title: Reduction of chemokine secretion in response to mycobacteria in infliximab-treated patients.
abstract: The use of anti-tumor necrosis factor (TNF) agents as a treatment for chronic inflammatory conditions has been shown to be associated with an increased risk of developing tuberculosis. We studied the effect of the anti-TNF antibody infliximab on antimycobacterial immunity in 26 patients with rheumatoid arthritis or ankylosing spondylitis by use of an in vitro whole-blood model employing a reporter mycobacterium. Blood samples taken before and 30 min and 7 days after a 2-hour infliximab infusion were compared in terms of their abilities both to suppress luminescence of Mycobacterium bovis bacillus Calmette-Guérin lux and to secrete chemokines and cytokines 24 and 96 h after infection. No immediate effect of infliximab on mycobacterial luminescence was detected using this bioassay, irrespective of whether patients were receiving their first (n = 14) or maintenance (n = 12) doses of infliximab. Moreover, no effect on mycobacterial luminescence was detected when blood was taken 7 days after infliximab treatment (n = 7). By contrast, there was a significant reduction in the chemokines implicated in cellular trafficking, namely, interleukin-8, macrophage-inhibitory protein-1alpha (MIP-1alpha), MIP-1beta (24 h and 96 h), and monocyte chemoattractant protein-1 (MCP-1) (24 h) following BCG lux strain infection in the 30-minute post-infliximab-infusion blood samples (P < 0.05). This effect was sustained by MIP-1beta and MCP-1 (24 h; P < 0.05) at 7 days after infusion. Our results suggest that the development of tuberculosis in infliximab-treated patients is not directly related to the mycobactericidal effects of TNF but may be due to inhibition of TNF-dependent chemokine gradients disrupting cellular migration necessary to maintain the integrity of the granuloma.
authors.affiliation: Wellcome Trust Centre for Clinical Tropical Medicine and Department of Paediatrics, Imperial College London, Wright Fleming Institute, United Kingdom.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Newton
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Mackie
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Martineau
authors.forename: Katalin A
authors.initials: KA
authors.lastname: Wilkinson
authors.forename: Beate
authors.initials: B
authors.lastname: Kampmann
authors.forename: Corinne
authors.initials: C
authors.lastname: Fisher
authors.forename: Shouma
authors.initials: S
authors.lastname: Dutta
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Pasvol
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001681:Biological Assay; D018925:Chemokines / Q000097:blood* / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D000069285:Infliximab; D049449:Luminescence; D008875:Middle Aged; D009163:Mycobacterium bovis / Q000235:genetics / Q000378:metabolism*; D013167:Spondylitis, Ankylosing / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001426:Bacterial Proteins; D018925:Chemokines; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab