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 re sponses are depressed transiently, whereas antibody levels are increas ed, Lymphoproliferative responses of peripheral blood mononuclear cell s (PBMCs) from Pakistani tuberculosis (TB) patients to both mycobacter ial and candidal antigens were suppressed by approximate to 50% when c ompared to healthy purified protein derivative (PPD)-positive househol d contacts, Production of interferon gamma (IFN-gamma) in response to PPD also was depressed by 78%. Stimulation with PPD and the 30-kD alph a antigen of MTB (30-kDa antigen) induced greater secretion of transfo rming growth factor beta (TGF-beta), but not interleukin 10 (IL-10) or tumor necrosis factor alpha (TNF-alpha), by PBMCs from TB patients co mpared to healthy contacts, The degree of suppression correlated with the duration of treatment; patients treated for <1 month had significa ntly lower T-cell blastogenesis and IFN-gamma production and higher le vels of TGF-beta than did patients treated for >1 month, Neutralizing antibody to TGF-beta normalized lymphocyte proliferation in response t o PPD, partially restored blastogenesis to candidal antigen, and signi ficantly increased PPD-stimulated production of IFN-gamma in TB patien ts but not in contacts, Neutralizing antibody to IL-10 augmented, but did not normalize, T-cell responses to both PPD and candida in TB pati ents and candidal antigen in contacts, TGF-beta, produced in response to MTB antigens, therefore plays a prominent role in dean-regulating p otentially protective host effector mechanisms and looms as an importa nt mediator of immunosuppression in TB.