Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of transforming growth factor-beta (TGF-beta) secreted by glioblastoma (T98G) cells on the secretion of interferon-gamma (IFN-gamma) by lymphokine-activated killer (LAK) cells stimulated with tumor cells was investigated in cocultures of LAK and Daudi cells supplemented with T98G culture supernatant, T98G culture supernatant preincubated with anti-TGF-beta 1 and anti-TGF-beta 2 neutralizing antibodies, anti-TGF-beta 1 and anti-TGF-beta 2 antibodies, or natural human TGF-beta 1 or recombinant human TGF-beta 2. LAK cells were incubated with anti-TGF-beta 1 and anti-TGF-beta 2 antibodies, and with T98G cells of which the supernatant contained both active and latent forms of TGF-beta 1 and TGF-beta 2, with or without neutralizing antibodies. Addition of the supernatant from T98G cells to LAK/Daudi culture caused inhibition of IFN-gamma secretion by LAK cells. The inhibition was abolished by pretreatment of the supernatants with anti-TGF-beta antibodies. Addition of TGF-beta 1 and TGF-beta 2 to the LAK/Daudi culture inhibited IFN-gamma secretion by LAK cells in a dose-dependent manner. Addition of anti-TGF-beta antibodies to the LAK culture resulted in increased IFN-gamma secretion. T98G cells failed to stimulate LAK cells to secrete more IFN-gamma. Addition of anti-TGF-beta antibodies to the LAK-T98G culture resulted in increased IFN-gamma secretion by LAK cells. These results suggest that most malignant glioma cells which secrete high levels of TGF-beta can inhibit IFN-gamma secretion by LAK cells even after tumor cell stimulation.
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PMID:Transforming growth factor-beta inhibits interferon-gamma secretion by lymphokine-activated killer cells stimulated with tumor cells. 942 Apr 30

Interleukin (IL)-12 has recently been shown to be directly involved in the activation of natural killer and alphabeta T cells via an IL-2-independent pathway. We show here that another type of human cytotoxic cell, gammadelta T cells activated by solid-phase anti-CD3 antibody and expanded using IL-2, obtained, in this case, from the peripheral blood of glioblastoma patients, displays significant tumoricidal activity. In addition, its cytotoxic activity against K562 or Daudi cells or against autologous glioblastoma targets (but not lymphocytes) is significantly enhanced when costimulated with IL-2 and IL-12. To study this synergistic activation by the two interleukins of the patients' gammadelta T cells, we screened the cells for the presence of the IL-2 receptor (IL-2R) and IL-12 receptor (IL-12R) using both flow cytometric analysis and PCR. The patients' gammadelta T cells constitutively expressed the high-affinity IL-2R; when stimulated with IL-12 plus IL-2, the levels of IL-2Ralpha and IL-2Rbeta increased, whereas that of IL-2gamma did not. They also expressed marginal levels of low-affinity IL-12R both immediately after IL-2 expansion and after 24-h incubation, and significantly higher levels after 72-h incubation, consistent with the level of gammadelta T-cell activation. IL-12 alone induced little proliferation of patients' gammadelta T cells in a 24-h assay and none in a 72-h assay; however, it caused a marked inhibition of the IL-2-induced proliferative response in the 72-h assay. The synergistic action of IL-2 and IL-12 was completely abolished by combined pretreatment with anti-IL-2alpha, beta, and gamma mAbs. IL-12-mediated enhancement of gammadelta T cell cytotoxic activity was inhibited by anti-IL-2Rbeta mAb in a dose-dependent manner but not by anti-IL-2Ralpha or anti-IL-2Rgamma mAbs. Thus, the increased expression of the IL-2Rbeta is critical for the synergistic activation of gammadelta T cells by IL-12 plus IL-2; it is also probable that at least the low-affinity IL-12R contributes to the activation of gammadelta T cells mediated by either IL-12 alone or IL-12 plus IL-2. We have, therefore, demonstrated that IL-12 can stimulate the cytotoxic activity of gammadelta T cells from glioblastoma patients, acting via the IL-2Rbeta component of the IL-2R and low-affinity IL-12R. IL-12 activation of patients' gammadelta T cells could possibly be of potential use in the treatment of glioblastoma patients.
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PMID:In vitro interleukin 12 activation of peripheral blood CD3(+)CD56(+) and CD3(+)CD56(-) gammadelta T cells from glioblastoma patients. 981 31


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