Pulmonary tuberculosis: evaluation of interferon-gamma levels as an immunological healing marker based on the response to the Bacillus Calmette-Guerin

Abstract

Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis whose interaction with the host may lead to a cell-mediated protective immune response. The presence of interferon-γ (IFN-γ) is related to this response. With the purpose of understanding the immunological mechanisms involved in this protection, the lymphoproliferative response, IFN-γ and other cytokines like interleukin , and tumor necrosis factor alpha (TNF-α) Key words: tuberculosis -interleukin-5 -interleukin-10 -tumor necrosis factor alpha -interferon-γ -peripheral blood mononuclear cells Tuberculosis (TB), a chronic infective-contagious disease, is caused by Mycobacterium tuberculosis and remains an important public health problem whose mechanisms related to a protective immunity in humans are not clear. The resurgence of TB has stimulated studies for the development of vaccines, new diagnostic methods and less toxic and more effective drugs for treatment (Laal et al. 1997). The cellular immunity plays an important role in TB healing (Ladel et al. 1997, Torres et al. 1998, Turner et al. 2000, Chackerian et al. 2001). Resistance to mycobacterial infections is conferred by immunological mechanisms mediated by T CD4 + lymphocytes, involving cytokines that increase the microbicide activity of macrophages (Dlugovitzky et al. 2000, Oberholzer et al. 2000. Studies in murine and human models allow differentiating two subpopulations of T CD4 + lymphocytes termed Th1 and Th2, that mediate the protection or the aggravation of the disease (Ladel et al. 1997, Kori et al. 2000. This existing dichotomy between the protective or non-protective immune responses is likely to be correlated with cytokine patterns produced by different subpopulations of lymphocytes during initial surviving stages of the pathogens inside macrophages. Interferon-γ (IFN- γ) acts as a powerful macrophage activator, increasing the molecule expression of the main class II histocompatibility complex and the potentialization of the cell response, including the production of cytokines, nitric oxide, and the increase of the cytolitic activity, with a main role in the Th1 type (Flesh et al. 1995). Studies carried out by Cooper et al. (1993) and Flynn et al. (1993) demonstrated that mice without the IFN-γ gene were not able to fight off the infection caused by M. tuberculosis. In humans, individuals who presented genetic mutations in the receptors for IFN-γ were observed to have had a high susceptibility to acquire infections caused by atypical mycobacteria (Jouanguy et al. 1996), suggesting an important role of IFN-γ in the protective response against TB.Besides the importance of better understanding the immunological mechanisms that may contribute to the healing, it becomes essential to determine markers of healing lesions, once this is currently carried out based on the clinical, radiological, and negative bacterioscopy.In this work, we proposed the in vitro evaluation of IFN-γ levels produced by peripheral blood mononuclear cells (PBMC) after Bacillus Calmette-Guerin (BCG) stimulati...

Citocinas e proteínas de fase aguda do soro como marcadores de regressão da resposta inflamatória ao tratamento da tuberculose pulmonar

“…Although cytokine production in the patients was always higher than in the controls, it decreased significantly during the treatment, and the final levels were lower than the baseline levels. These higher than normal levels after treatment, also found in another study, (20) suggest that TNF-α, in addition to its important role in the immunopathogenesis of the disease, plays a protective role.…”

“…(18,27,28) Although IL-10 levels are higher during the phase of great activity of the inflammatory process-pretreatment-than during or after the end of the specific therapy, these levels always remain above normal during treatment. (24) In another study, (20) high initial production of IL-10 by PBMCs of patients with PTB remained unchanged with the treatment. In the present study, the production of IL-10 by monocytes, stimulated or not, was also high before, during and after the with the levels found after three and six months of therapy, which suggests the usefulness of this marker in clinical practice to evaluate the response to the treatment.…”

“…Some studies have also demonstrated the relationship between the production of certain cytokines and the severity of the disease. (20)(21)(22)(23) In one study, (14) the production of IFN-γ by PBMCs, stimulated by M. tuberculosis, was found to be lower than normal before the treatment, progressively increasing to levels similar to those found at the end in the controls. Different from the results above, in the present study, the production of IFN-γ by cells, stimulated or not, was higher among patients than among controls, before treatment and after three months of treatment, with a progressive decrease until reaching normal values at the end of therapy.…”

“…(25) Finally, a number of authors have observed that PBMCs submitted to various antigenic stimuli present high production of IFN-γ before and after treatment in patients with tuberculosis. (20)(21)(22) Another cytokine that participates in the formation of granulomas is TNF-α, levels of which are high in the pleural fluid, plasma or monocyte culture of patients with tuberculosis, before or after the onset of the treatment, when compared with chronic patients or individuals without tuberc. There is evidence to suggest that TNF-α is necessary at the beginning of the inflammatory process in order to limit the multiplication of mycobacteria.…”

In Vitro Levels of Interleukin 10 (IL-10) and IL-12 in Response to a Recombinant 32-Kilodalton Antigen ofMycobacterium bovisBCG after Treatment for Tuberculosis

“…These changes are probably related to the Ag load, which decreases after treatment (14,20). No data for EPTB patients were reported by other studies with respect to the 32-kDa Ag.…”