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Clinical and Vaccine Immunology, March 2008, p. 506-512, Vol. 15, No. 3
1071-412X/08/$08.00+0     doi:10.1128/CVI.00401-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Reduction of Chemokine Secretion in Response to Mycobacteria in Infliximab-Treated Patients

Sandra M. Newton,¹ Sarah L. Mackie,^2, Adrian R. Martineau,¹ Katalin A. Wilkinson,^1, Beate Kampmann,¹ Corinne Fisher,^2, Shouma Dutta,² Michael Levin,¹ Robert J. Wilkinson,^1, and Geoffrey Pasvol^1*

Wellcome Trust Centre for Clinical Tropical Medicine and Department of Paediatrics, Imperial College London, Wright Fleming Institute, Norfolk Place, London W2 1PG,¹ Rheumatology Department, Northwick Park Hospital, Harrow, Middlesex HA1 3UJ, United Kingdom²

Received 3 October 2007/ Returned for modification 29 November 2007/ Accepted 14 December 2007

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-1 (MIP-1), MIP-1β (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-1β 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.

Published ahead of print on 26 December 2007.

Present address: Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.

Present address: Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa.

Present address: Rheumatology Department, University College Hospital, London NW1 2PQ, United Kingdom.