Tumor Necrosis Factor-Alpha and Interleukin-10 in Whole Blood Is Associated with Disease Progression in Pulmonary Mulitdrug-Resistant Tuberculosis Patients
Abstract:Background: Cytokine production profiles may reflect the clinical pictures of patients with tuberculosis (TB). Objective: We examined the relationship between cytokine levels and clinical parameters indicating the state of disease in active pulmonary TB patients. Methods: We measured interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-10 levels in whole blood after stimulation with culture filtrate protein of Mycobacterium tuberculosis in 33 multi-drug resistant (MDR)-TB and 51 non-MDR-TB pa… Show more
“…In this study, we build upon our previous findings that TNF-α, IFN-γ and IL-10 profiles are distinct in non-MDR-TB versus MDR-TB patients [5]. Using sputum clearance as an indicator of positive responses to chemotherapies, we report that patients on anti-Mtb chemotherapies have altered TNF-α and IFN-γ levels that correlate with favorable responses to the drugs.…”
Section: Introductionmentioning
confidence: 76%
“…Cytokine production patterns in TB patients are presumed to vary according to the disease state, and we have previously reported that TNF-α was associated with MDR-TB and mycobacterial load in sputum [5]. However, our previous study was cross-sectional, limiting our ability to evaluate these correlations as markers to potentially predict outcome.…”
Section: Discussionmentioning
confidence: 94%
“…It has already been demonstrated that some MDR-TB patients produce lower levels of TNF-α but not IFN-γ compared with non-MDR-TB patients in PBMCs [27] or in whole blood [5]. Also, antigenic stimulation of peripheral blood monocytes from MDR-TB induces different trends of TNF-α and IL-12 production compared to those from non-MDR-TB patients [27].…”
Section: Discussionmentioning
confidence: 99%
“…Blood samples were drawn into heparinized Vacutainers and processed within 2 h for the cytokine whole-blood assay [5,8]. Blood was collected at the time of admission, and 2 and 6 months after the start of treatment prescribed by NMTH staff.…”
Background: We have previously reported that TNF-α levels correlate to total mycobacterial burden in tuberculosis (TB) patients. Objective: To characterize the dynamics of cytokine responses in TB patients during chemotherapy to identify potential surrogate markers for effective treatment. Methods: Following induction by culture filtrate proteins in whole blood, production patterns of TNF-α, IL-10, IFN-γ and IL-12 were measured in 23 non-multidrug-resistant (MDR)-TB and 16 MDR-TB patients and in 31 healthy controls. Rates of mycobacterial clearance from the sputum were then measured and compared. Results: Prior to the initiation of chemotherapy, TNF-α and IL-10 levels were significantly higher in TB patients than in healthy controls while IFN-γ and IL-12 levels were similar. During chemotherapy, the levels of all 4 cytokines increased. We evaluated these responses separately in patients that did and did not clear their sputum culture at 2 and 6 months. At 2 months, decreases in both IFN-γ and IL-12 correlated strongly with a successful early response, while after 6 months of therapy, when half (7/14) of MDR-TB patients were still sputum culture positive, downregulation of TNF-α was uniquely correlated with sputum conversion between the groups. Conclusion: Our findings suggest the possibility that the regulation of TNF-α production in whole blood may be a more specific indicator of sputum conversion at 6 months than IFN-γ, IL-12 or IL-10 in MDR-TB patients.
“…In this study, we build upon our previous findings that TNF-α, IFN-γ and IL-10 profiles are distinct in non-MDR-TB versus MDR-TB patients [5]. Using sputum clearance as an indicator of positive responses to chemotherapies, we report that patients on anti-Mtb chemotherapies have altered TNF-α and IFN-γ levels that correlate with favorable responses to the drugs.…”
Section: Introductionmentioning
confidence: 76%
“…Cytokine production patterns in TB patients are presumed to vary according to the disease state, and we have previously reported that TNF-α was associated with MDR-TB and mycobacterial load in sputum [5]. However, our previous study was cross-sectional, limiting our ability to evaluate these correlations as markers to potentially predict outcome.…”
Section: Discussionmentioning
confidence: 94%
“…It has already been demonstrated that some MDR-TB patients produce lower levels of TNF-α but not IFN-γ compared with non-MDR-TB patients in PBMCs [27] or in whole blood [5]. Also, antigenic stimulation of peripheral blood monocytes from MDR-TB induces different trends of TNF-α and IL-12 production compared to those from non-MDR-TB patients [27].…”
Section: Discussionmentioning
confidence: 99%
“…Blood samples were drawn into heparinized Vacutainers and processed within 2 h for the cytokine whole-blood assay [5,8]. Blood was collected at the time of admission, and 2 and 6 months after the start of treatment prescribed by NMTH staff.…”
Background: We have previously reported that TNF-α levels correlate to total mycobacterial burden in tuberculosis (TB) patients. Objective: To characterize the dynamics of cytokine responses in TB patients during chemotherapy to identify potential surrogate markers for effective treatment. Methods: Following induction by culture filtrate proteins in whole blood, production patterns of TNF-α, IL-10, IFN-γ and IL-12 were measured in 23 non-multidrug-resistant (MDR)-TB and 16 MDR-TB patients and in 31 healthy controls. Rates of mycobacterial clearance from the sputum were then measured and compared. Results: Prior to the initiation of chemotherapy, TNF-α and IL-10 levels were significantly higher in TB patients than in healthy controls while IFN-γ and IL-12 levels were similar. During chemotherapy, the levels of all 4 cytokines increased. We evaluated these responses separately in patients that did and did not clear their sputum culture at 2 and 6 months. At 2 months, decreases in both IFN-γ and IL-12 correlated strongly with a successful early response, while after 6 months of therapy, when half (7/14) of MDR-TB patients were still sputum culture positive, downregulation of TNF-α was uniquely correlated with sputum conversion between the groups. Conclusion: Our findings suggest the possibility that the regulation of TNF-α production in whole blood may be a more specific indicator of sputum conversion at 6 months than IFN-γ, IL-12 or IL-10 in MDR-TB patients.
“…Further, antigen-specific IL-10 production is found in pulmonary TB patients (341, 342) and along with TNF-α production can be used to reliably distinguish between latent TB and pulmonary TB (342). In addition, increased accumulation of T REGS expressing IL-10 correlates with increased bacterial burden and more severe TB in an Indian population (343, 344) and a high level of IL-10 at the end of treatment in pulmonary TB patients is associated with TB recurrence (345). Finally, infection with helminths in TB patients results in decreased antigen-specific IFNγ and IL-17 responses, which is dependent on IL-10, as IL-10 blockade significantly increases frequencies of IFNγ producing cells (346, 347).…”
Chemokines and cytokines are critical for initiating and coordinating the organized and sequential recruitment and activation of cells into
Mycobacterium tuberculosis
-infected lungs. Correct mononuclear cellular recruitment and localization are essential to ensure control of bacterial growth without the development of diffuse and damaging granulocytic inflammation. An important block to our understanding of TB pathogenesis lies in dissecting the critical aspects of the cytokine/chemokine interplay in light of the conditional role these molecules play throughout infection and disease development. Much of the data highlighted in this review appears at first glance to be contradictory, but it is the balance between the cytokines and chemokines that is critical, and the “goldilocks” (not too much and not too little) phenomenon is paramount in any discussion of the role of these molecules in TB. Determination of how the key chemokines/cytokines and their receptors are balanced and how the loss of that balance can promote disease is vital to understanding TB pathogenesis and to identifying novel therapies for effective eradication of this disease.
Over thousands of years microbes and mammals have co-evolved, resulting in extraordinarily sophisticated molecular mechanisms permitting the organisms to survive together. Mycobacterium tuberculosis is one of the best examples of successful co-evolution, since the bacilli have infected one third of the human population, but in 90% of the cases without causing overt disease. Despite this, increasing incidence of Human Immunodeficiency Virus (HIV) infection and the emergence of drug-resistant strains means that tuberculosis is in fact an extremely serious emerging threat to global health. Decades of work have focused on the interaction of this pathogen with its established cellular host, the macrophage, but still novel therapeautics remain elusive. While the macrophage is clearly important, recent evidence suggests that understanding the role of dendritic cells, which are key regulators of immunity, may be a crucial step in identifying new means of controlling this disease. Novel technologies, in particular genome-wide transcriptome analyses, are advancing our ability to dissect the complex dynamic relationships between dendritic cells and mycobacteria, highlighting new areas for study that have not been previously explored.
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