Corticosteroid modulated immune activation in the TB immune reconstitution inflammatory syndrome

RATIONALE: HIV-tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an immunopathological reaction to mycobacterial antigens induced by antiretroviral therapy (ART). Prednisone reduces morbidity in TB-IRIS, but the mechanisms are unclear. OBJECTIVES: To determine the effect of prednisone on the inflammatory response in TB-IRIS (antigen-specific effector T cells, cytokines and chemokines). METHODS: Samples were taken from participants in a randomized placebo-controlled trial of prednisone for TB-IRIS, at 0, 2 and 4 weeks. Participants received prednisone at a dose of 1.5mg/kg/day for 2 weeks followed by 0.75mg/kg/day for 2 weeks, or identical placebo. MEASUREMENTS: Interferon gamma ELISpot. RT-PCR on PBMC after restimulation with heat-killed Mycobacterium tuberculosis and Luminex multiplex cytokine analysis on corresponding tissue culture supernatants. Luminex multiplex cytokine analysis of serum. MAIN RESULTS: 58 participants with TB-IRIS (31 prednisone, 27 placebo) were included. In serum, significant decreases in IL-6, IL-10, IL-12p40, TNFalpha, IFNgamma and IP-10 concentrations during prednisone, but not placebo, treatment were observed. No differences in ELISpot responses comparing prednisone and placebo groups were shown in response to ESAT-6, Acr1, Acr2, 38kDa or heat killed H37Rv M. tuberculosis. PPD ELISpot responses increased over 4 weeks in prednisone group and decreased in placebo group (p=0.007). CONCLUSIONS: The beneficial effects of prednisone in TB-IRIS appear mediated via suppression of predominantly pro-inflammatory cytokine responses of innate immune origin, not via a reduction of the numbers of antigen-specific T cells in peripheral blood.