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Abstract: TH-OR053

Myeloperoxidase Mediates Renal Damage in Crescentic Glomerulonephritis That Can Be Successfully Targeted In Vivo

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Antonelou, Marilina, University College London, London, United Kingdom
  • Michaëlsson, Erik, AstraZeneca, Gothenburg, Sweden
  • Wang, Chun Jing, Institute of Immunity and Transplantation, University College London, London, United Kingdom
  • Walker, Lucy S.K., Institute of Immunity and Transplantation, University College London, London, United Kingdom
  • Unwin, Robert J., AstraZeneca, Gothenburg, Sweden
  • Salama, Alan D., University College London, London, United Kingdom
Background

Myeloperoxidase (MPO) released following neutrophil and monocyte activation can lead to host tissue damage by generating ROS and promoting further leukocyte activation. Extracellular glomerular MPO deposition has been shown in ANCA associated vasculitis (AAV) and may promote T and B cell glomerular targeting to enhance crescentic glomerulonephritis (CGN). MPO-deficient mice have less CGN but enhanced T cell activity (Odobasic, 2007). We investigated the role of MPO in mediating glomerular damage and leukocyte activation using a novel MPO inhibitor, AZM198.

Methods

A) We stained renal biopsies from patients with CGN due to SLE, IgA,anti-GBM disease, ANCA- and ANCA+ GN, for MPO and CD15. B) We measured MPO activity in the supernatants of AAV patient neutrophils and healthy controls, stimulated by different means in the absence and presence of AZM198. C) We induced nephrotoxic nephritis (NTN) in C57BL/6 mice investigating the effect of AZM198 on CGN severity and T cell activity and D) tested the effect of AZM198 on antigen-specific T cell responses using adoptive transfer of DO11.10 lymphocytes into OVA immunised mice.

Results

All biopsies with CGN had extracellular glomerular MPO deposition. In vitro, AZM198 led to a significant reduction in MPO activity measured in the supernatants of PMA (n=16,median(IQR) 37.4(9-175.6) vs12.93(1.9-152.8)U/g, p<0.05), TNF(n=8, 229.2(130.3-950.6) vs108.5(33.3-138.1)U/g, p<0.05) and pANCA(n=6,185.8(79.9-278.9) vs114.3(45.9-340.6)U/g, p=0.19) stimulated neutrophils. In vivo, AZM198 attenuated glomerular inflammation (NTN model), defined by proteinuria (A,p=0.01) and glomerular thrombosis (B,p=0.04,vehicle n=13, MPOi n=15), while reducing CD4 activation. In the adoptive cell transfer model, AZM198 led to a non-significant reduction of CD44 and KJ expression on CD4+ T cells in the draining lymph nodes (C, vehicle n=3, MPOi n=3).

Conclusion

Therapeutic MPO inhibition reduced neutrophil degranulation in patients with AAV and attenuated kidney damage in preclinical models of CGN without augmenting adaptive immune responses, suggesting it may be a novel adjunctive therapy in various forms of CGN.