Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interpretation of results with the use of effector populations generated in human mixed lymphocyte tumor cultures (MLTC) has in many cases been clouded by the presence of two distinct cytolytic effectors: specific cytolytic T lymphocytes (CTL) and nonspecific anomalous killers (AK). The addition of 5 to 50 X 10(-6) M hydrocortisone sodium succinate (HC) to "three-cell" allogeneic human MLTC containing responder lymphocytes, irradiated allogeneic glioma cells, and irradiated third-party stimulator lymphocytes consistently reduced the generation of AK by greater than 90% while having little or no effect on the generation of CTL specific for antigens present on the glioma cells. HC was similarly effective in blocking the generation of AK when added to cultures of responder cells incubated with lymphokine-containing supernatants from mixed lymphocyte cultures. Kinetic experiments indicated that HC both decreased the initial rate of appearance of AK activity and subsequently caused the AK response to decline more rapidly. HC had only a small inhibitory effect on the lytic action of AK generated in its absence. The ability of HC to suppress strongly the generation of nonspecific but not specific cytolytic effectors suggests that nonspecific AK are not polyclonally activated CTL or CTL at an early stage of differentiation, but rather represent a distinct cytolytic effector system. The inclusion of HC in human MLTC may provide a useful tool for distinguishing between lysis due to the generation of specific CTL and lysis due to the generation of nonspecific AK.
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PMID:Hydrocortisone suppresses the generation of nonspecific "anomalous" killers but not specific cytolytic T lymphocytes in human mixed lymphocyte-tumor cultures. 619 83

A novel approach toward the treatment of glioma was developed in a murine model. The genes for both interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) were first transfected into a mouse fibroblast cell line that expresses defined major histocompatibility complex (MHC) determinants (H-2k). The double cytokine-secreting cells were then cotransplanted intracerebrally with the Gl261 murine glioma cell line into syngeneic C57BL/6 mice (H-2b) whose cells differed at the MHC from the cellular immunogen. The results indicate that the survival of mice with glioma injected with the cytokine-secreting allogeneic cells was significantly prolonged, relative to the survival of mice receiving equivalent numbers of glioma cells alone. Using a standard 51Cr-release assay, the specific release of isotope from labeled Gl261 cells coincubated with spleen cells from mice injected intracerebrally with the glioma cells and the cytokine-secreting fibroblasts was significantly higher than the release of isotope from glioma cells coincubated with spleen cells from nonimmunized mice. The cellular antiglioma response was mediated by natural killer/lymphokine-activated killer and Lyt-2.2+ (CD8+) cells. The increased survival of mice with glioma and the specific immunocytotoxic responses after immunization with fibroblasts modified to secrete both IL-2 and IFN-gamma indicate the potential of an immunotherapeutic approach to gliomas with cytokine-secreting cells.
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PMID:Prolonged survival of mice with glioma injected intracerebrally with double cytokine-secreting cells. 749 Jun 18

An established human astrocytoma cell line (T67) was shown to constitutively produce the proteinase inhibitor alpha 2 macroglobulin (alpha 2M). Interferon gamma (IFN gamma), a potent immunoregulatory lymphokine, was able to increase the synthesis of alpha 2M by these cells, as measured by ELISA on cell supernatants. The alpha 2M induction was also observed in other human glioma cell lines (T70 and ADF) and in human fetal astrocyte cultures following IFN gamma treatment. In T67 cells this effect was dose-dependent and the maximum (2.7-fold increase) was obtained with 2000 U/ml of IFN gamma. A corresponding enhanced alpha 2M mRNA accumulation was demonstrated by PCR and Northern blot techniques. Our results suggest an important role of alpha 2M during inflammatory and immune processes in the CNS. An increased release of alpha 2M following IFN gamma stimulation may allow the removal of the bulk of proteases released at the site of inflammation, strengthening at the same time the antigen presentation processes.
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PMID:Interferon gamma up-regulates alpha 2 macroglobulin expression in human astrocytoma cells. 751 32

The use of autologous lymphokine-activated killer (LAK) cells to treat malignant brain tumors was evaluated in 10 patients, one with metastatic malignant melanoma and nine with malignant glioma. LAK cells were obtained by culturing autologous peripheral blood lymphocytes with human recombinant interleukin-2 (rIL-2) for 7-28 days. All patients underwent surgery to remove as much tumor as possible and an Ommaya reservoir was implaced in the tumor cavity. Two of the 10 patients had received radiotherapy elsewhere, so were treated with LAK cells alone. Eight patients were treated with a combination of LAK cells and radiotherapy, using 1.8-2.0 Gy fractions given five times a week with a total dosage between 54 and 65 Gy. LAK cells and rIL-2 were injected to the tumor cavity via the Ommaya reservoir once a week for inpatients and once a month for outpatients. The duration of the LAK therapy ranged from 3 to 23 months (mean 13.7 mos). Neuroimaging evaluation revealed two complete responses, three partial responses, four no changes, and one progressive disease. In one patient with pontine glioma, the Karnofsky performance score was raised from 20 to 60. There were no side effects after the injection of LAK cells and rIL-2. The results suggest low-dose LAK therapy is a useful and safe treatment modality for malignant brain tumors.
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PMID:Effect of lymphokine-activated killer cells with or without radiation therapy against malignant brain tumors. 770 Apr 78

The genes for interleukin (IL)-2, interferon (IFN)-gamma, or both IL-2 and IFN-gamma were introduced into a mouse fibroblast cell line (LM) expressing defined major histocompatibility complex determinants (H-2k). The cytokine-secreting cells were then co-transplanted with the Gl261 murine glioma cell line (H-2b) into syngeneic C57BL/6 mice that differed at the major histocompatibility complex from the cytokine-secreting cells. The period of survival of mice with glioma treated with IL-2- or IL-2/IFN-gamma-secreting allogeneic cells was significantly prolonged (P < 0.025) relative to the survival of mice receiving equivalent numbers of tumor cells alone or mice with glioma treated with nonsecreting fibroblast (LM) cells. Gliomas in the treated mice had an extensive lymphocytic cell infiltrate. Using a 51Cr release assay, the specific release of isotope from labeled Gl261 cells co-incubated with spleen from mice injected with the glioma cells and IL-2-secreting fibroblasts was higher (P < 0.001) than the release from glioma cells co-incubated with spleen cells from nonimmunized mice. Significantly higher levels of release (P < 0.005) were found in the group immunized with fibroblasts secreting both IL-2 and IFN-gamma. Based upon the effect of monoclonal antibodies for T-cell subsets on the antiglioma response, the immunity was mediated predominantly by natural killer/lymphokine-activated killer cells.
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PMID:Fibroblasts genetically engineered to secrete cytokines suppress tumor growth and induce antitumor immunity to a murine glioma in vivo. 775 55

The authors evaluated the effect of liposomal transfection of human gamma-interferon (HuIFN-gamma) gene into human glioma cells and lymphokine-activated killer (LAK) cells, alone and in combination. An HuIFN-gamma gene inserted in a eukaryotic expression vector was entrapped in liposomes bearing positive surface charges. Liposomal gene transfection induced production of HuIFN-gamma and its secretion in culture medium of human glioma cell lines (SK-MG-1 and U-251 MG). At 4 days after transfection, the cells produced 10 to 50 U/ml of HuIFN-gamma in the medium, whereby the major histocompatibility complex (MHC) class I and II antigens, as well as intercellular adhesion molecule-1 (ICAM-1), were induced on the glioma cell surface. The growth-inhibiting effect of transfection-induced HuIFN-gamma was much stronger in comparison with control cultures exposed to 500 U/ml of exogenously added HuIFN-gamma. In addition, 20% to 40% growth inhibition was obtained in the glioma cells when they were treated with LAK cells alone at a 5:1 ratio of effector to target cells. Liposomal transfection of HuIFN-gamma gene into human glioma cells combined with immunotherapy using LAK cells was more effective than either technique alone. The reinforcement of growth inhibition in the case of combined therapy was quenched by anti-ICAM-1 monoclonal antibody, but not by anti-MHC class I or II monoclonal antibodies. These results suggest that the combined effect of liposomal transfection of HuIFN-gamma gene plus LAK cells into human glioma cells is a potentially useful therapy for malignant glioma, and that the mechanisms of the reinforcement of growth inhibition are closely related to the expression of ICAM-1 on the glioma cell surface.
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PMID:Liposomal transfection of human gamma-interferon gene into human glioma cells and adoptive immunotherapy using lymphokine-activated killer cells. 790 27

To develop more effective adoptive immunotherapy, we transfected the human tumor necrosis factor-alpha (TNF-alpha) gene into human glioma cells (U251-SP), which were used as target cells. TNF-alpha is known to increase both the expression of intercellular adhesion molecule-1 (ICAM-1) on the surface of glioma cells and the susceptibility of glioma cells to lymphokine-activated killer (LAK) cell cytolysis. We compared the expression of ICAM-1 induced by TNF-alpha generated by the TNF-alpha gene-transfected cells with that induced by exogenously added TNF-alpha. When the TNF-alpha gene was transfected into U251-SP cells, the expression of ICAM-1 was detected on the cell surface from 3 days after the transfection and continued until at least 9 days. In contrast, it was expressed only transiently in the case of exogenously added TNF-alpha. Also, the cytolytic activity of LAK cells induced by transfection-induced TNF-alpha was significantly stronger than that induced by exogenously added TNF-alpha. The increased susceptibility was quenched by anti-ICAM-1 monoclonal antibody. These data indicated that continuous expression of ICAM-1 induced by TNF-alpha gene transfection of glioma cells resulted in higher cytolytic activity of LAK cells.
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PMID:Transfection-induced tumor necrosis factor-alpha increases the susceptibility of human glioma cells to lysis by lymphokine-activated killer cells: continuous expression of intercellular adhesion molecule-1 on the glioma cells. 791 64

The humoral interactions between three malignant glioma early-passage cell cultures and in vitro interleukin (IL)-1 alpha- and IL-2-activated autologous peripheral blood mononuclear cells (PBMC's) were investigated, employing standard and modified (separated by permeable membranes) mixed lymphocyte tumor cell (MLTC) cultures. In modified MLTC's, glioma cells clearly inhibit proliferation of PBMC's (up to 60%), whereas lymphokine-activated PBMC's enhance glioma cell growth up to 12-fold, as determined by 3H-thymidine incorporation assays. Glioma cells produce both stimulatory (IL-6) and inhibitory proteins (transforming growth factor-beta) for PBMC's. Lymphokine-activated PBMC's secrete IL-1 alpha, IL-2, IL-4, IL-6, interferon-gamma, and tumor necrosis factor-alpha, which may modulate glioma cell proliferation. None of these cytokines stimulated glioma cells as intensely as modified MLTC systems. These observations indicate that in vitro lymphokine-activated PBMC's, although suppressed by humoral glioma-derived factors, may enhance glioma cell proliferation with soluble factors secreted into the culture medium. The authors conclude that glioma-lymphocyte growth regulatory networks include stimulatory and inhibitory factors from both cell populations, which may modulate tumor progression. These observations may have relevance for adoptive immunotherapy in patients with gliomas.
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PMID:In vitro studies of cytokine-mediated interactions between malignant glioma and autologous peripheral blood mononuclear cells. 793 92

Tumor necrosis factor (TNF)-alpha gene were transfected into lymphokine-activated killer (LAK) cells generated from peripheral blood lymphocytes incubated with recombinant interleukin-2 by means of novel liposomes with a positive charge on their surface. The cells secreted significant amounts of TNF-alpha into the culture medium and exhibited reinforcement of cytotoxicity toward a human glioma cell line (U251-SP), being three times more cytotoxic than nontransfected LAK cells. The mechanism for the reinforcement of cytotoxicity is considered to involve not only an increase in TNF-alpha secretion from LAK cells but also its expression on their surface. Intratumoral or intrathecal injection of LAK cells transfected with the TNF-alpha gene may be useful for the treatment of patients with malignant glioma.
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PMID:[Enhanced anti-tumor effect of lymphokine-activated killer cells transfected with tumor necrosis factor-alpha gene on human glioma cells]. 795 91

This in vitro study was aimed at restitution of transforming growth factor (TGF)-beta 2-mediated suppression of T-lymphocyte activation within malignant gliomas. In early-passage tumor cell cultures of two glioblastomas (HTZ-153 and HTZ-209) and one malignant astrocytoma classified as World Health Organization Grade III (HTZ-243), autologous peripheral blood mononuclear cells were activated by interleukin-1 alpha and interleukin-2 in vitro (lymphokine-activated killer cells) and tested for cytotoxic and proliferative activity. In expression studies (Western blot and Northern hybridization) of all three tumors, TGF-beta could be detected at the protein and messenger ribonucleic acid (mRNA) levels. A polyclonal anti-TGF-beta neutralizing antibody did not enhance lymphocyte proliferation upon stimulation with tumor targets (3H-thymidine incorporation) and slightly stimulated lymphocyte cytotoxicity against autologous target cells. Preincubation of target cells for 12 hours with TGF-beta 2-specific phosphorothioate-anti-sense oligodeoxynucleotides (S-ODN's) did, however, enhance lymphocyte proliferation up to 2.5-fold and autologous tumor cytotoxicity up to 60%, compared to controls not treated with S-ODN's. Incubation of tumor cells with TGF-beta 2-specific S-ODN's resulted in decreased TGF-beta-specific immunoreactivity in cultured glioma cells, in reduced TGF-beta 2 protein concentration (Western blot), and in a change in the expression pattern of TGF-beta 2 mRNA's. These observations may have implications for in vivo and in vitro activation of a cellular immune response against autologous malignant glioma cells.
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PMID:The effect of transforming growth factor-beta 2-specific phosphorothioate-anti-sense oligodeoxynucleotides in reversing cellular immunosuppression in malignant glioma. 848 77


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