Alkylating histone deacetylase inhibitors may have therapeutic value in experimental myeloperoxidase-ANCA vasculitis.

Abstract

Current therapies for treating antineutrophil cytoplasm autoantibody (ANCA)-associated vasculitis include cyclophosphamide and corticosteroids. Unfortunately, these agents are associated with severe adverse effects, despite inducing remission in most patients. Histone deacetylase inhibitors are effective in rodent models of inflammation and act synergistically with many pharmacological agents, including alkylating agents like cyclophosphamide. EDO-S101 is an alkylating fusion histone deacetylase inhibitor molecule combining the DNA alkylating effect of Bendamustine with a pan-histone deacetylase inhibitor, Vorinostat. Here we studied the effects of EDO-S101 in two established rodent models of ANCA-associated vasculitis: a passive mouse model of anti-myeloperoxidase IgG-induced glomerulonephritis and an active rat model of myeloperoxidase-ANCA microscopic polyangiitis. Although pretreatment with EDO-S101 reduced circulating leukocytes, it did not prevent the development of passive IgG-induced glomerulonephritis in mice. On the other hand, treatment in rats significantly reduced glomerulonephritis and lung hemorrhage. EDO-S101 also significantly depleted rat B and T cells, and induced DNA damage and apoptosis in proliferating human B cells, suggesting a selective effect on the adaptive immune response. Thus, EDO-S101 may have a role in treatment of ANCA-associated vasculitis, operating primarily through its effects on the adaptive immune response to the autoantigen myeloperoxidase.

• Authors: Dearbhaile Dooley, Mirjan M van Timmeren, Vincent P O'Reilly, Gareth Brady, Eóin C O'Brien, Barbara Fazekas, Fionnuala B Hickey, Emma Leacy, Charles D Pusey, Frederick W K Tam, Thomas Mehrling, Peter Heeringa, Mark A Little
• Journal: Kidney international (Kidney Int) Vol. 94 Issue 5 Pg. 926-936 (11 2018) ISSN: 1523-1755 [Electronic] United States
• PMID: 30158055 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Benzimidazoles
• Histone Deacetylase Inhibitors
• tinostamustine
• Peroxidase

Topics

• Adaptive Immunity (drug effects)
• Alkylation
• Animals
• Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis (drug therapy, pathology)
• Apoptosis (drug effects)
• Benzimidazoles (pharmacology, therapeutic use)
• DNA Repair (drug effects)
• Female
• HL-60 Cells
• Histone Deacetylase Inhibitors (therapeutic use)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Peroxidase (immunology)
• Rats
• Rats, Inbred WKY