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

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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
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
Science & Technology
Life Sciences & Biomedicine
Urology & Nephrology
albuminuria
ANCA
glomerulonephritis
inflammation
renal pathology
AUTOANTIGEN GENES
RENAL VASCULITIS
GLOMERULONEPHRITIS
MICE
PATHOGENESIS
ANTIBODIES
HUMANS
MODEL
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



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