Reduction of chemokine secretion in response to mycobacteria in infliximab-treated patients

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

^* To whom correspondence should be addressed. Email: g.pasvol{at}imperial.ac.uk.

	Abstract

The use of anti-tumour necrosis factor 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 using an in vitro whole blood model employing a reporter mycobacterium. Blood samples taken before, 30 minutes and 7 days after a 2-hour infliximab infusion were compared both in their ability to suppress luminescence of Mycobacterium bovis Bacille 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 IL-8, MIP-1, MIP-1 (24 h and 96 h) and MCP-1 (24 h) following BCG lux infection in the 30-minute post-infliximab infusion blood samples (p < 0.05). This effect was sustained by MIP-1 and MCP-1 (24 h, p < 0.05) at 7 days after infusion.

Our results suggest that development of tuberculosis in infliximab-treated patients is not directly related to the myobactericidal 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.