Systemic small vessel vasculitis is associated with antineutrophil cytoplasm antibodies (ANCAs). While there is mounting in vitro evidence to suggest that ANCAs are capable of enhancing leukocyte-endothelial interactions, no in vivo evidence for this has been provided. In this study a novel rat model of ANCA-associated experimental autoimmune vasculitis (EAV), induced by immunization with human myeloperoxidase (MPO), was used to analyze directly the potential effect of ANCAs on leukocyte-venular wall interactions in vivo as observed by intravital microscopy. These rats developed anti-MPO antibodies directed against rat leukocytes, showed pathologic evidence of small vessel vasculitis, and had enhanced leukocyte adhesion and transmigration in response to the chemokine Gro␣ ( IntroductionSystemic small vessel vasculitis (SVV) results in rapidly progressive glomerulonephritis and lung hemorrhage in humans and is usually fatal if untreated. 1 It is characterized by microvascular inflammation and necrosis in a variety of organs. The 2 organs that are most extensively injured in this manner are the kidney, through the development of pauci-immune crescentic glomerulonephritis, and the lung, with consequent alveolar hemorrhage. The association between antineutrophil cytoplasm antibodies (ANCAs) and SVV, initially described in the 1980s, 2 has attracted considerable interest over the past decade. These autoantibodies are principally directed against myeloperoxidase (MPO) and proteinase-3. 3,4 At first, ANCAs were regarded only as clinical markers of disease activity, but it is now apparent that they have direct biologic effects on neutrophils 5,6 and monocytes. 7 The binding of ANCAs to antigen expressed on the leukocyte cell surface following cytokine priming is followed by the activation of an array of intracellular signaling pathways, 8 with resultant degranulation and dysregulated apoptosis. 9 Granulocyte infiltration and fibrinoid necrosis of the vessel wall are the pathologic hallmarks of SVV. For this reason, investigative efforts have focused on the influence that ANCAs have on the interaction between leukocytes and the vascular endothelium, specifically with reference to the inflammatory cascade of leukocyte rolling, adhesion, and transmigration. In this context, in vitro studies using flow chamber models have shown that ANCAs can cause rolling neutrophils to arrest on platelet monolayers 10 and to promote firm adhesion and migration of rolling neutrophils on endothelial cells. 11,12 Despite growing in vitro evidence implicating ANCAs as an inducer of leukocyte-endothelial cell interactions, there has been no evidence to date demonstrating such an effect of these antibodies in vivo. The ability of ANCAs to induce systemic small vessel vasculitis and crescentic glomerulonephritis, however, has been demonstrated by transfer of anti-MPO antibodies in a mouse model of vasculitis. 13 Crescent formation in these animals occurred secondary to fibrinoid necrosis of the glomerular tuft, which was induced by necrosis and...

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-␣, with encouraging uncontrolled data in humans with one agent (infliximab) but disappointing controlled data from another (etanercept). For investigating the potential role of TNF-␣ as a therapeutic target in AASV, the effect of an anti-rat TNF-␣ mAb (CNTO 1081) in a rat model of AASV was investigated. For testing the effect of TNF-␣ 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-␣ 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-␣ reagents may be mediated, in part, by suppression of the enhanced leukocyte-endothelial interactions in this disorder.

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