Alkylating histone deacetylase inhibitors may have therapeutic value in experimental myeloperoxidase-ANCA vasculitis
File(s)
Accepted version
Author(s)
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.
Date Issued
2018-11-01
Date Acceptance
2018-05-24
Citation
Kidney International, 2018, 94 (5), pp.926-936
ISSN
0085-2538
Publisher
Elsevier
Start Page
926
End Page
936
Journal / Book Title
Kidney International
Volume
94
Issue
5
Replaces
10044/1/64793
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000447799800014&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Urology & Nephrology
albuminuria
ANCA
glomerulonephritis
inflammation
renal pathology
AUTOANTIGEN GENES
RENAL VASCULITIS
GLOMERULONEPHRITIS
MICE
PATHOGENESIS
ANTIBODIES
HUMANS
MODEL
Publication Status
Published
Date Publish Online
2018-08-26