Cross-modulation by transforming growth factor beta in human tuberculosis: suppression of antigen-driven blastogenesis and interferon gamma production.
In tuberculosis, Mycobacterium tuberculosis (MTB)-stimulated T-cell responses are depressed transiently, whereas antibody levels are increased. Lymphoproliferative responses of peripheral blood mononuclear cells (PBMCs) from Pakistani tuberculosis (TB) patients to both mycobacterial and candidal antigens were suppressed by approximately 50% when compared to healthy purified protein derivative (PPD)-positive household contacts. Production of interferon gamma (IFN-gamma) in response to PPD also was depressed by 78%. Stimulation with PPD and the 30-kDa alpha antigen of MTB (30-kDa antigen) induced greater secretion of transforming growth factor beta (TGF-beta), but not interleukin 10 (IL-10) or tumor necrosis factor alpha (TNF-alpha), by PBMCs from TB patients compared to healthy contacts. The degree of suppression correlated with the duration of treatment; patients treated for <1 month had significantly lower T-cell blastogenesis and IFN-gamma production and higher levels of TGF-beta than did patients treated for >1 month. Neutralizing antibody to TGF-beta normalized lymphocyte proliferation in response to PPD, partially restored blastogenesis to candidal antigen, and significantly increased PPD-stimulated production of IFN-gamma in TB patients but not in contacts. Neutralizing antibody to IL-10 augmented, but did not normalize, T-cell responses to both PPD and candida in TB patients and candidal antigen in contacts. TGF-beta, produced in response to MTB antigens, therefore plays a prominent role in down-regulating potentially protective host effector mechanisms and looms as an important mediator of immunosuppression in TB.
Hirsch
C S
CS
Department of Medicine, Case Western Reserve University Hospitals, Cleveland, OH 44106-4984, USA.
Hussain
R
R
Toossi
Z
Z
Dawood
G
G
Shahid
F
F
Ellner
J J
JJ
D000942:Antigens, Bacterial; D000946:Antigens, Fungal; D001483:Base Sequence; D002175:Candida / Q000276:immunology; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D014373:Tuberculin / Q000276:immunology; D014374:Tuberculin Test; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
D000942:Antigens, Bacterial; D000946:Antigens, Fungal; D017931:DNA Primers; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014373:Tuberculin; D007371:Interferon-gamma