Dose-dependent synergy of Th1-stimulating cytokines on bacille Calmette-Guérin-induced interferon-gamma production by human mononuclear cells.
Successful bacille Calmette-Guérin (BCG) immunotherapy of bladder cancer depends on the proper induction of a T helper-type 1 (Th1) immune response. In this study we investigated the possible involvement of Th1-stimulating cytokines in BCG-induced interferon (IFN)-gamma production as well as their potential roles in enhancing BCG-induced IFN-gamma from human peripheral blood mononuclear cells (PBMCs). BCG efficiently induced IFN-gamma production by PBMCs in a dose-dependent manner. Neutralization of endogenous cytokines interleukin (IL)-2, IL-12 and IFN-alpha reduced BCG-induced IFN-gamma by 38%, 67% and 49%, respectively. Although single recombinant (r) IL-2, rIL-12 and rIFN-alpha induced no or a marginal amount of IFN-gamma, a combination of any two or three cytokines increased IFN-gamma production. When BCG (a subsaturated dose) was combined with mono, dual or triple cytokines, a synergy on IFN-gamma production was observed. Such a synergy was readily achievable even when minimal or low doses of cytokines were used. No saturation of IFN-gamma production was observed even when a subsaturated BCG dose was combined with very high doses of cytokines. A robust IFN-gamma production was also observed when a minimal BCG dose was combined with minimal doses of triple cytokines. In addition, we demonstrated that IL-2- and IFN-alpha-expressing rBCGs were superior to wild-type BCG for PBMC IFN-gamma induction and that combination of both rBCGs showed a synergy in IFN-gamma production. Taken together, these results suggest that combination of BCG with certain exogenous or endogenous (expressed by rBCGs) Th1-stimulating cytokines is a rational candidate for further study in bladder cancer treatment.
Chen
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Department of Urology, University of Iowa, Iowa City, IA, USA.
O'DONNELL
M A
MA
Luo
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Y
D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D009163:Mycobacterium bovis / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*
D016207:Cytokines; D016898:Interferon-alpha; D011994:Recombinant Proteins; D007371:Interferon-gamma