transforming-growth-factor-beta and Tuberculosis

transforming-growth-factor-beta has been researched along with Tuberculosis* in 49 studies

Reviews

7 review(s) available for transforming-growth-factor-beta and Tuberculosis

ArticleYear
Transforming growth factor-β and matrix metalloproteinases as potential biomarkers of fibrotic lesions induced by tuberculosis: a systematic review and meta-analysis.
    BMJ open, 2023, 10-12, Volume: 13, Issue:10

    Very few studies and limited information are available regarding the mechanism of fibrosis in tuberculosis (TB). This study aimed to identify, describe and synthesise potential biomarkers of the development of tissue fibrosis induced by TB through a systematic method and meta-analysis.. A literature search was performed using keywords according to the topic from electronic databases (ScienceDirect and PubMed) and other methods (websites, organisations and citations). Studies that matched predetermined eligibility criteria were included. The quality assessment tool used was the Quality Assessment of Diagnostic Accuracy Score 2, and the data obtained were processed using Review Manager V.5.3.. Of the 305 studies, 7 met the eligibility criteria with a total sample of 365. The results of the meta-analysis showed that the post-TB group of patients with pulmonary parenchymal fibrosis had a higher transforming growth factor (TGF)-β level (6.09) than the control group (1.82), with a 4.27 (95% CI: 0.92 to 7.61) mean difference. Moreover, patients with residual pleural thickening post-TB had a higher mean of TGF-β (0.61) than the control group (0.56), with a 0.05 (95% CI: 0.04 to 0.06) mean difference. Besides TGF-β, our qualitative synthesis also found that matrix metalloproteinase-1 might have a role in forming and developing pulmonary tissue fibrosis, thus, could be used as a predictor marker in the formation of fibrotic lesions in patients with TB. In addition, several other biomarkers were assessed in the included studies, such as tumour necrosis factor-α, interleukin (IL)-4, IL-8, IL-10, plasminogen activator inhibitor-1 and platelet-derived growth factor. However, this study is not intended to examine these biomarkers.. There were differences in the results of TGF-β levels in patients with fibrotic lesions compared with controls. TGF-β might be a biomarker of fibrotic tissue formation or increased pulmonary tissue fibrosis in post-TB patients. However, further studies are needed on a larger scale.

    Topics: Biomarkers; Fibrosis; Humans; Matrix Metalloproteinases; Pulmonary Fibrosis; Transforming Growth Factor beta; Transforming Growth Factors; Tuberculosis

2023
Immunologic and imaging signatures in post tuberculosis lung disease.
    Tuberculosis (Edinburgh, Scotland), 2022, Volume: 136

    Post Tuberculosis Lung Disease (PTLD) affects millions of tuberculosis survivors and is a global health burden. The immune mechanisms that drive PTLD are complex and have historically been under investigated. Here, we discuss two immune-mediated paradigms that could drive human PTLD. We review the characteristics of a fibrotic granuloma that favors the development of PTLD via an abundance of T-helper-2 and T-regulatory cells and an upregulation of TGF-β mediated collagen deposition. Next, we discuss the post-primary tuberculosis paradigm and the complex mixture of caseous pneumonia, cavity formation and fibrosis that can also lead to PTLD. We review the delicate balance between cellular subsets and cytokines of the innate and adaptive immune system in conjunction with host-derived proteases that can perpetuate the parenchymal lung damage seen in PTLD. Next, we discuss the role of novel host directed therapies (HDT) to limit the development of PTLD and in particular, the recent repurposing of established medications such as statins, metformin and doxycycline. Finally, we review the emerging role of novel imaging techniques as a non-invasive modality for the early recognition of PTLD. While access to computed tomography imaging is unlikely to be available widely in countries with a high TB burden, its use in research settings can help phenotype PTLD. Due to a lack of disease-specific biomarkers and controlled clinical trials, there are currently no evidence-based recommendations for the management of PTLD. It is likely that an integrated antifibrotic strategy that could simultaneously target inflammatory and pro-fibrotic pathways will probably emerge as a successful way to treat this complex condition. In a disease spectrum as wide as PTLD, a single immunologic or radiographic marker may not be sufficient and a combination is more likely to be a successful surrogate that could aid in the development of successful HDTs.

    Topics: Biomarkers; Collagen; Complex Mixtures; Cytokines; Doxycycline; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lung; Lung Diseases; Metformin; Mycobacterium tuberculosis; Peptide Hydrolases; Transforming Growth Factor beta; Tuberculosis

2022
Immunoregulation in TB: observations and implications.
    Clinical and translational science, 2010, Volume: 3, Issue:1

    Regulation of the immune response during active tuberculosis (TB) has been partly deciphered. In pulmonary TB there is transient systemic immunosuppression due to overexpression of transforming growth factor beta and interleukin-10. This is superimposed on a primary T-cell defect. Locally there is intense inflammation (lung, pleural fluid) with overexpression of immunosuppressive factors (bronchoalveolar lavage) and extensive apoptosis. These observations suggest that immune therapies should be aimed at neutralizing the negative regulatory factors rather than accentuating an already intense immune response. Also a partially effective vaccine carries the potential risk of exacerbating disease.

    Topics: Apoptosis; Bronchoalveolar Lavage; Clinical Trials as Topic; Cytokines; Humans; Immune System; Immunosuppressive Agents; Immunotherapy; Interferon-gamma; Interleukin-10; Leukocytes, Mononuclear; Lung; Mycobacterium tuberculosis; Transforming Growth Factor beta; Tuberculosis

2010
Immunotherapeutics for tuberculosis in experimental animals: is there a common pathway activated by effective protocols?
    The Journal of infectious diseases, 2007, Jul-15, Volume: 196, Issue:2

    The increasing threat posed by drug-resistant strains of M. tuberculosis is leading to a reappraisal of the possibility of treating tuberculosis (TB) by immunotherapy. We analyze 6 strategies that have been shown to be therapeutic in animal models of TB and identify a common pathway underlying the activity of the superficially different immunotherapeutic protocols. This pathway involves enhanced induction of CD8(+) cytotoxic T lymphocytes (CTLs) and down-regulation of interleukin-4 and transforming growth factor- beta , leading to further enhancement of the activity of CD8(+) CTLs and of other microbicidal pathways. This unifying analysis strengthens the rationale for future trials of immunotherapy in humans and points to surrogate markers that could be studied in such trials.

    Topics: Animals; CD8-Positive T-Lymphocytes; Disease Models, Animal; Humans; Immunotherapy, Active; Interleukin-4; Mice; Transforming Growth Factor beta; Tuberculosis; Tuberculosis Vaccines

2007
[Transforming growth factor-beta immunogenic participating in tuberculous pathogenesis].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2000, Volume: 23, Issue:3

    Topics: Animals; Humans; Macrophage Activation; T-Lymphocytes; Transforming Growth Factor beta; Tuberculosis

2000
The role of TGF beta in the pathogenesis of human tuberculosis.
    Clinical immunology and immunopathology, 1998, Volume: 87, Issue:2

    Topics: Animals; Humans; Transforming Growth Factor beta; Tuberculosis

1998
Mechanisms of anergy in tuberculosis.
    Current topics in microbiology and immunology, 1996, Volume: 215

    Topics: Animals; Humans; Hypersensitivity, Delayed; Immune Tolerance; T-Lymphocytes; Transforming Growth Factor beta; Tuberculin Test; Tuberculosis

1996

Other Studies

42 other study(ies) available for transforming-growth-factor-beta and Tuberculosis

ArticleYear
Inflammation-mediated changes in haemostatic variables of pulmonary tuberculosis patients during treatment.
    Tuberculosis (Edinburgh, Scotland), 2023, Volume: 138

    Tuberculosis (TB) disease is usually marked by inflammation which is closely linked to haemostasis both in health and disease. Close monitoring of haemostatic response to inflammatory changes during treatment is important to improve TB management. Here we studied associations between haemostatic markers and inflammatory cytokines in 60 TB-infected individuals, aged 18-65 years who received anti-TB therapy. They were recruited before commencement of therapy and followed up till completion of therapy after 6-months. The TNF-α, IL-6, IL-2 (pro-inflammatory cytokines) and P-selectin, GP IIb/IIIa, thrombopoietin (haemostatic variables) were significantly increased at 2 month into therapy compared to pre-treatment values and decreased at 6 month into therapy. Also at 6 month into therapy in comparison to 2-month into therapy, there were significant increase in IL-10 and TGF-β (anti-inflammatory cytokines) as well as a significant decline in PF-4. There were significant positive correlations between GP IIb/IIIa and TNF-α, IL-6 and PSEL, IL-6 and TPO, PF4 and TGF-β. Conclusively, the changes in the TNF-α, IL-6, IL-2 aligned with changes in the levels of P-selectin, GP IIb/IIIa, and TPO in the course of TB therapy. This may suggest that the levels of inflammatory cytokines are linked to the levels of these haemostatic variables in TB individuals.

    Topics: Cytokines; Hemostasis; Hemostatics; Humans; Inflammation; Interleukin-2; Interleukin-6; Mycobacterium tuberculosis; P-Selectin; Platelet Membrane Glycoprotein IIb; Transforming Growth Factor beta; Tuberculosis; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha

2023
Association Between Functional Nucleotide Polymorphisms Up-regulating Transforming Growth Factor β1 Expression and Increased Tuberculosis Susceptibility.
    The Journal of infectious diseases, 2022, 03-02, Volume: 225, Issue:5

    Previous studies demonstrated that transforming growth factor (TGT) β1 plays an immunosuppressive role in clinical tuberculosis. However, the contribution of TGF-β1 gene polymorphisms to human tuberculosis susceptibility remains undetermined. In this study, we showed that single-nucleotide polymorphisms (SNPs) in TGF-β1 gene were associated with increased susceptibility to tuberculosis in the discovery cohort (1533 case patients and 1445 controls) and the validation cohort (832 case patients and 1084 controls), and 2 SNPs located in the promoter region (rs2317130 and rs4803457) are in strong linkage disequilibrium. The SNP rs2317130 was associated with the severity of tuberculosis. Further investigation demonstrated that rs2317130 CC genotype is associated with higher TGF-β1 and interleukin 17A production. The mechanistic study showed that rs2317130 C allele affected TGF-β1 promoter activity by regulating binding activity to nuclear extracts. These findings provide insights into the pathogenic role of TGF-β1 in human tuberculosis and reveal a function for the TGF-β1 promoter SNPs in regulating immune responses during Mycobacterium tuberculosis infection.

    Topics: Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Single Nucleotide; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tuberculosis

2022
MAIT cell-directed therapy of Mycobacterium tuberculosis infection.
    Mucosal immunology, 2021, Volume: 14, Issue:1

    Mucosal-associated invariant T (MAIT) cells are potential targets of vaccination and host-directed therapeutics for tuberculosis, but the role of MAIT cells during Mycobacterium tuberculosis (Mtb) infection in vivo is not well understood. Here we find that following Mtb infection MAIT cells mount minimal responses, and MAIT cell-deficient MR1

    Topics: Adoptive Transfer; Animals; Biomarkers; CD4-Positive T-Lymphocytes; Disease Models, Animal; Female; Host-Pathogen Interactions; Immunophenotyping; Lymphocyte Activation; Male; Mice; Mucosal-Associated Invariant T Cells; Mycobacterium tuberculosis; T-Cell Antigen Receptor Specificity; Transforming Growth Factor beta; Tuberculosis

2021
TGFβ restricts expansion, survival, and function of T cells within the tuberculous granuloma.
    Cell host & microbe, 2021, 04-14, Volume: 29, Issue:4

    CD4 T cell effector function is required for optimal containment of Mycobacterium tuberculosis (Mtb) infection. IFNɣ produced by CD4 T cells is a key cytokine that contributes to protection. However, lung-infiltrating CD4 T cells have a limited ability to produce IFNɣ, and IFNɣ plays a lesser protective role within the lung than at sites of Mtb dissemination. In a murine infection model, we observed that IFNɣ production by Mtb-specific CD4 T cells is rapidly extinguished within the granuloma but not within unaffected lung regions, suggesting localized immunosuppression. We identified a signature of TGFβ signaling within granuloma-infiltrating T cells in both mice and rhesus macaques. Selective blockade of TGFβ signaling in T cells resulted in an accumulation of terminally differentiated effector CD4 T cells, improved IFNɣ production within granulomas, and reduced bacterial burdens. These findings uncover a spatially localized immunosuppressive mechanism associated with Mtb infection and provide potential targets for host-directed therapy.

    Topics: Adaptive Immunity; Animals; CD4-Positive T-Lymphocytes; Cell Death; Cytokines; Disease Models, Animal; Female; Granuloma; Inflammation; Interferon-gamma; Lung; Macaca mulatta; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mycobacterium tuberculosis; T-Lymphocytes; Th1 Cells; Transforming Growth Factor beta; Tuberculosis

2021
Plasma Biomarkers of Risk of Tuberculosis Recurrence in HIV Co-Infected Patients From South Africa.
    Frontiers in immunology, 2021, Volume: 12

    There is an urgent need to identify immunological markers of tuberculosis (TB) risk in HIV co-infected individuals. Previously we have shown that TB recurrence in HIV co-infected individuals on ART was associated with markers of systemic inflammation (IL-6, IL1β and IL-1Rα). Here we examined the effect of additional acute inflammation and microbial translocation marker expression on risk of TB recurrence. Stored plasma samples were drawn from the TB Recurrence upon Treatment with HAART (TRuTH) study, in which individuals with previously treated pulmonary TB were screened for recurrence quarterly for up to 4 years. Recurrent TB cases (n = 37) were matched to controls (n = 102) by original trial study arm assignment and ART start date. Additional subsets of HIV infected (n = 41) and HIV uninfected (n = 37) individuals from Improving Recurrence Success (IMPRESS) study were sampled at active TB and post successful treatment completion. Plasma concentrations of soluble adhesion molecules (sMAdCAM, sICAM and sVCAM), lipopolysaccharide binding protein (LBP) and transforming growth factor-beta (TGF-β1, TGF-β2, TGF-β3) were measured by multiplex immunoassays and ELISA. Cytokine data was square root transformed in order to reduce variability. Multivariable analysis adjusted for a number of potential confounders measured at sample time-point: age, BMI, CD4 count, viral load (VL) and measured at baseline: presence or absence of lung cavities, previous history of TB, and WHO disease stage (4 vs 3). The following analytes were associated with increased risk of TB recurrence in the multivariable model: sICAM (aOR 1.06, 95% CI: 1.02-1.12, p = 0.009), LBP (aOR 8.78, 95% CI: 1.23-62.66, p = 0.030) and TGF-β3 (aOR 1.44, 95% CI 1.01-2.05, p = 0.044). Additionally, we observed a positive correlation between LBP and sICAM (r= 0.347, p<0.0001), and LBP and IL-6, identified to be one of the strongest predictors of TB risk in our previous study (r=0.623, p=0.03). These data show that increased risk of TB recurrence in HIV infected individuals on ART is likely associated with HIV mediated translocation of microbial products and the resulting chronic immune activation.

    Topics: Acute-Phase Proteins; Adult; Antiretroviral Therapy, Highly Active; Bacterial Translocation; Biomarkers; Carrier Proteins; CD4 Lymphocyte Count; Cohort Studies; Cytokines; Female; HIV Infections; Humans; Male; Membrane Glycoproteins; Recurrence; Risk Factors; South Africa; Transforming Growth Factor beta; Tuberculosis; Viral Load

2021
Transforming Growth Factor-β Suppresses Interleukin (IL)-2 and IL-1β Production in HIV-Tuberculosis Co-Infection.
    Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2019, Volume: 39, Issue:6

    Interleukin (IL)-1β and IL-2 play important roles in protective immune responses against

    Topics: HIV Infections; Humans; Interleukin-1beta; Interleukin-2; Transforming Growth Factor beta; Tuberculosis

2019
Oxidization of TGFβ-activated kinase by MPT53 is required for immunity to Mycobacterium tuberculosis.
    Nature microbiology, 2019, Volume: 4, Issue:8

    Mycobacterium tuberculosis (Mtb)-derived components are usually recognized by pattern recognition receptors to initiate a cascade of innate immune responses. One striking characteristic of Mtb is their utilization of different type VII secretion systems to secrete numerous proteins across their hydrophobic and highly impermeable cell walls, but whether and how these Mtb-secreted proteins are sensed by host immune system remains largely unknown. Here, we report that MPT53 (Rv2878c), a secreted disulfide-bond-forming-like protein of Mtb, directly interacts with TGF-β-activated kinase 1 (TAK1) and activates TAK1 in a TLR2- or MyD88-independent manner. MPT53 induces disulfide bond formation at C

    Topics: Animals; Antigens, Bacterial; Bacterial Proteins; Cytokines; Female; HEK293 Cells; Humans; Immunity, Innate; Inflammation; Lung; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mycobacterium tuberculosis; Myeloid Differentiation Factor 88; Oxidation-Reduction; Signal Transduction; Toll-Like Receptor 2; Transforming Growth Factor beta; Tuberculosis; Type VII Secretion Systems

2019
Diagnostic Value of Vascular Endothelial Growth Factor, Transforming Growth Factor-β, Interleukin-8, and the Ratio of Lactate Dehydrogenase to Adenosine Deaminase in Pleural Effusion.
    Lung, 2018, Volume: 196, Issue:2

    We studied the diagnostic value of cytokines, including vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and interleukin-8 (IL-8), and the ratio of lactate dehydrogenase (LDH) to adenosine deaminase (ADA) in pleural fluid.. Prospective analysis of 44 inpatients or outpatients with pleural fluid, from December 2016 to March 2017 was conducted.. We enrolled patients with malignant pleural effusion (MPE, N = 15), empyema (N = 11), parapneumonic effusion (PPE, N = 7), chronic renal failure (CRF)/chronic heart failure (CHF) (N = 7), and tuberculous pleural effusion (TBPE, N = 4). The pleural fluid values of IL-8 and VEGF were significantly higher in empyema patients than in CRF/CHF or PPE patients. In all patients, the pleural fluid VEGF and IL-8 values were significantly positively correlated (r = 0.405, p = 0.006; r = 0.474, p = 0.047, respectively). TGF-β was elevated in patients with empyema, PPE, TBPE, and MPE. The pleural LDH-to-ADA ratio in patients with MPE or empyema/PPE was significantly higher than in patients with CRF/CHF or TBPE. LDH and ADA levels correlated significantly only in patients with MPE (r = 0.648, p = 0.009) and empyema/PPE (r = 0.978, p < 0.001).. VEGF and IL-8 production in the pleural cavity appear to accelerate the progression of PPE to empyema, by enhancing vascular permeability associated with inflammation. Sequential sampling would be needed to confirm this. The pleural LDH/ADA ratio may be a useful diagnostic tool for discriminating between various pleural effusion etiologies.

    Topics: Adenosine Deaminase; Aged; Aged, 80 and over; Biomarkers; Diagnosis, Differential; Empyema, Pleural; Female; Heart Failure; Humans; Interleukin-8; Kidney Failure, Chronic; L-Lactate Dehydrogenase; Male; Middle Aged; Pleural Effusion; Pleural Effusion, Malignant; Pneumonia; Predictive Value of Tests; Prospective Studies; Transforming Growth Factor beta; Tuberculosis; Vascular Endothelial Growth Factor A

2018
[Effects of Mycobacterium tuberculosis antigen and anti-TCRγδ antibody on IL-17 production of human γδT cells in polarization culture].
    Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology, 2015, Volume: 31, Issue:2

    To investigate the effects of Mycobacterium tuberculosis heat-resistant antigen (MTB-HAg) and anti-TCR γδ monoclonal antibody (mAb) on the induction and differentiation of human IL-17-producing γδT cells under polarization culture conditions.. From human peripheral blood mononuclear cells, the γδT cells were purified by magnetic-activated cell sorting (MACS) and then stimulated with MTB-HAg or anti-TCRγδ mAb and with or without anti-CD28 mAb, and cultured in the presence or absence of the cytokine cocktails (CK) (IL-1β, IL-6, TGF-β and IL-23) for 10 to 12 days. The polarized cultured γδT cells were collected and re-stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin for 6 hours, and the number of IL-17-producing cells was detected by ELISPOT.. The number of IL-17-producing cells (per 10⁵ γδT cells) in anti-TCRγδ combined with CK group was significantly higher than that in the anti-TCRγδ group. Meanwhile, the IL-17-producing γδT cell number in anti-TCRγδ combined with anti-CD28 group was lower than that in the anti-TCRγδ combined with anti-CD28 and CK group. The IL-17-producing γδT cell number of anti-TCRγδ combined with anti-CD28 and CK group was significantly higher than that in anti-TCRγδ combined with CK group, and that in MTB-HAg combined with anti-CD28 and CK group was significantly lower than that in anti-TCRγδ combined with anti-CD28 and CK group, but higher than that in MTB-HAg combined with anti-CD28 group.. The CK (IL-1β, IL-6, TGF-β and IL-23) required for the differentiation of Th17 cells also induced the differentiation of IL-17⁺ γδT cells after pre-activated by MTB-HAg or anti-TCRγδ antibody, while anti-TCRγδ mAb showed the stronger stimulatory effect than MTB-HAg. In addition, CD28 co-stimulation enhanced the differentiation of IL-17 from activated γδT cells.

    Topics: Adolescent; Adult; Antibodies, Monoclonal; Antigens, Bacterial; Cell Differentiation; Female; Humans; Interleukin-17; Interleukin-23; Interleukin-6; Male; Mycobacterium tuberculosis; Receptors, Antigen, T-Cell, gamma-delta; T-Lymphocyte Subsets; Th17 Cells; Transforming Growth Factor beta; Tuberculosis; Young Adult

2015
Investigating the causes for decreased levels of glutathione in individuals with type II diabetes.
    PloS one, 2015, Volume: 10, Issue:3

    Tuberculosis (TB) remains an eminent global burden with one third of the world's population latently infected with Mycobacterium tuberculosis (M. tb). Individuals with compromised immune systems are especially vulnerable to M. tb infection. In fact, individuals with Type 2 Diabetes Mellitus (T2DM) are two to three times more susceptible to TB than those without T2DM. In this study, we report that individuals with T2DM have lower levels of glutathione (GSH) due to compromised levels of GSH synthesis and metabolism enzymes. Transforming growth factor beta (TGF-β), a cytokine that is known to decrease the expression of the catalytic subunit of glutamine-cysteine ligase (GCLC) was found in increased levels in the plasma samples from individuals with T2DM, explaining the possible underlying mechanism that is responsible for decreased levels of GSH in individuals with T2DM. Moreover, increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-17 (IL-17) were observed in plasma samples isolated from individuals with T2DM. Increased levels of IL-6 and IL-17 was accompanied by enhanced production of free radicals further indicating an alternative mechanism for the decreased levels of GSH in individuals with T2DM. Augmenting the levels of GSH in macrophages isolated from individuals with T2DM resulted in improved control of M. tb infection. Furthermore, cytokines that are responsible for controlling M. tb infection at the cellular and granuloma level such as tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), interferon-gamma (IFN-γ), and interleukin-12 (IL-12), were found to be compromised in plasma samples isolated from individuals with T2DM. On the other hand, interleukin-10 (IL-10), an immunosuppressive cytokine was increased in plasma samples isolated from individuals with T2DM. Overall, these findings suggest that lower levels of GSH in individuals with T2DM lead to their increased susceptibility to M. tb infection.

    Topics: Adult; Blotting, Western; Cytokines; Diabetes Complications; Diabetes Mellitus, Type 2; Disease Susceptibility; Flow Cytometry; Glutathione; Humans; Immunoblotting; Interleukin-17; Interleukin-6; Macrophages; Middle Aged; Reactive Oxygen Species; Rosaniline Dyes; Transforming Growth Factor beta; Tuberculosis

2015
Immunomodulation in host-protective immune response against murine tuberculosis through regulation of the T regulatory cell function.
    Journal of leukocyte biology, 2015, Volume: 98, Issue:5

    Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, is characterized by an infection in lung and spleen. In the present study, we have elucidated the mechanism by which Mycobacterium indicus pranii renders protection in in vivo Mycobacterium tuberculosis infection. We observed that Mycobacterium indicus pranii treated infected C57BL/6 mice showed a strong host-protective Th1 immune response along with a marked decrease in immunosuppressive cytokines, TGF-β, and IL-10-secreting CD4(+) T cells. This Mycobacterium indicus pranii mediated decrease in immunosuppressive cytokines was correlated with the reduction in the elevated frequency of CD4(+)CD25(+) T regulatory cells, along with the reduced TGF-β production from these T regulatory cells in tuberculosis-infected mice. This reduction in the T regulatory cell population was a result of effective modulation of STAT4-STAT5 transcription factor counter-regulation by Mycobacterium indicus pranii, which in turn, reduced the immunosuppressive activity of T regulatory cells. Thus, these findings put forward a detailed mechanistic insight into Mycobacterium indicus pranii mediated regulation of the T regulatory cell functioning during experimental murine tuberculosis, which might be helpful in combating Mycobacterium-induced pathogenesis.

    Topics: Animals; Female; Interleukin-10; Mice; Mycobacterium tuberculosis; STAT4 Transcription Factor; STAT5 Transcription Factor; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tuberculosis

2015
Sec13 Regulates Expression of Specific Immune Factors Involved in Inflammation In Vivo.
    Scientific reports, 2015, Dec-03, Volume: 5

    The Sec13 protein functions in various intracellular compartments including the nuclear pore complex, COPII-coated vesicles, and inside the nucleus as a transcription regulator. Here we developed a mouse model that expresses low levels of Sec13 (Sec13(H/-)) to assess its functions in vivo, as Sec13 knockout is lethal. These Sec13 mutant mice did not present gross defects in anatomy and physiology. However, the reduced levels of Sec13 in vivo yielded specific immunological defects. In particular, these Sec13 mutant mice showed low levels of MHC I and II expressed by macrophages, low levels of INF-γ and IL-6 expressed by stimulated T cells, and low frequencies of splenic IFN-γ+CD8+ T cells. In contrast, the levels of soluble and membrane-bound TGF-β as well as serum immunoglobulin production are high in these mice. Furthermore, frequencies of CD19+CD5-CD95+ and CD19+CD5-IL-4+ B cells were diminished in Sec13(H/-) mice. Upon stimulation or immunization, some of the defects observed in the naïve mutant mice were compensated. However, TGF-β expression remained high suggesting that Sec13 is a negative modulator of TGF-β expression and of its immunosuppressive functions on certain immune cells. In sum, Sec13 regulates specific expression of immune factors with key functions in inflammation.

    Topics: Animals; Carrier Proteins; CD8-Positive T-Lymphocytes; Immunologic Factors; Inflammation; Interferon-gamma; Interleukin-6; Macrophages; Mice, Mutant Strains; Mycobacterium tuberculosis; Nuclear Proteins; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tuberculosis

2015
Inhibition of Mycobacterium tuberculosis-induced signalling by transforming growth factor-β in human mononuclear phagocytes.
    Scandinavian journal of immunology, 2012, Volume: 75, Issue:3

    Tuberculosis (TB) is associated with excessive production and bioactivation of transforming growth factor bets (TGF-β) in situ. Here, modification of expression of components of plasminogen/plasmin pathway in human monocytes (MN) by inhibitors of TGF-β signalling was examined. Smad3 siRNA effectively inhibited TGF-β-induced urokinase plasminogen activator receptor (uPAR). Agents known to interfere with TGF-β signalling, including the Smad inhibitors SIS3 and erythromycin derivatives, and ALK5 receptor inhibitor (SB 431542) in inhibition of uPAR expression in response to Mycobacterium tuberculosis (MTB) were examined. Inhibition by SIS3 only inhibited uPAR mRNA significantly. SIS3 may prove to be an effective adjunct to TB therapy.

    Topics: Benzamides; Dioxoles; Humans; Isoquinolines; Leukocytes, Mononuclear; Mycobacterium tuberculosis; Phagocytes; Plasminogen Activators; Plasminogen Inactivators; Pyridines; Pyrroles; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Tuberculosis

2012
Early secreted antigen ESAT-6 of Mycobacterium tuberculosis promotes protective T helper 17 cell responses in a toll-like receptor-2-dependent manner.
    PLoS pathogens, 2011, Volume: 7, Issue:11

    Despite its relatively poor efficacy, Bacillus Calmette-Guérin (BCG) has been used as a tuberculosis (TB) vaccine since its development in 1921. BCG induces robust T helper 1 (Th1) immune responses but, for many individuals, this is not sufficient for host resistance against Mycobacterium tuberculosis (M. tb) infection. Here we provide evidence that early secreted antigenic target protein 6 (ESAT-6), expressed by the virulent M. tb strain H37Rv but not by BCG, promotes vaccine-enhancing Th17 cell responses. These activities of ESAT-6 were dependent on TLR-2/MyD88 signalling and involved IL-6 and TGF-β production by dendritic cells. Thus, animals that were previously infected with H37Rv or recombinant BCG containing the RD1 region (BCG::RD1) exhibited improved protection upon re-challenge with virulent H37Rv compared with mice previously infected with BCG or RD1-deficient H37Rv (H37RvΔRD1). However, TLR-2 knockout (TLR-2⁻/⁻) animals neither showed Th17 responses nor exhibited improved protection in response to immunization with H37Rv. Furthermore, H37Rv and BCG::RD1 infection had little effect on the expression of the anti-inflammatory microRNA-146a (miR146a) in dendritic cells (DCs), whereas BCG and H37RvΔRD1 profoundly induced its expression in DCs. Consistent with these findings, ESAT-6 had no effect on miR146a expression in uninfected DCs, but dramatically inhibited its upregulation in BCG-infected or LPS-treated DCs. Collectively, our findings indicate that, in addition to Th1 immunity induced by BCG, RD1/ESAT-6-induced Th17 immune responses are essential for optimal vaccine efficacy.

    Topics: Animals; Antigens, Bacterial; Bacterial Proteins; BCG Vaccine; Dendritic Cells; Interleukin-6; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Mycobacterium bovis; Mycobacterium tuberculosis; Myeloid Differentiation Factor 88; Th1 Cells; Th17 Cells; Toll-Like Receptor 2; Transforming Growth Factor beta; Tuberculosis

2011
Reduced Th17 response in patients with tuberculosis correlates with IL-6R expression on CD4+ T Cells.
    American journal of respiratory and critical care medicine, 2010, Apr-01, Volume: 181, Issue:7

    Although it is well recognized that CD4(+) T cells and T helper (Th) 1 cytokines are critical in the cell-mediated response to Mycobacterium tuberculosis, it is also clear that this immunity alone is not enough. Understanding the roles of other T cell subsets and cytokines is essential for vaccine design and clinical immunotherapy against tuberculosis (TB).. To investigate the clinical significance and possible regulatory mechanism of Th17 responses in human TB.. The frequencies of IFN-gamma-, IL-4-, IL-17-, FoxP3- and IL-6 receptor (IL-6R)-expressing CD4(+) T cells in blood and/or pleural effusion samples of healthy donors, subjects with latent TB infection, and patients with active TB were analyzed by flow cytometry. Cytokines, transforming growth factor-beta and IL-6, in plasma and pleural fluid samples were determined by ELISA.. The frequency of Th17 cells in patients with active TB is significantly lower than those in healthy donors and individuals with latent TB infection. Correlation analysis showed that reduced Th17 responses observed in patients with active TB was significantly correlated with the decreased expression of IL-6R on CD4(+) T cells, but did not correlate with the concentrations of the cytokines, transforming growth factor-beta and IL-6. Consistently; in vitro study showed that M. tuberculosis products inhibit the expression of IL-6R on CD4(+) T cells.. Our results demonstrate that reduced Th17 responses were associated with the clinical outcome of M. tuberculosis infection. Suppression of Th17 response through down-regulation of IL-6R expression may be an important mechanism in the development of active TB.

    Topics: Adult; BCG Vaccine; Biomarkers; Case-Control Studies; CD4-Positive T-Lymphocytes; Cell Movement; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-6; Male; Mycobacterium tuberculosis; Receptors, Interleukin-6; Severity of Illness Index; T-Lymphocytes, Helper-Inducer; Transforming Growth Factor beta; Tuberculosis

2010
Boosting with mycobacterial heparin-binding haemagglutinin enhances protection of Mycobacterium bovis BCG-vaccinated newborn mice against M. tuberculosis.
    Vaccine, 2010, Jun-17, Volume: 28, Issue:27

    Heterologous prime-boost regimens are a valuable strategy to improve the generation of effector-memory T cell responses against intracellular pathogens. In this study we show that newborn mice vaccinated with bacillus Calmette-Guérin (BCG) and boosted with heparin-binding haemagglutinin (HBHA) had enhanced protective immunity against intranasal or aerosol Mycobacterium tuberculosis challenge over non-boosted mice, as evidenced by a considerable reduction of mycobacterial load in spleen and lung. The route of HBHA delivery had a differential impact on cytokine and antibody production in BCG-primed mice. The prime-boost regimen induced not only HBHA-specific IFN-gamma, but also other cytokines, such as IL-12 and TGF-beta, which may be associated with the generation of lung Th1 effector-memory lymphocytes, responsible for the enhanced protection against M. tuberculosis challenge.

    Topics: Animals; Animals, Newborn; Enzyme-Linked Immunosorbent Assay; Immunization, Secondary; Interferon-gamma; Interleukin-12; Lectins; Mice; Mice, Inbred BALB C; Mycobacterium bovis; Mycobacterium tuberculosis; Transforming Growth Factor beta; Tuberculosis

2010
Lactoferrin modulation of mycobacterial cord factor trehalose 6-6'-dimycolate induced granulomatous response.
    Translational research : the journal of laboratory and clinical medicine, 2010, Volume: 156, Issue:4

    The immune system responds to tuberculosis (TB) infection by forming granulomas. However, subsequent immune-mediated destruction of lung tissue is a cause of significant morbidity and contributes to disease transmission. Lactoferrin, an iron-binding glycoprotein, has demonstrated immunomodulatory properties that decrease tissue destruction and promote T(H)1 immune responses, both of which are essential for controlling TB infection. The cord factor trehalose 6,6'-dimycolate (TDM) model of granuloma formation mimics many aspects of TB infection with a similar histopathology accompanied by proinflammatory cytokine production. C57BL/6 mice were injected intravenously with TDM. A subset of mice was given 1 mg of bovine lactoferrin 24 h post-TDM challenge. Lung tissue was analyzed for histological response and for the production of proinflammatory mediators. C57BL/6 mice demonstrated a granuloma formation that correlated with an increased production of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α,) IL-12p40, interferon-gamma (IFN-γ), and IL-10 protein. Mice treated with lactoferrin postchallenge had significantly fewer and smaller granulomas compared with those given TDM alone. Proinflammatory and T(H)1 cytokines essential to the control of mycobacterial infections, such as TNF-α and IFN-γ, were not significantly different in mice treated with lactoferrin. Furthermore, the anti-inflammatory cytokines IL-10 and transforming growth factor-β were increased. A potential mechanism for decreased tissue damage observed in the lactoferrin-treated mice is proposed. Because of its influence to modulate immune responses, lactoferrin may be a useful adjunct in the treatment of granulomatous inflammation occurring during mycobacterial infection.

    Topics: Animals; Cord Factors; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Granuloma; Interleukin-10; Lactoferrin; Lung; Lung Diseases; Macrophages; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Protein Biosynthesis; Transforming Growth Factor beta; Tuberculosis

2010
Tuberculosis due to high-dose challenge in partially immune individuals: a problem for vaccination?
    The Journal of infectious diseases, 2009, Mar-01, Volume: 199, Issue:5

    The currently available vaccine for tuberculosis (TB) is ineffective in developing countries. We need to understand the pathogenesis of TB in those countries and how it differs from the pathogenesis of TB in wealthy countries, to facilitate the design and interpretation of clinical trials of new vaccine candidates that are now available. We show here that these geographical differences parallel the strikingly different immunology and bacterial growth curves seen in animal models after high-dose and low-dose challenge with M. tuberculosis (Mtb). We consider this point in the light of recent insights into the multiple pathways used by the immune response to control M. tuberculosis and the susceptibilities of these pathways to regulation and suppression. There are important implications for the screening, testing, and likely success of vaccine candidates.

    Topics: Animals; Cytokines; Developing Countries; Disease Models, Animal; Environmental Microbiology; Housing; Humans; Mice; Mycobacterium tuberculosis; Th2 Cells; Transforming Growth Factor beta; Tuberculosis; Tuberculosis Vaccines

2009
Differential expression of mycobacterial antigen MPT64, apoptosis and inflammatory markers in multinucleated giant cells and epithelioid cells in granulomas caused by Mycobacterium tuberculosis.
    Virchows Archiv : an international journal of pathology, 2008, Volume: 452, Issue:4

    The development of granulomas is a major histopathological feature of tuberculosis. Very little information is available concerning the physiology and functions of different cell types in the tuberculous granulomas. The aim of this study was to compare the epithelioid cells (ECs) and multinucleated giant cells (MGCs) in the granulomas caused by Mycobacterium tuberculosis complex organisms. Lymph node biopsies from 30 cases of lymphadenitis were studied for expression of the secreted mycobacterial protein MPT64, caspase 3 as a marker of apoptosis, apoptosis-related proteins (Fas Ligand, Fas and Bax) and inflammatory cytokines (interleukin-10, transforming growth factor-beta (TGF-beta), tumour necrosis factor-alpha and interferon-gamma) by immunohistochemistry. MGCs more often contained M. tuberculosis secretory antigen MPT64 (p < 0.001) and expressed more TGF-beta (p = 0.004) than ECs. The total number of apoptotic MGCs was higher than the number of apoptotic ECs (p = 0.04). Interestingly, there was a significant negative correlation between apoptosis and MPT64 expression in MGCs (r = -0.569, p = 0.003), but not in ECs, implying that the heavy antigen load would lead to inhibition of apoptosis in these cells. When compared with ECs, higher percentage of MGCs expressed Fas Ligand and Fas (p < 0.004). The role of MGCs may thus be different from surrounding ECs and these cells by virtue of higher mycobacterial antigen load, more TGF-beta and reduced apoptosis may contribute towards persistence of infection.

    Topics: Antigens, Bacterial; Apoptosis; bcl-2-Associated X Protein; Biopsy; Caspase 3; Cytokines; Epithelioid Cells; Fas Ligand Protein; fas Receptor; Giant Cells; Granuloma; Humans; Inflammation; Interferon-gamma; Interleukin-10; Lymphadenitis; Mycobacterium tuberculosis; Transforming Growth Factor beta; Tuberculosis; Tumor Necrosis Factor-alpha

2008
Relative levels of M-CSF and GM-CSF influence the specific generation of macrophage populations during infection with Mycobacterium tuberculosis.
    Journal of immunology (Baltimore, Md. : 1950), 2008, Apr-01, Volume: 180, Issue:7

    Members of the CSF cytokine family play important roles in macrophage recruitment and activation. However, the role of M-CSF in pulmonary infection with Mycobacterium tuberculosis is not clear. In this study, we show the lungs of mice infected with M. tuberculosis displayed a progressive decrease in M-CSF in contrast to increasing levels of GM-CSF. Restoring pulmonary M-CSF levels during infection resulted in a significant decrease in the presence of foamy macrophages and increased expression of CCR7 and MHC class II, specifically on alveolar macrophages. In response to M-CSF, alveolar macrophages also increased their T cell-stimulating capacity and expression of DEC-205. These studies show that the levels of expression of M-CSF and GM-CSF participate in the progression of macrophages into foamy cells and that these cytokines are important factors in the differentiation and regulation of expression of dendritic cell-associated markers on alveolar macrophages. In addition, these studies demonstrate that M-CSF may have a role in the adaptive immune response to infection with M. tuberculosis.

    Topics: Animals; Biomarkers; CD4-Positive T-Lymphocytes; Cell Count; Cells, Cultured; Chronic Disease; Dendritic Cells; Disease Progression; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Histocompatibility Antigens Class II; Interferon-gamma; Lymphocyte Culture Test, Mixed; Macrophage Colony-Stimulating Factor; Macrophages; Mice; Mycobacterium tuberculosis; Phenotype; Sensitivity and Specificity; Transforming Growth Factor beta; Tuberculosis

2008
Changes in the levels of interferon-gamma and transforming growth factor-beta influence bronchial stenosis during the treatment of endobronchial tuberculosis.
    Respiration; international review of thoracic diseases, 2007, Volume: 74, Issue:2

    Endobronchial tuberculosis (EBTB) has been shown to frequently complicate bronchial stenosis, a condition which can induce dyspnea as a result of airway obstruction, and is also frequently misdiagnosed as either bronchial asthma or lung cancer.. This study attempted to determine whether there was a correlation between interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta) levels in the serum and bronchial washing fluid (BWF), and the results of the treatment of EBTB patients.. Thirty patients, all of whom were diagnosed as EBTB, were enrolled, as were 10 healthy control subjects. IFN-gamma and TGF-beta levels were measured by the ELISA method in the serum and BWF of these 30 EBTB patients before and after treatment. The EBTB patients were divided into two groups: those who exhibited bronchial stenosis after treatment and those who did not. Chest computed tomography (CT) and pulmonary function test (PFT) were performed in 16 and 25 patients, respectively, at initial bronchoscopy.. IFN-gamma and TGF-beta levels in the BWF of the EBTB patients were elevated compared to the controls (p < 0.05). After 2 months of treatment, 13 of the 30 EBTB patients exhibited bronchial fibrostenosis and the other 17 cases had recovered without sequelae. In the bronchial stenosis group, the initial serum TGF-beta levels were lower than in the patients without bronchial stenosis (p < 0.05). Moreover, the levels of serum TGF-beta after treatment were shown to have decreased more than in the patients without bronchial stenosis (p < 0.05). On chest CT findings of 16 EBTB patients, bronchial narrowing was suspected except in 2 cases (1 edematous-hyperemic type, 1 actively caseating type of segmental bronchus). The common features of PFT in EBTB at the initial diagnosis were a restrictive pattern and normal ventilatory function.. Elevated IFN-gamma and TGF-beta levels in the BWF of the EBTB patients may be related to EBTB pathogenesis. Lowered initial serum TGF-beta levels as well as the observed changes in the levels of TGF-beta in the serum after treatment have been implicated in bronchial fibrostenosis during the course of the disease.

    Topics: Adult; Aged; Airway Obstruction; Antitubercular Agents; Biomarkers; Bronchial Diseases; Bronchoalveolar Lavage Fluid; Bronchoscopy; Female; Follow-Up Studies; Humans; Interferon-gamma; Male; Middle Aged; Mycobacterium tuberculosis; Prognosis; Severity of Illness Index; Tomography, X-Ray Computed; Transforming Growth Factor beta; Tuberculosis

2007
Immunosuppression during active tuberculosis is characterized by decreased interferon- gamma production and CD25 expression with elevated forkhead box P3, transforming growth factor- beta , and interleukin-4 mRNA levels.
    The Journal of infectious diseases, 2007, Mar-15, Volume: 195, Issue:6

    The balance between effector and regulatory responses after Mycobacterium tuberculosis infection may dictate outcome and progression to active disease. We investigated effector and regulatory T cell responses in bacille Calmette-Guerin (BCG)-stimulated peripheral blood mononuclear cells and whole blood cultures from persons with active tuberculosis (TB), persons with TB at the end of 6 months of treatment, and healthy control subjects with latent TB infection. All 3 groups displayed BCG-induced increases in effector and regulatory T cell phenotypes as defined by CD4(+)CD25(lo) and CD4(+)CD25(hi) T cells, respectively. In case patients with active disease, BCG stimulation induced the lowest increase of CD25, CD4(+)CD25(hi), CTLA-4, and interferon- gamma . However, these case patients expressed the highest mRNA levels of forkhead box P3, transforming growth factor (TGF)- beta , and interleukin (IL)-4 and a lower T-bet : GATA-3 ratio. There were no significant differences in IL-4 delta 2, IL-10, or TGF- beta receptor-II mRNA expression between groups. Together, these results suggest that immunosuppression seen after mycobacterial stimulation in case patients with active TB is associated with naturally occurring regulatory T cells.

    Topics: Antigens, CD; BCG Vaccine; CD3 Complex; CD4 Lymphocyte Count; DNA Primers; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Immunosuppression Therapy; Interferon-gamma; Interleukin-2 Receptor alpha Subunit; Interleukin-4; Lymphocyte Count; Mycobacterium tuberculosis; Polymerase Chain Reaction; RNA, Messenger; T-Lymphocytes; Transforming Growth Factor beta; Tuberculosis

2007
Induction of cell cycle arrest and apoptosis by BCG infection in cultured human bronchial airway epithelial cells.
    American journal of physiology. Lung cellular and molecular physiology, 2007, Volume: 293, Issue:2

    Bronchial airway epithelial cells (BAEpC) are among the first cells to encounter M. tuberculosis following airborne infection. However, the response of BAEpC to M. tuberculosis infection has been little studied. This study investigates the response of a human BAEpC cell line (BEAS-2B) to infection with Mycobacterium bovis Bacille Calmette Guerin (BCG). Cultured human BEAS-2B cells were experimentally infected with BCG. Uninfected BEAS-2B cultures were included as controls. Following infection, BEAS-2B cells were evaluated by various methods at various time points up to 3 days. Cell proliferation was evaluated by cellular bioreduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Distribution of cells along the cell cycle was evaluated by FACS analysis of cellular DNA. Apoptotic cells were identified by cell death ELISA and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling method. Eighty-four apoptosis-relevant genes were screened by PCR gene microarray. Translation of Fas, Fas ligand (Fas-L), and Fas-associated death domain (FADD) were evaluated quantitatively by real-time PCR. Expression of Fas and FADD proteins was evaluated by immunofluorescence and Western blot. Activity of caspase-3 and caspase-8 was evaluated by colorimetric assay of their enzymatic activity. BCG infection of BEAS-2B cells inhibits proliferation, induces cell cycle arrest at the G(0)/G(1) phase, causes apoptosis, modulates transcription of multiple apoptosis-relevant genes, promotes translation of Fas, Fas-L, and FADD, upregulates expression of Fas and FADD proteins, and increases activity of caspase-3 and caspase-8. Infection with BCG does not cause any significant change in the secretion of TGF-beta. The roles of Fas and FADD as mediators of BCG-induced apoptosis in BEAS-2B cells were tested by partial blockade of Fas and FADD expression with silencing RNA. Partial blockade of Fas or FADD expression results in a decreased apoptotic response to BCG infection. In conclusion, BCG induces cell cycle arrest and apoptosis in BEAS-2B cells. BCG induced apoptosis of BEAS-2B cells via the Fas death receptor pathway.

    Topics: Apoptosis; Bronchi; Caspase 3; Caspase 8; Cell Cycle; Cell Division; Cell Line; Epithelial Cells; Fas Ligand Protein; fas Receptor; Fas-Associated Death Domain Protein; Humans; In Vitro Techniques; Mycobacterium bovis; Respiratory Mucosa; RNA, Messenger; RNA, Small Interfering; Transforming Growth Factor beta; Tuberculosis

2007
In vitro expansion of CD4+CD25highFOXP3+CD127low/- regulatory T cells from peripheral blood lymphocytes of healthy Mycobacterium tuberculosis-infected humans.
    Microbes and infection, 2007, Volume: 9, Issue:11

    CD4+CD25highFOXP3+ regulatory T (Treg) cells have recently been found at elevated levels in the peripheral blood of tuberculosis patients, compared to Mycobacterium tuberculosis latently infected (LTBI) healthy individuals and non-infected controls. Here, we show that CD4+CD25highFOXP3+ T lymphocytes can be expanded in vitro from peripheral blood mononuclear cells (PBMC) of LTBI individuals, but not of uninfected controls by incubating them with BCG in the presence of TGF-beta. These expanded cells from the PBMC of LTBI subjects expressed CTLA-4, GITR and OX-40, but were CD127low/- and have therefore the phenotype of Treg cells. In addition, they inhibited in a dose-dependant manner the proliferation of freshly isolated mononuclear cells in response to polyclonal stimulation, indicating that they are functional Treg lymphocytes. In contrast, incubation of the PBMC with BCG alone preferentially induced activated CD4+ T cells, expressing CD25 and/or CD69 and secreting IFN-gamma. These results show that CD4+CD25highFOXP3+ Treg cells can be expanded or induced in the peripheral blood of LTBI individuals in conditions known to predispose to progression towards active tuberculosis and may therefore play an important role in the pathogenesis of the disease.

    Topics: Antigens, CD; Antigens, Differentiation; Antigens, Differentiation, T-Lymphocyte; CD4-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; CTLA-4 Antigen; Forkhead Transcription Factors; Glucocorticoid-Induced TNFR-Related Protein; Humans; In Vitro Techniques; Interferon-gamma; Interleukin-2 Receptor alpha Subunit; Interleukin-7 Receptor alpha Subunit; Lectins, C-Type; Leukocytes, Mononuclear; Mycobacterium bovis; Receptors, Nerve Growth Factor; Receptors, OX40; Receptors, Tumor Necrosis Factor; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tuberculosis

2007
Regulatory T cells are expanded in blood and disease sites in patients with tuberculosis.
    American journal of respiratory and critical care medicine, 2006, Apr-01, Volume: 173, Issue:7

    T-cell responses during tuberculosis (TB) help contain Mycobacterium tuberculosis in vivo but also cause collateral damage to host tissues. Immune regulatory mechanisms may limit this immunopathology, and suppressed cellular immune responses in patients with TB suggest the presence of regulatory activity. CD4+CD25(high) regulatory T cells mediate suppressed cellular immunity in several chronic infections but have not been described in TB.. To determine whether regulatory T cells are increased in patients with TB and whether they suppress cellular immune responses.. We compared the frequency of circulating regulatory T cells in 27 untreated patients with TB and 23 healthy control subjects using two specific markers: cell-surface CD25 expression and FoxP3 mRNA expression in peripheral blood mononuclear cells.. We detected a threefold increase in the frequency of CD4 + CD25(high) T cells (p < 0.001) and a 2.2-fold increase in FoxP3 expression (p = 0.006) in patients with TB, and there was a positive correlation between these markers (r = 0.58, p < 0.001). Increased expression of interleukin-10 and transforming growth factor-beta1 mRNA was also detected in patients with TB but did not correlate with regulatory T-cell markers. Ex vivo depletion of CD4 + CD25(high) cells from peripheral blood mononuclear cells resulted in increased numbers of M. tuberculosis antigen-specific IFN-gamma-producing T cells in seven of eight patients with TB (p = 0.005). Finally, FoxP3 expression was increased 2.3-fold in patients with extrapulmonary TB compared with patients with purely pulmonary TB (p = 0.01) and was amplified 2.6-fold at disease sites relative to blood (p = 0.043).. Regulatory T cells are expanded in patients with TB and may contribute to suppression of Th1-type immune responses.

    Topics: Adult; Biomarkers; Female; Flow Cytometry; Forkhead Transcription Factors; Gene Expression; Humans; Interleukin-10; Lymphocyte Activation; Male; Middle Aged; Receptors, Interleukin-2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tuberculosis

2006
Impact of circulating TGF-Beta and IL-10 on T cell cytokines in patients with asthma and tuberculosis.
    Journal of Korean medical science, 2006, Volume: 21, Issue:1

    Regulatory T cells, which stimulate or inhibit the effector functions of distinct T cell subsets, are critical in the control of the immune response. We investigated the effect of TGF-beta and IL-10 on T cell subsets according to the Th1/Th2 immune status. Sixty-two patients with asthma and 38 patients with pulmonary tuberculosis were included. Allergy skin tests, tuberculin tests, and chest radiography were performed. The levels of circulating IL-4, IFN-gamma, TGF-beta1, and IL-10 were measured using ELISA. The level of TGF-beta1 was higher in patients with asthma than in those with tuberculosis, but the IL-10 levels were the same between the asthma and tuberculosis groups. Atopy was unrelated to the tuberculin response. The IFN-gamma level was correlated with the IL-10 level, and the level of IL-4 was unrelated to the IL-10 or TGF-beta1 level. The level of IL-10 was higher in the negative tuberculin reactors than in the positive tuberculin reactors among patients with asthma, and TGF-beta1 was higher in the positive tuberculin reactors than in the negative tuberculin reactors among patients with tuberculosis. These results demonstrate that the regulatory effects of circulating TGF-beta and IL-10 on T cell cytokines may be different between Th2-type asthma and Th1 tuberculosis.

    Topics: Adult; Asthma; Cytokines; Female; Humans; Interferon-gamma; Interleukin-10; Interleukin-4; Male; Respiratory Function Tests; Skin Tests; Th1 Cells; Th2 Cells; Transforming Growth Factor beta; Tuberculin Test; Tuberculosis

2006
Interleukin-10 (IL-10) gene polymorphism as a potential host susceptibility factor in tuberculosis.
    Cytokine, 2006, Volume: 35, Issue:3-4

    Several genes encoding for different cytokines may play crucial roles in host susceptibility to tuberculosis (TB), since the cytokine production capacity varies among individuals and depends on the cytokine gene polymorphism. The association of the cytokine gene polymorphisms with the development of TB was investigated in this study. DNA samples were obtained from a Turkish population of 81 patients with the different clinical forms of TB, and 50 healthy control subjects. All genotyping (IL-6, IL-10, IFN-gamma, TGF-beta and TNF-alpha) experiments were performed using sequence-specific primers PCR (PCR-SSP). Analysis of allele frequencies showed that IL-10 -1082 G allele frequency was significantly more common in TB patients than healthy controls (37.7% vs 23.0%, p: 0.014). No statistically significant differences were observed between the different clinical forms of the disease. These results suggest that the polymorphisms in IL-10 gene may affect susceptibility to TB and increase risk of developing the disease. To confirm the biological significance of our results, further studies should be performed on other population groups.

    Topics: Alleles; Case-Control Studies; Cytokines; Female; Gene Frequency; Genotype; Humans; Interferon-gamma; Interleukin-10; Interleukin-6; Male; Polymorphism, Single Nucleotide; Transforming Growth Factor beta; Tuberculosis; Turkey

2006
Differential pattern of cytokine expression by macrophages infected in vitro with different Mycobacterium tuberculosis genotypes.
    Clinical and experimental immunology, 2005, Volume: 140, Issue:3

    It has been shown recently that different genotypes of Mycobacterium tuberculosis induce distinct immune responses in the host, as reflected by variations in cytokine and iNOS expression. Because these molecules are probably regulated by multiple factors in vivo this complex phenomenon was partially analysed by assessing cytokine and iNOS expression by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) in an in vitro model of bone marrow-derived macrophages infected with three different M. tuberculosis genotypes: Canetti, H37 Rv and Beijing. Although the three genotypes induced production of iNOS and the different cytokines tested at 24 h post-infection, macrophages infected with the Beijing isolate expressed the highest levels of mRNA for iNOS, interleukin (IL)-1beta, tumour necrosis factor (TNF)-alpha, IL-12 cytokines and lower levels of IL-10 compared with cells infected with other genotypes. This expression pattern has been associated with infection control, but during infection in vivo with the Beijing genotype it is lost upon progression to chronic phase. The failure to control infection is likely to be influenced by cytokines produced by other cell types and bacterial molecules expressed during the course of disease. Results presented in this work show that each genotype has the ability to induce different levels of cytokine expression that could be related to its pathogenesis during infection.

    Topics: Animals; Bone Marrow Cells; Cells, Cultured; Cytokines; Genotype; Interleukin-1; Interleukin-10; Interleukins; Macrophages; Mice; Mycobacterium tuberculosis; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phagocytosis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta; Tuberculosis

2005
Solution structure of the Mycobacterium tuberculosis complex protein MPB70: from tuberculosis pathogenesis to inherited human corneal desease.
    The Journal of biological chemistry, 2003, Oct-31, Volume: 278, Issue:44

    The closely related mycobacteria responsible for tuberculosis produce an unusually high number of secreted proteins, many of which are clearly implicated in pathogenesis and protective immunity. Falling within this category are the closely related proteins MPB70 and MPB83. The structure of MPB70 reveals a complex and novel bacterial fold, which has clear structural homology to the two C-terminal FAS1 domains of the cell adhesion protein fasciclin I, whose structures were reported very recently. Assessment of the surface features of MPB70, the sequence divergence between MPB70 and MPB83, the conservation of residues across a group of FAS1 domains, and the locations of disease-inducing mutations in betaig-h3 strongly suggests that MPB70 and MPB83 contain two functional surfaces on opposite faces, which are probably involved in binding to host cell proteins. This analysis also suggests that these functional surfaces are retained in the FAS1 proteins associated with mediating interactions between cells and the extracellular matrix (fasciclin I, periostin, and betaig-h3) and furthermore that some of the human corneal disease-inducing substitutions identified in betaig-h3 will perturb interactions at these sites.

    Topics: Amino Acid Sequence; Antigens, Bacterial; Bacterial Proteins; Cell Adhesion Molecules; Cell Adhesion Molecules, Neuronal; Corneal Diseases; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Magnetic Resonance Spectroscopy; Membrane Proteins; Models, Molecular; Molecular Sequence Data; Mutation; Mycobacterium tuberculosis; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Transforming Growth Factor beta; Tuberculosis

2003
In situ expression of CD40, CD40L (CD154), IL-12, TNF-alpha, IFN-gamma and TGF-beta1 in murine lungs during slowly progressive primary tuberculosis.
    Scandinavian journal of immunology, 2003, Volume: 58, Issue:3

    The distribution and expression of CD40, its ligand CD40L (154) and related cytokines interleukin-12 (IL-12), tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and transforming growth factor-beta1 (TGF-beta1) were studied in the lungs of B6D2F1 hybrid mice during slowly progressive primary tuberculosis (TB) by immunohistochemistry. CD40 and CD40L are implicated in cell-mediated immunity (CMI) causing activation or apoptosis of infected cells. The phenomenon of apoptosis is associated with Mycobacterium tuberculosis survival. In this study, using frozen lung sections (n = 33), our results showed increased CD40, IL-12 and TGF-beta1 expression in macrophages with progression of disease. High percentages of mycobacterial antigens (M.Ags), CD40L and IFN-gamma expression were maintained throughout infection, and TNF-alpha-expressing cells were decreased. In lymphocytes, the percentage of IFN-gamma-positive cells was increased, but CD40L and IL-12 were maintained with the progression of disease. M.Ags, CD40 and CD40L were expressed in the same areas of the lesions. We conclude that changes in the expression of CD40-CD40L and cytokines associated with M. tuberculosis infection favour the hypothesis that M. tuberculosis causes resistance of host cells to apoptosis causing perpetuation of infection.

    Topics: Animals; Antigens, Bacterial; CD40 Antigens; CD40 Ligand; Crosses, Genetic; Cytokines; Immunohistochemistry; Interferon-gamma; Interleukin-12; Lung; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mycobacterium tuberculosis; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tuberculosis; Tumor Necrosis Factor-alpha

2003
Analysis of transforming growth factor-beta 1 (TGF-beta1) expression in human monocytes infected with Mycobacterium avium at a single cell level by ELISPOT assay.
    Journal of immunological methods, 2002, Jan-01, Volume: 259, Issue:1-2

    Transforming growth factor beta 1 (TGF-beta1) has been implicated in the pathogenesis of a number of diseases including infection with intracellular pathogens such as Mycobacterium avium complex (MAC). In this study, we developed an ELISPOT assay for measurement of active TGF-beta1 produced by peripheral blood mononuclear cells (PBMC) from healthy individuals in response to LPS or MAC. The frequency of TGF-beta1 producing cells was significantly (p<0.04) higher in response to LPS (10 microg/ml) as compared to unstimulated cells (n=4). Moreover, the frequency of TGF-beta1 producing cells was threefold higher in monocyte (MN)-enriched cell population than those in PBMC indicating that the source of TGF-beta1 producing cells in PBMC was MN. In addition, the frequency of TGF-beta1 producing cells in response to MAC (10:1, cfu:MN) was significantly higher (p<0.03) than unstimulated cells. However, the frequency of TGF-beta1 producing cells in response to MAC (10:1) was eight to ninefold lower than that by LPS (10 microg/ml). Moreover, there was a correlation between the level of total TGF-beta1 in 24-h culture supernatants and the number of TGF-beta1 producing cells upon MAC stimulation. TGF-beta1 ELISPOT-assay may be a sensitive and a powerful tool for detection of TGF-beta1 producing cells, and may be helpful in elucidation of the nature of TGF-beta1 production at sites of diseases.

    Topics: Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Humans; Immunoassay; Monocytes; Mycobacterium avium; Sensitivity and Specificity; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tuberculosis

2002
Mycobacterium avium infection of macrophages results in progressive suppression of interleukin-12 production in vitro and in vivo.
    Journal of leukocyte biology, 2002, Volume: 71, Issue:1

    Interleukin-12 (IL-12) has been shown to have an important role in the host defense against Mycobacterium avium. We sought to determine if human monocyte-derived macrophages produce IL-12 upon M. avium infection. Although IL-12 can be measured in supernatants of M. avium-infected macrophages at 24, 48, and 72 h following infection, intracellular staining showed that 24 to 48 h after infection, IL-12 was synthesized chiefly by uninfected macrophages in the monolayer, suggesting that M. avium infection inhibits IL-12 production. In addition, the data also suggest that the longer macrophage monolayers were infected, the less IL-12 they were able to produce. Stimulation of macrophages with IFN-gamma prior to infection with M. avium resulted in greater production of IL-12 compared with unstimulated macrophages. Culture supernatant of M. avium-infected macrophage monolayers, but not control macrophages, partially inhibited IL-12 production by IFN-gamma-stimulated macrophages. This partial inhibition was not reversed by anti-interleukin-10 (anti-IL-10) and anti-transforming growth factor beta 1 (anti-TGF beta 1)-neutralizing antibodies. M. avium infection of macrophages in vitro also suppressed IL-12 synthesis induced by Listeria monocytogenes infection. Immunohistochemistry staining of spleen of infected mice showed that IL-12 production by splenic macrophages was more pronounced in the beginning of the infection but decreased later. Our data indicate that M. avium infection of macrophages suppresses IL-12 production by infected cells and that the suppression was not a result of the presence of IL-10 and TGF beta 1 in the culture supernatant.

    Topics: Animals; Cells, Cultured; Humans; Interleukin-10; Interleukin-12; Macrophages; Mice; Mycobacterium avium; Transforming Growth Factor beta; Tuberculosis

2002
Enhanced antimycobacterial response to recombinant Mycobacterium bovis BCG expressing latency-associated peptide.
    Infection and immunity, 2001, Volume: 69, Issue:11

    With a view to exploring the role of transforming growth factor beta (TGF-beta) during mycobacterial infection, recombinant clones of bacillus Calmette-Guérin (BCG) were engineered to express the natural antagonist of TGF-beta, latency-activated peptide (LAP). Induction of TGF-beta activity was reduced when macrophages were infected with BCG expressing the LAP construct (LAP-BCG). There was a significant reduction in the growth of LAP-BCG in comparison to that of control BCG following intravenous infection in a mouse model. The enhanced control of mycobacterial replication was associated with an increase in the production of gamma interferon by splenocytes challenged during the acute stage of infection but with a diminished recall response assessed after 13 weeks. Organ weight and hydroxyproline content, representing tissue pathology, were also lower in mice infected with LAP-BCG. The results are consistent with the hypothesis that TGF-beta has a detrimental effect on mycobacterial immunity. While a reduction in TGF-beta activity augments the initial response to BCG vaccination, early bacterial clearance may adversely affect the induction of a long-term memory response by LAP-BCG.

    Topics: Animals; Cell Line; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Mycobacterium bovis; Peptide Fragments; Protein Precursors; Recombination, Genetic; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tuberculosis

2001
Latency-associated peptide of transforming growth factor beta enhances mycobacteriocidal immunity in the lung during Mycobacterium bovis BCG infection in C57BL/6 mice.
    Infection and immunity, 2000, Volume: 68, Issue:11

    Latency-associated peptide of transforming growth factor beta (TGF-beta) (LAP) was used to determine whether in vivo modulation of TGF-beta bioactivity enhanced pulmonary immunity to Mycobacterium bovis BCG infection in C57BL/6 mice. LAP decreased BCG growth in the lung and enhanced antigen-specific T-cell proliferation and gamma interferon mRNA expression. Thus, susceptibility of the lung to primary BCG infection may be partially mediated by the immunosuppressive effects of TGF-beta.

    Topics: Animals; Female; Interferon-gamma; Lung; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mycobacterium bovis; RNA, Messenger; T-Lymphocytes; Transforming Growth Factor beta; Tuberculosis

2000
Expression of the IL-12 receptor beta 1 and beta 2 subunits in human tuberculosis.
    Journal of immunology (Baltimore, Md. : 1950), 1999, Feb-15, Volume: 162, Issue:4

    To determine whether the Th1 response in tuberculosis correlated with IL-12R expression, we measured expression of the IL-12R beta 1 and IL-12R beta 2 subunits, as well as IL-12R beta 2 mRNA expression in tuberculosis patients and healthy tuberculin reactors. In tuberculosis patients, IFN-gamma production by Mycobacterium tuberculosis-stimulated PBMC was reduced, the percentages of T cells expressing IL-12R beta 1 and IL-12R beta 2 were significantly decreased, and IL-12R beta 2 mRNA expression was also markedly reduced. In contrast, in pleural fluid and lymph nodes at the site of disease in tuberculosis patients, in which IFN-gamma production is enhanced, IL-12R beta 2 mRNA expression was also increased. In M. tuberculosis-stimulated peripheral blood T cells from tuberculosis patients, anti-IL-10 and anti-TGF-beta enhanced IL-12R beta 1 and IL-12R beta 2 expression, and IFN-gamma production. In M. tuberculosis-stimulated peripheral blood T cells from healthy tuberculin reactors, recombinant IL-10 and TGF-beta reduced IL-12R beta 1 and IL-12R beta 2 expression, as well as IFN-gamma production. In combination with prior studies showing increased production of TGF-beta by blood monocytes from tuberculosis patients, this suggests that increased TGF-beta production is the underlying abnormality that reduces IL-12R beta 1 and IL-12R beta 2 expression in tuberculosis. Our findings provide evidence that IL-12R expression correlates well with IFN-gamma production in human tuberculosis, and that expression of IL-12R beta 1 and IL-12R beta 2 may play a central role in mediating a protective Th1 response.

    Topics: Cells, Cultured; Humans; Interleukin-10; Interleukin-12; Lymphocyte Activation; Mycobacterium tuberculosis; Receptors, Interleukin; Receptors, Interleukin-12; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; T-Lymphocyte Subsets; Transforming Growth Factor beta; Tuberculosis

1999
In vitro synthesis of interferon-gamma, interleukin-4, transforming growth factor-beta and interleukin-1 beta by peripheral blood mononuclear cells from tuberculosis patients: relationship with the severity of pulmonary involvement.
    Scandinavian journal of immunology, 1999, Volume: 49, Issue:2

    Given the role of cell-mediated immune responses in resistance to mycobacteria, we sought to analyse whether there was a relationship between the severity of pulmonary tuberculosis (TB) and lymphocyte proliferation as well as in vitro cytokine production. To achieve this, 25 untreated TB patients showing mild (n = 5), moderate (n = 9) or advanced (n = 11) pulmonary disease, and 12 age-matched healthy controls (mean+/-SD, 37+/-14.5 years) were studied. Peripheral blood mononuclear cells were cultured for 5 days with 10 microg/ml whole, sonicated Mycobacterium tuberculosis (WSA) or 2.5 microg/ml Concanavalin A (Con A). Supernatants were collected on day 4, from cultures grown with or without WSA, for measurement of interferon-gamma (IFN-gamma), interleukin (IL)-4, IL-1beta and transforming growth factor-beta (TGF-beta). Antigen-specific proliferation was found to be reduced among patients and more profound in those with advanced disease who also displayed a depressed response to Con A. Patients with mild TB showed a preferential production of IFN-gamma over IL-4, gave the highest level of IFN-gamma synthesis upon specific antigen stimulation and showed increased levels of IL-1beta production. Findings in patients with moderate TB appeared compatible with a mixed production of IFN-gamma and IL-4 coexisting with a higher synthesis of TGF-beta, by comparison to patients with mild TB. Advanced disease showed the highest IL-4 and TGF-beta production, with IFN-gamma synthesis readily noticeable, yet decreased in comparison with the other patient groups. Differences in cytokine response according to the amount of lung involvement suggest a role for such mediators in the immunopathogenesis underlying the distinct clinical forms of pulmonary TB, that is a predominant T helper Th)1-like or Th2-like activity in mild or in progressive TB, respectively.

    Topics: Adolescent; Adult; Aged; Antigens, Bacterial; Cells, Cultured; Concanavalin A; Female; Humans; Interferon-gamma; Interleukin-1; Interleukin-4; Leukocytes, Mononuclear; Lung Diseases; Lymphocyte Activation; Male; Middle Aged; Mycobacterium tuberculosis; Severity of Illness Index; Statistics, Nonparametric; T-Lymphocytes; Transforming Growth Factor beta; Tuberculosis

1999
The modulating effects of proinflammatory cytokines interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), and immunoregulating cytokines IL-10 and transforming growth factor-beta (TGF-beta), on anti-microbial activity of murine perito
    Clinical and experimental immunology, 1999, Volume: 115, Issue:3

    We assessed the roles of proinflammatory cytokines IFN-gamma and TNF-alpha, and immunoregulatory cytokines IL-10 and TGF-beta in the modulation of the anti-microbial activity of murine peritoneal macrophages against Mycobacterium avium-intracellulare complex (MAIC). First, both IFN-gamma and TNF-alpha significantly reduced the bacterial growth in macrophages, indicating that these cytokines participate in up-regulation of macrophage anti-MAIC function. Second, although MAIC-infected macrophages produced substantial amounts of IL-10 and TGF-beta, neutralization of endogenous IL-10 and TGF-beta with anti-IL-10 and anti-TGF-beta antibodies, respectively, did not affect the intracellular growth of MAIC in macrophages from mice with BcgS (MAIC-susceptible) or BcgI (MAIC-resistant) genotype, regardless of the virulence of test MAIC strains. The same result was also obtained for macrophages stimulated with IFN-gamma or TNF-alpha. Third, in MAIC-infected mice, the growth of organisms at the sites of infection (lungs and spleens) was not affected by administration of anti-IL-10 or anti-TGF-beta antibodies. These findings indicate that, in the case of mice, endogenous IL-10 and TGF-beta are essentially ineffective in down-regulating macrophage anti-MAIC functions not only in vitro but also in vivo.

    Topics: Adjuvants, Immunologic; Animals; Cytokines; Female; In Vitro Techniques; Inflammation Mediators; Interferon-gamma; Interleukin-10; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred CBA; Mycobacterium avium Complex; Neutralization Tests; Recombinant Proteins; Transforming Growth Factor beta; Tuberculosis; Tumor Necrosis Factor-alpha

1999
Central nervous system tuberculosis--the paradox of the host immune response.
    The Journal of infection, 1998, Volume: 36, Issue:1

    Topics: Central Nervous System Diseases; Humans; Immunity, Cellular; Mycobacterium tuberculosis; Transforming Growth Factor beta; Tuberculosis; Tumor Necrosis Factor-alpha

1998
In vitro restoration of T cell responses in tuberculosis and augmentation of monocyte effector function against Mycobacterium tuberculosis by natural inhibitors of transforming growth factor beta.
    Proceedings of the National Academy of Sciences of the United States of America, 1997, Apr-15, Volume: 94, Issue:8

    We examined the capacity of the naturally occurring inhibitors of transforming growth factor beta (TGF-beta), decorin and latency associated peptide (LAP), to reverse depressed T cell functions in peripheral blood mononuclear cells (PBMCs) from patients with pulmonary tuberculosis (TB) in vitro and to counteract the suppressive properties of TGF-beta on mycobacterial replication in blood monocytes (MN) in vitro. T cell blastogenesis in response to purified protein derivative (PPD) in PBMCs of TB patients that were cocultured with decorin or LAP reached levels comparable to those observed in healthy tuberculin-responsive control subjects. Decorin and LAP were as effective as neutralizing antibody to TGF-beta in correcting depressed T cell proliferation. Coculture of PBMCs from healthy PPD reactive individuals with neutralizing antibody to TGF-beta, decorin, or LAP did not affect T cell blastogenesis. Levels of interferon-gamma in cultures of PPD-stimulated PBMCs from patients with TB increased by more than 2-fold in the presence of maximal concentrations of either of the inhibitors of TGF-beta, whereas TGF-beta immunoreactivity declined to background levels. Coculture with optimal concentrations of decorin or LAP also led to reductions in mycobacterial growth in MN infected with Mycobacterium tuberculosis (MTB) in vitro by 51% and 62%, respectively, when compared with cells left untreated. In parallel, levels of immunoreactive TGF-beta in MTB-infected MN cultures containing decorin or LAP decreased to background levels. These data indicate that the naturally occurring inhibitors of TGF-beta, decorin and LAP, efficiently abrogate the suppressive effects of TGF-beta in PBMCs of TB patients and in MN infected with MTB in vitro. Therefore, these agents may be considered as adjuncts to antituberculous chemotherapy, and may be particularly useful in treatment of TB that is unresponsive to conventional chemotherapy.

    Topics: Cell Division; Cells, Cultured; Decorin; Extracellular Matrix Proteins; Humans; Immunity, Cellular; Monocytes; Mycobacterium tuberculosis; Peptide Fragments; Protein Precursors; Proteins; Proteoglycans; T-Lymphocytes; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tuberculosis

1997
The role of tumor necrosis factor, interferon-gamma, transforming growth factor-beta, and nitric oxide in the expression of immunosuppressive functions of splenic macrophages induced by Mycobacterium avium complex infection.
    Journal of leukocyte biology, 1995, Volume: 58, Issue:6

    In order to verify the participation of some cytokines in the expression of the suppressor activity of splenic macrophages (M phi s) induced by Mycobacterium avium complex (MAC) infection, we studied whether anticytokine antibodies were capable of blocking their suppressor activity against concanavalin A (ConA)-induced mitogenesis of splenocytes (SPCs). When either anti-tumor necrosis factor (TNF), anti-transforming growth factor-beta (TGF-beta), or anti-interferon-gamma (IFN-gamma) antibody was added to culture medium, suppressor activity was markedly reduced, in the order of anti-TNF, anti-IFN-gamma, and anti-TGF-beta antibodies. By contrast, neither anti-interleukin-6 (IL-6) nor anti-IL-10 antibody exerted such a blocking effect. Therefore, TNF, IFN-gamma, and TGF-beta seem to be related to the full display of the suppressor function of MAC-induced M phi s. However, TNF-alpha and IFN-gamma but not TGF-beta were substantially lacking in inhibitory action against SPC mitogenesis, when added exogenously. Hence, it is unlikely that TNF-alpha and INF-gamma directly modulated the proliferative response of T cells. On the other hand, both TNF-alpha and IFN-gamma potentiated the effector function of the suppressor M phi s. Because their suppressor activity was severely reduced by NG-monomethyl-L-arginine and aminoguanidine, nitric oxide (NO) synthase inhibitors, an NO-dependent mechanism is important for the expression of the immunosuppressive function of MAC-induced M phi s. Moreover, because these M phi s seem to produce a substantial amount of TNF-alpha in membrane-bound form, cell-to-cell contact might be needed for efficient expression of their suppressor action on target T cells.

    Topics: Animals; Cell Communication; Cytokines; Female; Immune Tolerance; Interferon-gamma; Macrophages; Mice; Mice, Inbred BALB C; Mycobacterium avium; Nitric Oxide; Transforming Growth Factor beta; Tuberculosis; Tumor Necrosis Factor-alpha

1995
Production of TNF-alpha, IL-6 and TGF-beta, and expression of receptors for TNF-alpha and IL-6, during murine Mycobacterium avium infection.
    Immunology, 1995, Volume: 84, Issue:4

    The Mycobacterium avium complex comprises intracellular bacteria associated with disseminated infection in patients with acquired immune deficiency syndrome (AIDS). Immune defects that lead to infection are unknown but cytokines appear to play an important role in the immunomodulation of host defence mechanisms. We evaluated the cytokine profiles seen temporally after murine M. avium infection. Spleen cells were obtained from M. avium-infected C57BL/6 mice and uninfected mice at weeks 1, 2, 3, 4 and 5. Cells were cultured in vitro and subsequently pulsed with killed M. avium. Supernatants were collected from the cultured splenic cells and the concentrations of interleukin-6 (IL-6), transforming growth factor-beta 1 (TGF-beta 1) and tumour necrosis factor-alpha (TNF-alpha) were measured. TGF-beta 1 was detected at week 1, followed by IL-6 production at week 2. Elevated TNF-alpha levels were observed at week 3. The addition of polyclonal anti-TGF-beta 1 antibody to M. avium-infected peritoneal macrophages in the presence of splenic cell supernatants from weeks 1, 3 and 5 led to decreased bacterial counts compared to controls. Anti-IL-6 antibody did not have any effect on macrophage anti-mycobacterial activity. Concurrently, we observed decreased expression of TNF-alpha receptors on infected macrophages. We propose that the early elevated levels of TGF-beta 1, a known suppressor of macrophage function, in conjunction with down-regulation of TNF-alpha receptors may help explain the suboptimal macrophage response to TNF-alpha, leading to impaired anti-mycobacterial activity.

    Topics: Animals; Cytokines; Female; Interleukin-6; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mycobacterium avium; Receptors, Interleukin; Receptors, Interleukin-6; Receptors, Tumor Necrosis Factor; Spleen; Transforming Growth Factor beta; Tuberculosis; Tumor Necrosis Factor-alpha

1995
Transforming growth factor beta (TGF-b1) plays a detrimental role in the progression of experimental Mycobacterium avium infection; in vivo and in vitro evidence.
    Microbial pathogenesis, 1991, Volume: 11, Issue:5

    BALB/c mice were infected with 10(5) colony forming units (cfu) of Mycobacterium avium TMC 702 i.v. and the growth of the inoculum followed in the spleens of control mice. Other infected mice given weekly doses of 1 microgram of TGF-b1 or weekly doses of 2 mg of a rabbit antiserum against mouse TGF-b1 were evaluated for their resistance to M. avium TMC 702. Growth of M. avium in the spleens of mice given repeated doses of TGF-b1 (1 microgram weekly) was significantly higher than in the spleens of control mice starting at day 40 of infection. Similarly, growth of M. avium was significantly diminished (0.7 log difference at 80 days) in mice given infusions of anti-TGF-b1 (2 mg weekly). Macrophage activation status was similar in the three groups of mice, as seen by a comparable release of superoxide anion (O2-) and hydrogen peroxide (H2O2) by peritoneal macrophages of infected mice. However, TGF-b1-pulsed peritoneal macrophages were found to be more permissive for M. avium growth in vitro than control macrophage monolayers. Overall, these results suggest that TGF-b1 plays a detrimental role in the progression of experimental M. avium infections, by an unclear mechanism.

    Topics: Animals; Macrophage Activation; Mice; Mycobacterium avium; Spleen; Transforming Growth Factor beta; Tuberculosis

1991
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