F J Qasim1, P W Mathieson, S Thiru, D B Oliveira. 1. Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, United Kingdom.
Abstract
BACKGROUND: Administration of mercuric chloride (HgCl2) to the Brown Norway (BN) rat induces a necrotizing leukocytoclastic vasculitis (most marked in the gut) and anti-myeloperoxidase (anti-MPO) antibodies. The development of autoimmunity in the BN rat is a T cell-dependent phenomenon, and there is evidence that the induction of autoantibodies and tissue injury is a Th2-driven process. Cyclosporin A (CyA) is an anti-T cell agent with a dose-dependent differential effect on Th cell subsets that can ameliorate or enhance autoimmune responses. In the BN it can suppress HgCl2-induced autoantibody production, but the effect on tissue injury has not been previously examined. EXPERIMENTAL DESIGN: We have studied the effect of CyA given "early" (Days 1-10, concurrently with the HgCl2) or "late" (Days 11-14) on tissue injury and autoantibody response. Serial blood samples were taken for anti-glomerular basement membrane, anti-MPO, and IgE antibody levels. Necropsies were performed on animals killed on Day 15. The presence and extent of vasculitis was scored macroscopically and histologically. Controls were incorporated to assess the effect of vehicle and of CyA alone. RESULTS: CyA given early delayed the rise in anti-MPO and anti-glomerular basement membrane levels and ameliorated tissue injury, whereas CyA given late, although suppressing the rise in anti-MPO and anti-glomerular basement membrane antibodies, caused a marked exacerbation of vasculitis. CONCLUSIONS: The effect of CyA depends on the timing of treatment with respect to HgCl2. Anti-MPO antibodies are not of primary importance in the pathogenesis of tissue injury. The late effect may be due to a direct toxic effect on the endothelium or to loss of a protective T cell subset. These observations have implications for the use of CyA in the treatment of systemic vasculitis in humans.
BACKGROUND: Administration of mercuric chloride (HgCl2) to the Brown Norway (BN) rat induces a necrotizing leukocytoclastic vasculitis (most marked in the gut) and anti-myeloperoxidase (anti-MPO) antibodies. The development of autoimmunity in the BN rat is a T cell-dependent phenomenon, and there is evidence that the induction of autoantibodies and tissue injury is a Th2-driven process. Cyclosporin A (CyA) is an anti-T cell agent with a dose-dependent differential effect on Th cell subsets that can ameliorate or enhance autoimmune responses. In the BN it can suppress HgCl2-induced autoantibody production, but the effect on tissue injury has not been previously examined. EXPERIMENTAL DESIGN: We have studied the effect of CyA given "early" (Days 1-10, concurrently with the HgCl2) or "late" (Days 11-14) on tissue injury and autoantibody response. Serial blood samples were taken for anti-glomerular basement membrane, anti-MPO, and IgE antibody levels. Necropsies were performed on animals killed on Day 15. The presence and extent of vasculitis was scored macroscopically and histologically. Controls were incorporated to assess the effect of vehicle and of CyA alone. RESULTS:CyA given early delayed the rise in anti-MPO and anti-glomerular basement membrane levels and ameliorated tissue injury, whereas CyA given late, although suppressing the rise in anti-MPO and anti-glomerular basement membrane antibodies, caused a marked exacerbation of vasculitis. CONCLUSIONS: The effect of CyA depends on the timing of treatment with respect to HgCl2. Anti-MPO antibodies are not of primary importance in the pathogenesis of tissue injury. The late effect may be due to a direct toxic effect on the endothelium or to loss of a protective T cell subset. These observations have implications for the use of CyA in the treatment of systemic vasculitis in humans.