Induction of urinary interleukin-1 (IL-1), IL-2, IL-6, and tumour necrosis factor during intravesical immunotherapy with bacillus Calmette-Guérin in superficial bladder cancer

Abstract

To study the local immunological effects of intravesical bacillus Calmette-Guérin (BCG) therapy in superficial bladder cancer patients, the production of interleukin-1 (IL-1), IL-2, IL-6, tumour necrosis factor alpha (TNF alpha), and interferon gamma (IFN gamma) was investigated in the urine. Urine specimens were collected during the six weekly BCG instillations, before instillation, and 2, 4, 6, 8, and 24 h thereafter. Results were standardized to urine creatinine. In general, the concentration of IL-1 increased markedly during the first three BCG instillations, reaching a plateau from instillations 3 to 6. IL-2 was not detected after the first BCG instillation, but from the second instillation onwards the mean IL-2 concentration increased rapidly. With respect to IL-6, patients had relatively high levels in the urine after the first BCG instillation. A relatively moderate increase of the IL-6 concentration was observed during the following weeks. Like IL-2, TNF alpha was only detected after repeated BCG instillations. Generally the highest TNF levels were found after BCG instillation 5. The presence of IFN gamma could not be demonstrated. With respect to the occurrence of the cytokines during the first 24 h after the BCG instillation, TNF, IL-2, and IL-6 were detectable 2 h after the instillation. In contrast, IL-1 seemed to appear later, i.e. from 4 h onwards. TNF decreased most rapidly; it was nearly absent in 6-h samples. Generally IL-2 was not detectable in the 8-h samples, whereas IL-1 and IL-6 were present up to 8 h after instillation of BCG. The presence of TNF was found less frequently than the presence of IL-1, IL-2, and IL-6. Neutralization experiments indicated that most of the IL-1 present in the urine after BCG treatment was IL-1 alpha. In conclusion, activation of BCG-specific T cells was indicated by the detection of IL-2. The presence of IL-1, IL-6, and TNF alpha might suggest activation of macrophages by intravesically administered BCG, although production by other cell types cannot be excluded. It is suggested that these cytokines, in combination with the leucocytes that are known to be recruited to the bladder in reaction to the BCG treatment, may play an important role in the antitumour activity of BCG against bladder cancer. For monitoring purposes, collection of urine might be performed during the first 6 h after BCG instillations 4-6.(ABSTRACT TRUNCATED AT 400 WORDS)

Humoral response against heat shock proteins and other mycobacterial antigens after intravesical treatment with bacille Calmette–Guérin (BCG) in patients with superficial bladder cancer

“…Although cellular immune responses after BCG intravesical therapy have been recently studied [4,6,8], variations in antibody levels directed against mycobacterial antigens have been poorly investigated until now. The present study shows that repeated intravesical BCG instillations induce increases in IgG antibody levels against tuberculin and several mycobacterial hsp, but not against the AG85 complex of M. bovis BCG.…”

BCG Immunotherapy for Bladder Carcinoma

“…11 This has been demonstrated by analysis of urine following administration of BCG. IL-1, IL-6, and IL-8 are increased after the first BCG instillation 12,13 .…”

Immunostimulation in the urinary bladder by local application ofNocardia rubra cell wall skeleton preparation (Rubratin) for superficial bladder cancer immunotherapy — a phase I/II study

“…According to pre-defined stopping rules the compound should be given only adjuvantly after complete resection of all tumors, if no reaction is observed in the first four patients with a marker lesion, with the purpose of monitoring only toxicity and the possible immunostimulatory effects of this BRM as expressed by altered cytokine levels and/or leukocyte appearance in the dose applied to elucidate potential dose-related effects. Following Rubratin instillations, local immunostimulation was determined by the measurement of urinary cytokine induction [interleukin (IL)1 [3, IL2, IL6, and tumor necrosis factor alpha (TNF~)], leukocyte influx into the urine and phenotypic analysis of the lymphocyte fraction of these lymphocytes, as performed previously for BCG therapy [2,3,19].…”

“…Labeled cells were fixed in 300 gl paraformaldehyde solution (0.5% in PBS). Fluorescence-activated cell sorter (FACS) analysis (FACScan, Becton Dickinson Immunocytometry Systems, Mountain View, CA, USA) was performed the following day as described previously [3].…”

“…Based on observations that BCGinduced immunological events appear to be predictive of early clinical response in superficial bladder cancer, investigations directed to immunological events could also be a logical initial approach for the evaluation of new BRMs [18]. Several effects associated with BCG immunotherapy can be monitored, e.g., the conversion of the PPD skin test, granuloma formation in the bladder wall, production of cytokines and the presence of subtypes of leukocytes in the urine as a reflection of immunological events in the bladder wall [3,17].…”