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Published ahead of print on November 23, 2005
J Am Soc Nephrol 17: 160-169, 2006
© 2006 American Society of Nephrology
doi: 10.1681/ASN.2005060616
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Basic Immunology and Pathology

Therapeutic Effect of Anti–TNF-{alpha} Antibodies in an Experimental Model of Anti-Neutrophil Cytoplasm Antibody–Associated Systemic Vasculitis

Mark A. Little*,{dagger}, Gurjeet Bhangal*, C. Lucy Smyth*, Marian T. Nakada{ddagger}, H. Terence Cook§, Sussan Nourshargh{dagger} and Charles D. Pusey*

* Renal Section, {dagger} The Eric Bywaters Centre for Vascular Inflammation, § Department of Histopathology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom; and {ddagger} Centocor Inc., Malvern, Pennsylvania

Address correspondence to: Dr. Charles Pusey, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. Phone: +44-20-8383-3152; Fax: +44-20-8383-2062; E-mail: c.pusey{at}imperial.ac.uk

Received for publication June 14, 2005. Accepted for publication October 5, 2005.

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.




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