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)

Human glioblastoma cells secrete factors, such as prostaglandin E (PGE) and transforming growth factor beta type 2, which are capable of suppressing several immune functions. The present study investigated the effect of PGE2 and agents known to increase intracellular cyclic adenosine monophosphate (cAMP) levels on 1) the induction of lymphokine-activated killer (LAK) cell activity from the peripheral blood lymphocytes (PBL) of both normal and glioma patients and on 2) the cytolytic activities of tumor-infiltrating lymphocytes (TIL's) isolated from malignant gliomas after expansion in vitro with interleukin-2 (IL-2). Cytolytic activity was measured against autologous and allogeneic tumor cells and the natural killer-resistant Daudi cell line. The results demonstrate that PGE2 and agents known to increase intracellular cAMP levels can significantly suppress the IL-2-dependent generation of cytolytic activity from the PBL of normal and glioma patients and from glioblastoma-derived TIL's. The inhibitory effects of these agents could not be reduced by higher concentrations of IL-2 or by cyclic guanosine monophosphate. Although the suppressive effect of PGE2 was most significant during the early stages of LAK cell generation, an inhibitory effect was still evident when PGE2 was added directly to the cytotoxicity assay. Secretion of PGE2 by glioblastoma cells in vivo may regulate both the generation of an immune response and the effectiveness of adoptively transferred immune cells.
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PMID:Influence of PGE2- and cAMP-modulating agents on human glioblastoma cell killing by interleukin-2-activated lymphocytes. 196 67

Peripheral blood mononuclear cells (PBM) from normal donors and patients with recurrent glioma were activated initially for 48-72 h with phytohemagglutinin-P (PHA) and recombinant human interleukin-2 (IL-2), and then proliferated in vitro for up to 5 months with IL-2. These cells are termed mitogen-stimulated lymphokine-activated T killer (T-LAK) cells. We measured patterns of T-LAK cell growth, in vitro cytolytic activity on a panel of continuous and primary tumor cells, and the phenotypes of the cells in these cultures. Lymphocyte viability declined dramatically over the first 3-5 days; and then the remaining cells in these cultures began to divide and maintained a constant 30-36 h doubling time for long periods in vitro. Phenotyping revealed that cells in the initial few days of culture were heterogeneous, but became almost totally CD3 T cells after 7-10 days in culture. The T-LAK cells from individual normal donors and cancer patients demonstrated a non-genetically restricted cytolytic ability against a panel of both continuous cell lines and primary autologous and allogeneic glioblastoma cells in vitro. This technique provides a method of generating large numbers of autologous cytolytic T cells with non-restricted anti-tumor activity that can be derived from peripheral blood mononuclear cells.
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PMID:Generation of stimulated, lymphokine activated T killer (T-LAK) cells from the peripheral blood of normal donors and adult patients with recurrent glioblastoma. 201 99

An in vitro technique was developed to generate activated rat T cells, with antitumor activity. Splenic mononuclear cells (SMC) from outbred Wistar and inbred Wistar-Munich rats were stimulated with Concanavalin A and recombinant human interleukin-2 (rIL-2) in vitro for 48 h. After 2 days, the nonadherent cells began proliferating and were maintained in rIL-2 for up to 18 days in vitro. FACScan analysis revealed that SMC was a mixture of cell types; however, CD5+ T cells rapidly increased and became the predominant cell type after 5 days in culture. SMC induced cytolysis of YAC-1, but not C6 glioma cells in 4 h 51Cr release assays. In contrast, 5- and 9-day T cells lysed C6 glioma and YAC-1 cells. The C6 cells were admixed with cultured effector cells at various effector-to-target (E:T) ratios and were injected into the right cerebral hemisphere of Wistar and Wistar-Munich rats for a Winn assay. Histopathologic evaluations revealed that a) SMC had no effect; b) 2- and 5-day T cells, injected at E:T ratios greater than 5:1, caused significant reduction in tumor size; and c) 2- or 5-day T cells, at a 40:1 E:T ratio, resulted in little or no histologic evidence of tumor. Eighty-three percent of animals receiving C6 and 5-day mitogen-stimulated lymphokine activated killer cells at an E:T ratio of 40:1 were alive 120 days postinjection (p less than 0.05).
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PMID:Rat mitogen-stimulated lymphokine-activated T killer cells: production and effects on C6 glioma cells in vitro and in vivo in the brain of Wistar rats. 204 93

In the present study, we have investigated not only the infiltrative and cytotoxic activities of lymphokine-activated killer (LAK) cells on a tumor mass, but also the ultrastructural cell-to-cell interaction between LAK effector cells and target tumor cells during the cytolytic process within a three-dimensional solid tumor. A multicellular tumor spheroid (MTS) of a human malignant glioma cell line (U-251MG) was utilized as a solid tumor model. LAK cells were generated from peripheral blood lymphocytes (PBL) of a healthy donor after 4-day culture in the presence of interleukin-2 (IL-2). MTSs of 500 microns diameter were cocultivated with either LAK cells or non-activated PBL, and then time-sequential kinetic, morphological, and ultrastructural examinations were carried out. It was demonstrated that the number of viable tumor cells present within MTSs gradually decreased in parallel with the increase in the number of LAK cells. Morphological analyses revealed that LAK cells directly infiltrated toward the inner areas of MTSs and caused a progressive tumor destruction. In contrast, PBL hardly exhibited such activities. Ultrastructurally, it was found that the infiltrating LAK effector cells were composed of heterogeneous subpopulations, T-like cells and large granular lymphocyte (LGL)-like cells, and that both types of lymphocytes tightly adhered to the tumor cells and extended their cytoplasmic extensions deeply into the targets which underwent a progressive degeneration. Concerning the cellular interaction, it was found that these two kinds of LAK cells displayed some distinct ultrastructural feature in the process of target cell killing. Particularly, it should be stressed that LGL-like LAK cells exhibited a significant development of the intracytoplasmic secretory granules, suggesting an association with the lethal hit of target cell lysis.
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PMID:[Infiltrative and cytolytic activities of lymphokine-activated killer (LAK) cells against a human glioma mass: ultrastructural analysis using a three-dimensional multicellular spheroid model]. 213 Jul 68

A bifunctional hetero-F(ab')2 antibody fragment was developed that contained the Fab portions from anti-CD3 and anti-glioma monoclonal antibodies. The antibody simultaneously recognized two different molecules, the CD3 complex on effector T cells and a human glioma-associated antigen; thus, it could cross-link effector and target cells. This bispecific F(ab')2 fragment induced peripheral blood mononuclear cells (PBMC's) from healthy donors to lyse cells of the human glioma cell line, U251MG, which are resistant to natural killer cell-mediated cytolysis. The effect of the bispecific antibody on lymphokine-activated killer (LAK) cell activity was tested in patients suffering from malignant glioma. For this study, PBMC's from these patients were preactivated with recombinant interleukin-2 and their killer activity against U251MG cells was investigated in vitro with and without the bispecific antibody. The LAK cell activity of the PBMC's from patients with malignant gliomas was found to be suppressed compared with those of healthy donors. However, after preincubation with bispecific antibody, the patients' LAK cells exhibited marked cytolytic activity against U251MG cells. These findings suggest that this bispecific antibody may be a useful addition to anti-glioma immunotherapy.
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PMID:Induction of cytotoxicity in human T cells coated with anti-glioma x anti-CD3 bispecific antibody against human glioma cells. 213 33

Over the past few years, we and a number of other groups have conducted laboratory experiments and clinical trials of human recombinant interleukin-2 (rIL-2) alone or in combination with autologous 'activated' lymphocytes expressing in vitro tumoricidal activity in order to define toxicity and indicate its potential efficacy in patients with high-grade glioma. Because high rIL-2 concentrations can be attained with considerably less toxicity than with a systemic approach, all of the clinical trials, to date, have chosen a direct route; injecting lymphokine and cells into tumor tissue, the cystic cavity remaining after tumor excision, and/or neural parenchyma surrounding the site of tumor excision. While the rIL-2 therapies, as they have been applied in animal glioma models and patients, are safe, cerebral edema around the site of treatment has been a consistent finding. We have also seen, however, that steroid medications used by patients to control their cerebral edema may depress the anti-tumor activity of rIL-2 by depressing the capacity of lymphocytes to develop normal LAK activity. Although none of the immunotherapies involving rIL-2 have produced cures, the fact that sustained clinical responses have been reported, suggests that such therapies may slow a recurrence of tumor at the site of treatment. Efforts to improve outcome from rIL-2--based immunotherapies for malignant glioma are continuing with manipulation of rIL-2 dosing and scheduling and also with combinations of rIL-2 and other recombinant cytokines.
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PMID:Immunotherapy for malignant glioma using human recombinant interleukin-2 and activated autologous lymphocytes. A review of pre-clinical and clinical investigations. 219 21

A bifunctional hetero-F (ab') 2 fragment containing the Fab portions from anti-CD3 and anti-glioma monoclonal antibodies was prepared. The antibody simultaneously recognized two different molecules, the CD3 complex on effector T cells and human glioma-associated antigens on target glioma cells. This bispecific F (ab') 2 fragment induced peripheral blood lymphocytes (PBLs) from healthy donors to lyse cells of the human glioma cell line, U251MG, that is resistant to natural killer cell-mediated cytolysis. Compared with lymphokine-activated killer (LAK) activity which is obtained by exposure to interleukin (IL)-2 for more than 3 days, the maximum bispecific antibody-dependent cytotoxicity can be generated only after 24 hour exposure to IL-2. And cytotoxicity of lymphocytes triggered by the bispecific antibody was dependent upon the concentration of IL-2 in the culture medium. The effect of the bispecific antibody on LAK cells was tested in patients suffering from malignant glioma. One patient who received specific targeting therapy (LAK plus bispecific antibody) showed the disappearance of high density tumor mass from CT scan. But the patient who received only LAK therapy showed the recurrence of tumor one year after LAK treatment. These are preliminary data, but may be a promising approach in cancer immunotherapy.
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PMID:[Induction of cytotoxicity from human lymphocytes coated with bispecific antibody against human glioma cells]. 224 92

Local brain tumor therapy using lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) has not proved to be effective in preliminary clinical trials. One obstacle to effective use of this therapy is ignorance about the events that follow contact of the LAK cells with glioma tissue. We used multicellular spheroids grown from human glioma cell lines as targets to study, in vitro, the effect of LAK cells against three-dimensional glioma tissue. Here we describe the ultrastructural changes in spheroids of H-2 glioma cells incubated in pellets of LAK cells for up to 24 hours. In H-2 spheroids, cellular damage was not restricted to the effector cell-target cell (effector-target) contact; it extended farther, at least partly because of nonspecific changes in the spheroid micromilieu. Formation of cytoplasmic blebs, a characteristic effect of T cells, natural killer cells, and LAK cells on single target cells, also occurs in H-2 spheroids, and it is not limited to the effector-target contact area either. These findings suggest that LAK cells release membrane-damaging agents that remain active outside the effector-target area, in the micromilieu of H-2 spheroid tissue.
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PMID:Damage to multicellular human H-2 glioma spheroids incubated with LAK cells: an ultrastructural study. 231 22

In the present study, we investigated not only the cytotoxic effects of lymphokine-activated killer (LAK) cells on a tumor mass but also the ultrastructural cell-to-cell interaction between LAK effector cells and tumor cells during the cytolytic process within a three-dimensional solid tumor. A multicellular tumor spheroid of a human glioma cell line (U-251MG) was utilized as a solid tumor model. LAK cells were generated from peripheral blood lymphocytes of a healthy donor after stimulation by interleukin 2. Multicellular tumor spheroids with diameters of 500 microns were cocultivated with either LAK cells or nonactivated peripheral blood lymphocytes at the effector:target cell ratio of 20:1, and then time-sequential kinetic, morphological, and ultrastructural analyses were carried out. Morphological and kinetic studies showed that LAK cells directly infiltrated toward the inner areas of multicellular tumor spheroids and caused a progressive tumor destruction. In contrast, peripheral blood lymphocytes hardly exhibited such activities. Ultrastructurally, it was found that the infiltrating LAK effector cells were composed of heterogeneous subpopulations, T-like cells, and large granular lymphocyte-like cells. Both types of lymphocytes tightly adhered to the tumor cells and showed typical morphological features of killing them.
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PMID:Infiltrative and cytolytic activities of lymphokine-activated killer cells against a human glioma spheroid model. 231 27

The mechanisms by which lymphokine-activated killer (LAK) cells exert their cytotoxic effects are not well understood. This study demonstrates that phorbol ester pretreatment of a LAK cell-sensitive glioma cell line (SNB-19) induced a significant decrease in the susceptibility of cells to LAK cell-mediated lysis. This effect was produced by low concentrations of the tumor-promoting phorbol ester, phorbol-12,13-myristate acetate (PMA), and was reversible. Protein kinase C (PKC) inhibitors failed to block this phenomenon. No apparent alteration in the ability of LAK cells to bind to their targets was observed. Thus, PMA may have exerted its effects by a mechanism that does not require PKC, or these glioma cells may possess an isozyme of PKC which is insensitive to the inhibitors used in these studies.
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PMID:Effect of phorbol esters on the susceptibility of a glioma cell line to lymphokine-activated killer cell activity. 235 27


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