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.
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.
Hirsch
C S
CS
Department of Medicine, Case Western Reserve University, University Hospitals of Cleveland, OH 44106, USA. cxh40@po.cwru.edu
Ellner
J J
JJ
Blinkhorn
R
R
Toossi
Z
Z
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D058575:Decorin; D016326:Extracellular Matrix Proteins; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins / Q000494:pharmacology; D011509:Proteoglycans / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology*; D053773:Transforming Growth Factor beta1; D014376:Tuberculosis / Q000276:immunology*
C546878:DCN protein, human; D058575:Decorin; D016326:Extracellular Matrix Proteins; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins; D011509:Proteoglycans; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1