The therapeutic options for anti-neutrophil cytoplasm antibody (
ANCA)-associated
systemic vasculitis (AASV) remain limited and hampered by adverse effects. One potential novel therapeutic avenue involves inhibition of
TNF-alpha, with encouraging uncontrolled data in humans with one agent (
infliximab) but disappointing controlled data from another (
etanercept). For investigating the potential role of
TNF-alpha as a therapeutic target in AASV, the effect of an anti-rat
TNF-alpha mAb (CNTO 1081) in a rat model of AASV was investigated. For testing the effect of
TNF-alpha blockade in this model, starting on day 28 after immunization (a point when
glomerulonephritis is established), animals were randomized to treatment with CNTO 1081 or control mouse
IgG. Treatment with CNTO 1081 significantly reduced
albuminuria (mean 1.1 +/- 0.3 mg/24 h CNTO 1081 versus 8.0 +/- 1.9 controls; P < 0.05) and crescent formation (0% CNTO 1081 versus 60% controls; P < 0.05). Lung
hemorrhage was also reduced (CNTO 1081: median score 0, range 0 to 2; controls: 2, range 1 to 3; P < 0.05). When analyzed by intravital microscopy, there was a 43% inhibition of leukocyte transmigration in mesenteric venules in response to topical CXCL1 (a neutrophil
chemoattractant) in the CNTO 1081 group compared with controls (P < 0.001). Anti-
myeloperoxidase antibody titers were similar in both groups throughout the study. In conclusion, these findings indicate that
TNF-alpha plays an important role in the pathogenesis of experimental autoimmune
vasculitis and suggest that blockade of this
cytokine with an mAb is effective in treating established
vasculitis. The therapeutic action of anti-
TNF-alpha reagents may be mediated, in part, by suppression of the enhanced leukocyte-endothelial interactions in this disorder.