Tumor-necrosis-factor blockers: differential effects on mycobacterial immunity.

BACKGROUND: Tumor necrosis factor (TNF) plays a pathogenic role in rheumatoid arthritis but is essential for antimycobacterial host defenses. The risk of reactivation of latent Mycobacterium tuberculosis infection is greater with the TNF monoclonal antibody infliximab than with the soluble TNF receptor etanercept. The basis of this difference is not known. METHODS: The effects that the monoclonal antibodies infliximab and adalimumab and the receptor etanercept have on antimycobacterial immune functions were studied by use of therapeutic drug concentrations in whole-blood culture. RESULTS: Infliximab and adalimumab reduced the proportion of tuberculosis-responsive (CD69(+)) CD4 cells by 70% and 49%, respectively (P<.05), and suppressed antigen-induced interferon (IFN)- gamma production by 70% and 64% (P<.05), respectively; in contrast, etanercept produced no significant effect. Interleukin-10 production was equally suppressed by all 3 drugs. Adalimumab and etanercept had divergent, concentration-dependent effects on control of intracellular growth of M. tuberculosis. None of the drugs induced significant levels of apoptosis or necrosis, in either monocytes or T cells. CONCLUSIONS: The tuberculosis risk posed by infliximab may reflect its combined effects on TNF and IFN- gamma .

Survival and replication of clinical Mycobacterium tuberculosis isolates in the context of human innate immunity.

The initial host response to Mycobacterium tuberculosis is driven by innate immunity. For this study, we examined the ability of 18 recent clinical isolates and 5 reference strains to survive and replicate in the context of host innate immunity by using whole blood culture. Six healthy tuberculin-negative volunteers served as subjects. H(37)Ra showed the least capacity to replicate of any of the strains tested, decreasing in viability 1.3 log CFU during 72 h of whole blood culture, whereas H(37)Rv increased 0.32 log. Clinical isolates varied greatly in their ability to replicate in blood cells, ranging from -0.4 to +0.8 log (P < 0.001). Four showed significantly more growth than H(37)Rv, and one showed significantly reduced growth. Host mechanisms for restricting intracellular mycobacterial growth were more effective during the first 24 h of whole blood culture than during the 24- to 72-h period. Certain mycobacterial isolates appeared preferentially able to withstand host defenses during each of these intervals. Although there was relatively more homogeneity among subjects than among strains, one of the six subjects showed a reduced capacity to restrict intracellular mycobacterial growth due to a defect expressed during the first 24 h of culture. Our findings indicate substantial variability in the capacity of clinical tuberculosis isolates to replicate in host cells in the face of innate host immunity.

Lack of activity of orally administered clofazimine against intracellular Mycobacterium tuberculosis in whole-blood culture.

The activity of oral clofazimine against intracellular Mycobacterium tuberculosis was compared to that of ofloxacin in healthy volunteers by the use of whole-blood cultures. Clofazimine was inactive whether it was tested alone or combined with other drugs that are used to treat multidrug-resistant tuberculosis, despite a total dose of 2 g. Kanamycin was the most active drug tested.