15
IRUS TotalDownloads
Altmetric
Alkylating histone deacetylase inhibitors may have therapeutic value in experimental myeloperoxidase-ANCA vasculitis
File | Description | Size | Format | |
---|---|---|---|---|
_system_appendPDF_proof_hi.pdf | Accepted version | 3.31 MB | Adobe PDF | View/Open |
Title: | Alkylating histone deacetylase inhibitors may have therapeutic value in experimental myeloperoxidase-ANCA vasculitis |
Authors: | Dooley, D Van Timmeren, MM O'Reilly, VP Brady, G O'Brien, EC Fazekas, B Hickey, FB Leacy, E Pusey, CD Tam, FWK Mehrling, T Heeringa, P Little, MA |
Item Type: | Journal Article |
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. |
Issue Date: | 1-Nov-2018 |
Date of Acceptance: | 24-May-2018 |
URI: | http://hdl.handle.net/10044/1/60312 |
DOI: | 10.1016/j.kint.2018.05.028 |
ISSN: | 0085-2538 |
Publisher: | Elsevier |
Start Page: | 926 |
End Page: | 936 |
Journal / Book Title: | Kidney International |
Volume: | 94 |
Issue: | 5 |
Replaces: | 10044/1/64793 http://hdl.handle.net/10044/1/64793 |
Keywords: | Science & Technology Life Sciences & Biomedicine Urology & Nephrology albuminuria ANCA glomerulonephritis inflammation renal pathology AUTOANTIGEN GENES RENAL VASCULITIS GLOMERULONEPHRITIS MICE PATHOGENESIS ANTIBODIES HUMANS MODEL Science & Technology Life Sciences & Biomedicine Urology & Nephrology albuminuria ANCA glomerulonephritis inflammation renal pathology AUTOANTIGEN GENES RENAL VASCULITIS GLOMERULONEPHRITIS MICE PATHOGENESIS ANTIBODIES HUMANS MODEL ANCA albuminuria glomerulonephritis inflammation renal pathology Adaptive Immunity Alkylation Animals Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Apoptosis Benzimidazoles DNA Repair Female HL-60 Cells Histone Deacetylase Inhibitors Humans Male Mice Mice, Inbred C57BL Peroxidase Rats Rats, Inbred WKY HL-60 Cells Animals Mice, Inbred C57BL Rats, Inbred WKY Humans Mice Rats Benzimidazoles Peroxidase Apoptosis DNA Repair Alkylation Female Male Histone Deacetylase Inhibitors Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Adaptive Immunity Urology & Nephrology 1103 Clinical Sciences |
Publication Status: | Published |
Online Publication Date: | 2018-08-26 |
Appears in Collections: | Department of Immunology and Inflammation Faculty of Medicine |