PATIENTS WITH MULTIDRUG-RESISTANT TUBERCULOSIS WITH LOW CD4(-CELL COUNTS HAVE IMPAIRED TH1 RESPONSES() T)

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 wer e compared with those of healthy purified protein derivative (PPD)-pos itive and PPD-negative individuals, These responses were characterized by measuring the proliferation and cytokine production from PBMCs sti mulated in vitro with Mycobacterium tuberculosis, PPD, or mitogens. MD RTB patients with CD4 counts > 500/mu l stimulated in vitro with M. tu berculosis had similar immune responses (proliferation, IFN-gamma, and IL-2 production) as the PPD-positive and -negative controls, By contr ast, MDRTB patients with CD4 counts < 500/mu l had markedly deficient immune responses to similar stimuli, In these patients, IFN-gamma prod uction 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 e ndogenous IL-12 production was also studied, Addition of anti-IL-12 to cultures resulted in a two- to eightfold decrease in IFN-gamma produc tion 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 produc tion was also assessed from cells stimulated by M. tuberculosis. Addit ion of IL-12 to the cultures did not cause a significant enhancement o f TNF-alpha production, Last, production of IL-10 and IL-4 in response to M. tuberculosis and PHA, respectively, was not significantly diffe rent among all groups tested. These results suggest that patients with MDRTB tuberculosis with CD4 T cell counts < 500/mu l have impaired IF N-gamma and IL-2 responses and might benefit by adjunctive IL-12 thera py.