Profiles of IFN-γand its regulatory cytokines (IL-12, IL-18 and IL-10) in peripheral blood mononuclear cells from patients with multidrug-resistant tuberculosis

Abstract

SUMMARY This study investigated the profiles of IFN‐γ and its regulatory cytokines (IL‐12, IL‐18 and IL‐10) in response to a purified protein derivative (PPD) antigen in peripheral blood mononuclear cells (PBMC) from 18 HIV‐negative patients with multidrug‐resistant tuberculosis (MDRTB), and compared them with those from 19 healthy tuberculin reactors (HTR). ELISA results showed that following stimulation with PPD, IFN‐γ production was significantly reduced, whereas production of both IL‐18 and IL‐10 was significantly elevated in MDRTB patients compared with HTR. Three out of 18 patients with MDRTB of greater than 4 years duration showed significantly elevated IL‐12 p70 production, induced by in vitro PPD stimulation of their PBMC, when compared with data from HTR. However, when taken as a group, MDRTB patients were similar to HTR in their IL‐12 p70‐producing capacity. IL‐12 p70 protein paralleled IL‐12 p40 protein expression. In addition, the production of IL‐12 p40 was significantly correlated with IL‐10 in all patients, but was not correlated with IFN‐γ. Neutralization of IL‐10 increased IL‐12 p40 about twofold, but did not significantly alter IFN‐γ induction in MDRTB. IFN‐γ in MDRTB was highly correlated with lymphoproliferation and CD4 counts, but was not correlated with IL‐12, IL‐18 or IL‐10 production. Our findings suggest that patients with MDRTB have dysregulated IL‐12, IL‐18 and IL‐10 production during Mycobacterium tuberculosis infection, and the cytokine profiles are similar to those in patients with drug‐sensitive advanced TB previously reported in the literature. In addition, IL‐10 may not have a dominant role in defective IFN‐γ production in patients with MDRTB.

Association of Antigen-Stimulated Release of Tumor Necrosis Factor-Alpha in Whole Blood with Response to Chemotherapy in Patients with Pulmonary Multidrug-Resistant Tuberculosis

“…These results are in agreement with other published results for IL-10 [10,11] and for TNF-α [12,13,14]. In contrast, IFN-γ and IL-12 levels were not different between healthy controls and TB patients.…”

The Patterns of Interferon-Gamma and Interleukin-10 Production as a Potential Immunological Biomarker for the Outcome of Mycobacterium Tuberculosis Infection

“…This distinction also manifests in the two APTB patients with treatment failure, who recorded low INF-y/IL-10 ratio at baseline and fluctuating but consistently low ratios at the different time points during their unsuccessful TB treatment. The persistently elevated IL-10 responses noted in the APTB patients and, particularly, in the two with unresolved TB correlates with the previously reported association of high IL-10 production in pulmonary TB patients with MDR-TB [24], and in those with possible TB recurrence [33]. Taken together, these observations indicate that an altered balance between the pro-(INF-y) and anti-(IL-10) inflammatory cytokine is implicated in MTb infection progression and possibly resistance, rather than elevation or decrease of just one of the cytokines.…”

“…This is a study with limited population size, a limitation shared by many other studies in this area (20)(21)(22)(23)(24)(25). Nonetheless, the differences in the INF-y and IL-10 responses were sufficiently large enough to enable the detection of significant differences between the diagnostic groups and the time-points during treatment.…”

Patients with Multidrug-Resistant Tuberculosis Display Impaired Th1 Responses and Enhanced Regulatory T-Cell Levels in Response to an Outbreak of Multidrug-ResistantMycobacterium tuberculosisM and Ra Strains

“…This result may be related to the lack of host selective pressure suffered by the laboratory strain H37Rv. Low in vitro Th1 responses to different M. tuberculosis antigens have been observed in MDR-TB patients, such as impaired IFN-␥ production (4,16,25,26,33) and increased IL-4 production by CD4 ϩ T cells stimulated by a lipid extract of H37Rv (50). Likewise, in our study, both MDR-TB and S-TB patients showed an impaired expression of IFN-␥ in CD4 ϩ and CD8 ϩ T cells, irrespective of the tested strain; therefore, this might be ascribed to the altered Th1/Th2 profile characteristic of advanced disease (13).…”

“…Protective immunity against TB is mediated by a Th1-type immune response characterized by high levels of interleukin-12 (IL-12) from infected macrophages and gamma interferon (IFN-␥) from antigen-specific T cells, which control and contain infection in the lungs (24). Peripheral blood mononuclear cells (PBMC) from MDR-TB patients have been shown to poorly respond in vitro to H37Ra whole bacilli, purified protein derivative (PPD), and specific antigens, such as ESAT-6 and the 30-kDa protein (16,25,26,33). Furthermore, increased IL-4 secretion by CD4 ϩ T cells after H37Rv total lipid stimulation was observed in MDR-TB patients (50).…”