Document Detail


Therapeutic effect of anti-TNF-alpha antibodies in an experimental model of anti-neutrophil cytoplasm antibody-associated systemic vasculitis.
MedLine Citation:
PMID:  16306166     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Mark A Little; Gurjeet Bhangal; C Lucy Smyth; Marian T Nakada; H Terence Cook; Sussan Nourshargh; Charles D Pusey
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-11-23
Journal Detail:
Title:  Journal of the American Society of Nephrology : JASN     Volume:  17     ISSN:  1046-6673     ISO Abbreviation:  J. Am. Soc. Nephrol.     Publication Date:  2006 Jan 
Date Detail:
Created Date:  2005-12-28     Completed Date:  2006-06-08     Revised Date:  2007-08-13    
Medline Journal Info:
Nlm Unique ID:  9013836     Medline TA:  J Am Soc Nephrol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  160-9     Citation Subset:  IM    
Affiliation:
Renal Section, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies, Antineutrophil Cytoplasmic / biosynthesis,  immunology*
Antibodies, Monoclonal / therapeutic use*
Autoimmune Diseases / blood,  therapy*
Cell Movement
Disease Models, Animal
Leukocytes / physiology
Nephritis / therapy
Rats
Rats, Inbred WKY
Tumor Necrosis Factor-alpha / antagonists & inhibitors*
Vasculitis / blood,  therapy*
Grant Support
ID/Acronym/Agency:
//Wellcome Trust
Chemical
Reg. No./Substance:
0/Antibodies, Antineutrophil Cytoplasmic; 0/Antibodies, Monoclonal; 0/Tumor Necrosis Factor-alpha

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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