Patients with multidrug-resistant tuberculosis with low CD4+ T cell counts have impaired Th1 responses

Multidrug-resistant tuberculosis (MDRTB) has emerged as a challenging clinical problem in both HIV-infected and -uninfected individuals. In this study, immune responses from HIV-negative patients with MDRTB were compared with those of healthy purified protein derivative (PPD)-positive and PPD-negative individuals. These responses were characterized by measuring the proliferation and cytokine production from PBMCs stimulated in vitro with Mycobacterium tuberculosis, PPD, or mitogens. MDRTB patients with CD4 counts >500/microl stimulated in vitro with M. tuberculosis had similar immune responses (proliferation, IFN-gamma, and IL-2 production) as the PPD-positive and -negative controls. By contrast, MDRTB patients with CD4 counts <500/microl had markedly deficient immune responses to similar stimuli. In these patients, IFN-gamma production could be restored by adding IL-12 to the in vitro cultures. IL-12 also caused a striking increase in the amount of IFN-gamma produced from PBMCs of both PPD-positive and -negative controls. The role of endogenous IL-12 production was also studied. Addition of anti-IL-12 to cultures resulted in a two- to eightfold decrease in IFN-gamma production in response to PHA stimulation. Inhibition of IFN-gamma was also observed when cells were stimulated by M. tuberculosis and PPD. Using Staphylococcus aureus Cowan strain as a mitogenic stimulus, IL-12 p70 was produced in similar amounts in all groups tested. TNF-alpha production was also assessed from cells stimulated by M. tuberculosis. Addition of IL-12 to the cultures did not cause a significant enhancement of TNF-alpha production. Last, production of IL-10 and IL-4 in response to M. tuberculosis and PHA, respectively, was not significantly different among all groups tested. These results suggest that patients with MDRTB tuberculosis with CD4 T cell counts <500/microl have impaired IFN-gamma and IL-2 responses and might benefit by adjunctive IL-12 therapy.