti-myeloperoxidase glomerulonephritis. | Authors: | Kitching A.R. ;Gan P.-Y.;O'Sullivan K.M.;Ooi J.D.;Alikhan M.A.;Odobasic D.;Summers S.A.;Holdsworth S.R. | Institution: | (Gan, O'Sullivan, Ooi, Alikhan, Odobasic, Summers, Holdsworth) Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168, Australia (Kitching, Holdsworth) Department of Nephrology, Monash Health, 246 Clayton Road, Clayton, VIC 3168, Australia | Issue Date: | 30-May-2017 | Copyright year: | 2016 | Publisher: | American Society of Nephrology (E-mail: email@asn-online.org) | Place of publication: | United States | Publication information: | Journal of the American Society of Nephrology. 27 (5) (pp 1321-1333), 2016. Date of Publication: May 2016. | Journal: | Journal of the American Society of Nephrology | 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 disodiumcromoglycate tomast cell-deficientmice had no effect on the development of MPO autoimmunity or GN. MPO-specific CD4+ effector T cell proliferationwas enhanced by co-culture with mast cells, but in the presence of disodiumcromoglycate, 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.Copyright © 2016 by the American Society of Nephrology. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1681/ASN.2014090906 | Link to associated publication: | Click here for full text options | PubMed URL: | 26374606 [http://www.ncbi.nlm.nih.gov/pubmed/?term=26374606] | ISSN: | 1046-6673 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/39643 | Type: | Article | Subjects: | drug efficacy drug mechanism effector cell female *glomerulonephritis/dt [Drug Therapy] *glomerulonephritis/pc [Prevention] hematuria human human tissue immunomodulation in vitro study injury severity kidney biopsy kidney cell kidney dysfunction kidney function kidney injury kidney tubule damage lymphocyte proliferation male *mast cell degranulation mouse neutrophil nonhuman phenotype priority journal proteinuria *renal protection C reactive protein/ec [Endogenous Compound] creatinine/ec [Endogenous Compound] *cromoglycate disodium/dv [Drug Development] *cromoglycate disodium/dt [Drug Therapy] *cromoglycate disodium/ip [Intraperitoneal Drug Administration] *cromoglycate disodium/pd [Pharmacology] gamma interferon/ec [Endogenous Compound] glomerulus basement membrane antibody interleukin 10/ec [Endogenous Compound] interleukin 17/ec [Endogenous Compound] *myeloperoxidase/ec [Endogenous Compound] neutrophil cytoplasmic antibody/ec [Endogenous Compound] macrophage aged albuminuria *ANCA associated vasculitis/dt [Drug Therapy] *ANCA associated vasculitis/pc [Prevention] animal cell animal experiment animal model animal tissue article autoimmunity bone marrow derived mast cell CD4+ T lymphocyte cell interaction cellular immunity clinical article coculture controlled study creatinine blood level cytokine production dendritic cell coculture controlled study creatinine blood level cytokine production dendritic cell drug efficacy drug mechanism effector cell female *glomerulonephritis / *drug therapy / *prevention hematuria human human tissue immunomodulation in vitro study injury severity kidney biopsy kidney cell kidney dysfunction kidney function kidney injury kidney tubule damage lymphocyte proliferation macrophage male *mast cell degranulation mouse neutrophil animal model phenotype priority journal proteinuria *renal protection animal experiment animal cell *ANCA associated vasculitis / *drug therapy / *prevention albuminuria aged nonhuman animal tissue Article autoimmunity bone marrow derived mast cell CD4+ T lymphocyte cell interaction cellular immunity clinical article |
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