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 β

Christina S. Hirsch, Jerrold J. Ellner, Richard Blinkhorn, Zahra Toossi

Research output: Contribution to journalArticle

Abstract

We examined the capacity of the naturally occurring inhibitors of transforming growth factor β (TGF-β), 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-β 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-β in correcting depressed T cell proliferation. Coculture of PBMCs from healthy PPD reactive individuals with neutralizing antibody to TGF-β, decorin, or LAP did not affect T cell blastogenesis. Levels of interferon-γ 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-β, whereas TGF-β 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-β in MTB-infected MN cultures containing decorin or LAP decreased to background levels. These data indicate that the naturally occurring inhibitors of TGF-β, decorin and LAP, efficiently abrogate the suppressive effects of TGF-β 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.

Original languageEnglish (US)
Pages (from-to)3926-3931
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number8
DOIs
StatePublished - Apr 15 1997
Externally publishedYes

Fingerprint

Transforming Growth Factors
Decorin
Mycobacterium tuberculosis
Monocytes
Tuberculosis
T-Lymphocytes
Peptides
Blood Cells
Lymphocyte Activation
Coculture Techniques
Neutralizing Antibodies
In Vitro Techniques
Drug Therapy
Proteins
Tuberculin
Pulmonary Tuberculosis
Interferons
Cell Proliferation
Growth

Keywords

  • blastogenesis
  • decorin
  • latency associated peptide of transforming growth factor β
  • macrophage effector function

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

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title = "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 β",
abstract = "We examined the capacity of the naturally occurring inhibitors of transforming growth factor β (TGF-β), 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-β 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-β in correcting depressed T cell proliferation. Coculture of PBMCs from healthy PPD reactive individuals with neutralizing antibody to TGF-β, decorin, or LAP did not affect T cell blastogenesis. Levels of interferon-γ 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-β, whereas TGF-β 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-β in MTB-infected MN cultures containing decorin or LAP decreased to background levels. These data indicate that the naturally occurring inhibitors of TGF-β, decorin and LAP, efficiently abrogate the suppressive effects of TGF-β 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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T1 - 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 β

AU - Hirsch, Christina S.

AU - Ellner, Jerrold J.

AU - Blinkhorn, Richard

AU - Toossi, Zahra

PY - 1997/4/15

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N2 - We examined the capacity of the naturally occurring inhibitors of transforming growth factor β (TGF-β), 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-β 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-β in correcting depressed T cell proliferation. Coculture of PBMCs from healthy PPD reactive individuals with neutralizing antibody to TGF-β, decorin, or LAP did not affect T cell blastogenesis. Levels of interferon-γ 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-β, whereas TGF-β 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-β in MTB-infected MN cultures containing decorin or LAP decreased to background levels. These data indicate that the naturally occurring inhibitors of TGF-β, decorin and LAP, efficiently abrogate the suppressive effects of TGF-β 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.

AB - We examined the capacity of the naturally occurring inhibitors of transforming growth factor β (TGF-β), 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-β 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-β in correcting depressed T cell proliferation. Coculture of PBMCs from healthy PPD reactive individuals with neutralizing antibody to TGF-β, decorin, or LAP did not affect T cell blastogenesis. Levels of interferon-γ 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-β, whereas TGF-β 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-β in MTB-infected MN cultures containing decorin or LAP decreased to background levels. These data indicate that the naturally occurring inhibitors of TGF-β, decorin and LAP, efficiently abrogate the suppressive effects of TGF-β 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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KW - decorin

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KW - macrophage effector function

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U2 - 10.1073/pnas.94.8.3926

DO - 10.1073/pnas.94.8.3926

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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