Cross-modulation by transforming growth factor beta in human tuberculosis: suppression of antigen-driven blastogenesis and interferon gamma production.

Hirsch, Christina S.; Hussain, Rabia; Toossi, Zahra; Dawood, Ghaffar; Shahid, Firdaus; Ellner, Jerrold J.

doi:10.1073/pnas.93.8.3193

Cited by 188 publications

(152 citation statements)

References 46 publications

(17 reference statements)

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“…MTB and its major protein and polysaccharide constituents are potent inducers of production of cytokines in mononuclear phagocytes, some of which, such as TGF-␤, are immunosuppressive and macrophage deactivating (8)(9)(10)(11)(26)(27)(28). The recruitment of MN to sites of active MTB infection and activation of MN to production of cytokines, in particular TGF-␤, may be important in the immunopathogenesis of TB.…”

Section: Discussionmentioning

confidence: 99%

“…Excess TGF-␤ underlies the depressed in vitro T cell responses to MTB antigens in patients with TB, as coculture of peripheral blood mononuclear cells (PBMCs) from TB patients with neutralizing antibody to TGF-␤ normalizes T cell blastogenesis and enhances production of interferon ␥ (IFN-␥) (10). IFN-␥ appears to play a central role in limiting MTB infection, as recently shown in the murine models of TB (15,16).…”

mentioning

confidence: 99%

“…Also, the major secretory protein of growing mycobacteria, 30-kDa ␣ antigen (10), and the major mycobacterial cell wall lipoglycan, lipoarabinomannan (LAM) (11) induce MN production of TGF-␤. TGF-␤ is expressed in Langhans' giant cells and epithelioid cells in tuberculous pulmonary granulomas and in MN of patients with TB (12).…”

mentioning

confidence: 99%

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In vitrorestoration of T cell responses in tuberculosis and augmentation of monocyte effector function againstMycobacterium tuberculosisby natural inhibitors of transforming growth factor β

Hirsch

Ellner

Blinkhorn

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

126

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We examined the capacity of the naturally occurring inhibitors of transforming growth factor ␤ (TGF-␤), 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-␤ 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-␤ in correcting depressed T cell proliferation. Coculture of PBMCs from healthy PPD reactive individuals with neutralizing antibody to TGF-␤, decorin, or LAP did not affect T cell blastogenesis. Levels of interferon-␥ in cultures of PPDstimulated PBMCs from patients with TB increased by more than 2-fold in the presence of maximal concentrations of either of the inhibitors of TGF-␤, whereas TGF-␤ 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-␤ in MTB-infected MN cultures containing decorin or LAP decreased to background levels. These data indicate that the naturally occurring inhibitors of TGF-␤, decorin and LAP, efficiently abrogate the suppressive effects of TGF-␤ 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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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In vitrorestoration of T cell responses in tuberculosis and augmentation of monocyte effector function againstMycobacterium tuberculosisby natural inhibitors of transforming growth factor β

Hirsch

Ellner

Blinkhorn

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

126

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“…Neither cell proliferation nor antibody production completely reflect the expression or absence of protective immunity against tuberculosis, which may be mediated by the production of IFN-g [12,13]. Therefore, five BCG-SH and five patients with pleural or pulmonary disease were examined for the ability of the recombinant antigen to elicit IFN-g.…”

Section: Interferon-g and Il-10 Production In Response To The 16 Kda mentioning

confidence: 99%

Human T‐ and B‐Cell Reactivity to the 16 kDa α‐Crystallin Protein of Mycobacterium tuberculosis

Wilkinson

Smet

et al. 1998

Scand J Immunol

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The attributes of immunodominance, predominant expression during mycobacterial dormancy and restriction to the Mycobacterium tuberculosis complex make the 16 kDa protein an important candidate for the study of the immune response in humans. We therefore investigated the relationship between T‐ and B‐cell reactivity to the recombinant antigen and disease in a total of 127 subjects. The percentage of T‐cell responders towards both the intact antigen and its permissively recognised peptide 16p91‐110 was highest in healthy bacillus Calmette–Guérin (BCG)‐sensitized controls (96% and 68%, respectively) and lowest in those with extensive untreated tuberculosis (26% and 18%) (P < 0.001). By contrast, antibody levels (ABT50 > 100) were highest in patients with extensive disease (46–50%) (P < 0.005). There was significantly higher production of IFN‐γ in the BCG‐sensitized controls by comparison with untreated patients (P < 0.05), but complete antituberculous chemotherapy abolished this deficit in patients. The significance of these findings to immunodiagnosis and protective immunity is discussed.

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“…We and others have shown that M. tuberculosis-induced IFN-␥ production and mRNA expression are reduced in tuberculosis patients, compared with healthy tuberculin reactors (2,3,19,20). Transcription of the IFN-␥ gene depends on binding of specific nuclear proteins to the IFN-␥ promoter (10 -14).…”

Section: Complexes Binding To the Proximal Ifn-␥ Promoter Region In Tmentioning

confidence: 99%

Reduced Expression of Nuclear Cyclic Adenosine 5′-Monophospate Response Element-Binding Proteins and IFN-γ Promoter Function in Disease Due to an Intracellular Pathogen

Samten

Ghosh

et al. 2002

The Journal of Immunology

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Mycobacterium tuberculosis-induced IFN-γ protein and mRNA expression have been shown to be reduced in tuberculosis patients, compared with healthy tuberculin reactors. To determine whether this decrease was associated with reduced activity of the IFN-γ promoter, we first studied binding of nuclear proteins to the radiolabeled proximal IFN-γ promoter (−71 to −40 bp), using EMSAs with nuclear extracts of freshly isolated peripheral blood T cells. Nuclear extracts of T cells from most tuberculosis patients showed markedly reduced expression of proteins that bind to the proximal IFN-γ promoter, compared with findings in nuclear extracts of T cells from healthy tuberculin reactors. These DNA-binding complexes contained CREB proteins, based on competitive EMSAs, supershift assays, and Western blotting with an anti-CREB Ab. Transient transfection of PBLs with a luciferase reporter construct under the control of the IFN-γ promoter revealed reduced IFN-γ promoter activity in tuberculosis patients. Transient transfection of Jurkat cells with a dominant-negative CREB repressor plasmid reduced IFN-γ promoter activity. These data suggest that reduced expression of CREB nuclear proteins in tuberculosis patients results in decreased IFN-γ promoter activity and reduced IFN-γ production.

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Cross-modulation by transforming growth factor beta in human tuberculosis: suppression of antigen-driven blastogenesis and interferon gamma production.

Abstract: In tuberculosis, Mycobacterium tuberculosis (MTB)-stimulated T-cell

Cited by 188 publications

References 46 publications

In vitrorestoration of T cell responses in tuberculosis and augmentation of monocyte effector function againstMycobacterium tuberculosisby natural inhibitors of transforming growth factor β

In vitrorestoration of T cell responses in tuberculosis and augmentation of monocyte effector function againstMycobacterium tuberculosisby natural inhibitors of transforming growth factor β

Human T‐ and B‐Cell Reactivity to the 16 kDa α‐Crystallin Protein of Mycobacterium tuberculosis

Reduced Expression of Nuclear Cyclic Adenosine 5′-Monophospate Response Element-Binding Proteins and IFN-γ Promoter Function in Disease Due to an Intracellular Pathogen

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