Role of neutrophils in the pathogenesis of experimental vasculitis.
In the Brown-Norway rat, mercuric chloride (HgCl2) induces an autoimmune syndrome characterized by high IgE levels. There is widespread necrotizing leukocytoclastic vasculitis involving lung, skin, mucous membranes, pancreas, liver, and gut, with tissue injury being most marked in the cecum. As in systemic vasculitis in man, there are neutrophils at the site of tissue injury and the animals develop anti-neutrophil cytoplasmic antibodies, which in the Brown-Norway rat are directed against myeloperoxidase. To determine whether neutrophils are involved in the pathogenesis of the vasculitis, we have used a monoclonal antibody that was reported to deplete neutrophils in other rat strains. Rats treated with HgCl2 received antibody by intravenous injection at various time points. Serial blood samples were taken for neutrophil counts and to assay for anti-myeloperoxidase and IgE antibodies. The guts of animals killed after antibody therapy were scored for vasculitic changes and neutrophils infiltrate. RP3 (but not the control antibody MAC6) was shown to bind to Brown-Norway rat neutrophils and to block glycogen-induced influx of neutrophils into the peritoneum. When given at peak disease, RP3 caused a dose-dependent reduction in tissue injury with a marked reduction in circulating blood neutrophil numbers and in tissue neutrophil infiltrate. RP3 treatment did not affect the rise in titer of IgE and anti-myeloperoxidase antibodies. The data presented demonstrate that in this model neutrophils are necessary for the induction of vasculitis and that the degree of vasculitis correlates with neutrophil number. To our knowledge, this study is the first to provide direct evidence for a role for neutrophils in vasculitis. We suggest that antibodies directed against neutrophils, especially if they deplete neutrophils, may be useful in the therapy of vasculitis in man.
Qasim
F J
FJ
Department of Medicine, University of Cambridge, United Kingdom.
Mathieson
P W
PW
Sendo
F
F
Thiru
S
S
Oliveira
D B
DB
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D004064:Digestive System / Q000473:pathology; D005260:Female; D007075:Immunoglobulin M; D007275:Injections, Intravenous; D007958:Leukocyte Count; D008297:Male; D008627:Mercuric Chloride; D009504:Neutrophils / Q000502:physiology*; D051381:Rats; D014657:Vasculitis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*
D000911:Antibodies, Monoclonal; D007075:Immunoglobulin M; D008627:Mercuric Chloride