Role of Th1 and Th2 cytokines in BCG-induced IFN-γ production: Cytokine promotion and simulation of BCG effect

Department of Urology, University of Iowa Hospitals and Clinics, 200 Hawkins Avenue, Iowa City, IA 52242, USA.
Cytokine (Impact Factor: 2.66). 02/2003; 21(1):17-26. DOI: 10.1016/S1043-4666(02)00490-8
Source: PubMed


Induction of a T-helper-type 1 (Th1) immune response is indispensable for successful treatment of superficial bladder cancer with BCG. In this study possible involvement of various cytokines in BCG action as well as their potential roles in enhancing and mimicking BCG effect were explored. In immunocompetent cell cultures, IFN-gamma, a major Th1 cytokine, appears to be a late responsive cytokine to BCG stimulation. Its induction requires involvement of various endogenously produced Th1 and Th2 cytokines. Functional abolishment of any one of these cytokines (IL-2, IL-6, IL-12, IL-18, GMCSF, TNF-alpha, or IFN-alpha, except IL-10) by neutralizing antibodies leads to reduced IFN-gamma production (19-82% inhibition in mouse and 44-77% inhibition in human systems, respectively). In mice cytokines IL-2, IL-12, IL-18, and GMCSF are observed to synergize with BCG for IFN-gamma production, whereas in human cytokines IL-2, IL-12, TNF-alpha, and IFN-alpha exhibit similar synergistic effects. Rational combinations of these Th1-stimulating cytokines (IL-12 plus IL-18 in mice and IL-2 plus IL-12 in humans, respectively) dramatically up-regulate IFN-gamma production that is incomparably superior to BCG for induction of this cytokine. These results suggest that combined Th1-stimulating cytokines and combinations of BCG plus selected Th1-stimulating cytokines are rational candidates for further study in the treatment of bladder cancer patients.

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    • "However, FlowCytomix results revealed that IL-6 and IL-8 secretions were induced in the culture media of BCG-treated HUC-PC cells. IL-6 has evidenced for the ability in inducing interferon-gamma (IFN-γ), which is believed as a late responsive T-helper type 1 cytokine to stimulate the TRAIL expression, thus responsible for successful BCG prophylaxis [21, 22]. Thus, current findings speculate the delay of BCG cytotoxicity was due to the process of BCG internalization and subsequent immune response, which requiring further elucidation. "
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    ABSTRACT: Bacillus Calmette-Guérin (BCG) is conventionally used as an adjuvant immunotherapy to reduce the recurrence of bladder cancer. To address the issues of efficacy and safety, an ethanol extract of Ganoderma lucidum (GLe) was evaluated for its interaction with BCG. In a model of premalignant human uroepithelial cells (HUC-PC), GLe exerted immediate cytotoxic effects while BCG showed a delayed response, given that both were immunological active in inducing the secretion of interleukin (IL)-6, IL-8, and monocyte chemotactic protein-1 (MCP-1). Synergistic cytotoxic effects were observed when cells were either coincubated with both drugs or firstly preincubated with GLe. Synergism between GLe and BCG was demonstrated to achieve a complete cytostasis in 24 hours, and such effects were progressed in the subsequent 5 days. However, the pretreatment of GLe resulted in suppression of IL-6, IL-8, and MCP-1 secretions without affecting the cytotoxicity. Given that numerous proinflammatory cytokines are associated with the high side effects toll of BCG, results herein suggested the potential implications of GL to supplement the BCG immunotherapy in bladder cancer, for better efficacy and reducing side effects.
    Evidence-based Complementary and Alternative Medicine 08/2012; 2012(1):147896. DOI:10.1155/2012/147896 · 1.88 Impact Factor
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    • "Conceptually, combining BCG and IFN makes sense. BCG efficacy depends on the induction of a robust Th1 cytokine profile, and IFN-α2b has been shown to potentiate the Th1 immune response [12]. However, despite theoretical promise, data after translation to clinical practice has been mixed. "
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    ABSTRACT: Mycobacterium bovis bacillus Calmette-Guérin (BCG) has become the predominant conservative treatment for nonmuscle invasive bladder cancer. Its mechanism of action continues to be defined but has been shown to involve a T helper type 1 (Th1) immunomodulatory response. While BCG treatment is the current standard of care, a significant proportion of patients fails or do not tolerate treatment. Therefore, many efforts have been made to identify other intravesical and immunomodulating therapeutics to use alone or in conjunction with BCG. This paper reviews the progress of basic science and clinical experience with several immunotherapeutic agents including IFN-α, IL-2, IL-12, and IL-10.
    Advances in Urology 06/2012; 2012(3):181987. DOI:10.1155/2012/181987
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    • "We and others have suggested that adjusting this ‘immune rheostat' to a Th1-dominant setting can restore potent cell-mediated immunity, and result in objective tumour responses (Heriot et al, 2000; Dalgleish and O'Byrne, 2002). These approaches could include BCG, which is known to alter the profile of cytokine output of PBMCs (Alexandroff et al, 1999; Luo et al, 2003). For that reason, in the first part of our study, we cultured freshly harvested PBMCs from pathologically normal individuals, and assayed their responses to BCG vaccine used at a clinically achievable concentration (1 × 105 CFU ml−1). "
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    ABSTRACT: Reduced expression of class 1 human leucocyte antigens (HLA1) is often a mechanism by which tumours evade surveillance by the host immune system. This is often associated with an immune function that is unable to mount appropriate responses against disease, which can result in a state that favours carcinogenesis. In the current study, we have explored the effects of Bacillus Calmette-Guerin (BCG) on the cytokine output of leucocytes, which is a key determinant in generating antitumour action, and have also assessed the effect of these cytokine cocktails on HLA1 expression in solid tumour cell lines. BCG potently activated a broad range of leucocytes, and also enhanced the production of cytokines that were Th(1)-predominant. Supernatants from BCG-treated leucocytes significantly increased the expression of HLA1 on the surface of cancer cell lines, which correlated with increased cytolytic T-cell activity. We also showed that the increased HLA1 expression was associated with activation of intracellular signalling pathways, which was triggered by the increases in the Th(1)-cytokines interferon-γ and tumour necrosis factor-α, as counteracting their effects negated the enhancement. These studies reaffirm the role of BCG as a putative immunotherapy through their cytokine-modifying effects on leucocytes and their capacity to enhance tumour visibility.
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