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)

A mannoprotein preparation (MP) from Candida albicans induced MHC-unrestricted cytotoxicity in peripheral blood mononuclear cells (PBMC) from healthy subjects, but not in those from glioma-bearing subjects. The two groups of subjects did not significantly differ in the number of cells bearing typical natural killer (NK) markers (both in resting and MP stimulated PBMC) and NK activity. However, interferon gamma (IFN-gamma) production was in tumour patients minimal or significantly reduced, as compared to healthy subjects, following PBMC stimulation by MP or phytohaemoagglutinin, respectively. In addition, minimal, if any, stimulation of interleukin-2 (IL-2) production was achieved in MP stimulated PBMC from glioma patients. Considering the pivotal role of the above cytokines in immune responses, particularly in those concerning generation of antitumour effectors, our results consistently suggest that defective cytokine production is one possible mechanism of immunological impairment in glioma patients. They also provide indirect support for a possible clinical use of IFN-gamma as an immunopotentiating agent in gliomatous subjects.
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PMID:Cell mediated cytotoxicity and cytokine production in peripheral blood mononuclear cells of glioma patients. 171 54

Patients harboring a malignant brain tumor have been described as being highly immunosuppressed, as evidenced by reduced numbers of T cells and the decreased ability of their lymphocytes to produce interleukin-2 (IL-2). In order to determine whether an intrinsic abnormality exists in the T lymphocytes of glioma patients and to evaluate what role corticosteroids may play in glioma-associated immunosuppression, in vitro T cell proliferative function in the presence of recombinant IL-2 (rIL-2) was examined in age-matched groups of normal control subjects, steroid-free patients with glial tumors, steroid-dependent patients with glial tumors, and steroid-dependent patients with nonglial cerebral tumors. The results demonstrated that, when enriched T cell populations of all brain-tumor patients were stimulated with rIL-2 and phytohemagglutinin (PHA), there were no statistically significant differences between any groups. In contrast, when T cell populations were stimulated with mitogenic combinations of phorbol ester, calcium ionophore, and rIL-2, those from steroid-dependent patients with glial tumors had a significantly lower response than those from normal control subjects, suggesting that a population of T cells capable of responding to phorbol ester/ionomycin and not PHA stimulation is inhibited by corticosteroid therapy in glioma patients. In addition, T cells of four brain-tumor patient/age-matched control subject pairs were stimulated with either phorbol ester/ionomycin or PHA for 24 hours; three of the four patients expressed low-affinity IL-2 receptor levels as high or higher than their respective control subjects, suggesting that IL-2 receptor expression in these patients may be quantitatively normal once the T cell number is corrected. Taken together, these results show that the decreased PHA responsiveness that has been previously reported in lymphocytes of glioma patients is not due to a cellular abnormality within the potentially responsive cells, but rather reflects the reduced proportion of T cells within their peripheral blood which, as a consequence, reduces the level of IL-2 production attained upon activation.
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PMID:In vitro analysis of the proliferative potential of T cells from patients with brain tumor: glioma-associated immunosuppression unrelated to intrinsic cellular defect. 140 31

Methods have recently been described for the isolation and expansion of lymphocytes that have trafficked into animal and human tumors. These CD8-positive tumor-infiltrating lymphocytes (TIL's) have exceptional trafficking ability to, and efficacy against, tumor targets in extracranial sites. Prior to Phase I clinical trials for patients with gliomas, adoptive immunotherapy with TIL's was studied in a mouse model of primary brain tumors to determine if intracerebral tumors have a similar response. Glioma 261 (GL261) tumors were grown in the subcutaneous space of C57BL/6 mice. After enzymatic digestion, the cells were incubated in vitro with interleukin-2 (IL-2) until a confluent population of T lymphocytes was present. The in vitro efficacy of these TIL's was tested against fresh GL261 targets with a chromium release assay; the in vivo efficacy was tested against GL261 tumors in the liver and against irradiated and nonirradiated GL261 tumors in the brain. Mice received one of the following: intraperitoneal saline; intraperitoneal IL-2 (7500 to 50,000 U three times daily for 5 days); IL-2 plus intravenous TIL's (1 to 3 x 10(7) cells); 10 Gy cranial irradiation; irradiation plus IL-2; or irradiation plus IL-2 plus TIL's. The TIL preparation killed 77% of tumor targets in 4 hours at an effector:target ratio of 100:1. In animals with GL261 tumors in the liver, at 2 weeks there were 93 +/- 37, 128 +/- 45, and 21 +/- 14 liver metastases in the control, IL-2, and IL-2 plus TIL groups, respectively. However, in animals with GL261 tumors in the brain, no treatment group had an increased survival rate compared to the control group. It is concluded that, although TIL and IL-2 immunotherapy can be used effectively to treat brain tumors in vitro and at sites outside the central nervous system, it is ineffective against the same type of tumor in the brain. Different methods of delivery or different combinations of these immunomodulators may be more effective; however, based on these findings, treatment of patients with IL-2 and TIL cannot be recommended until efficacy has been demonstrated in an animal model.
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PMID:Treatment of murine primary brain tumors with systemic interleukin-2 and tumor-infiltrating lymphocytes. 173 33

The present study was conducted in order to examine the feasibility of isolating and growing glioma-infiltrating lymphocytes in vitro as possible effector cells for use in an adoptive immunotherapy. Thirty surgical specimens obtained from patients with malignant astrocytomas were studied. The glioma-infiltrating lymphocytes were separated from tumor tissue, expanded in the presence of interleukin-2, and evaluated their anti-tumor activities in vitro. Eighteen of 30 cultures of glioma-derived lymphocytes expanded with a substantial increase in cell numbers, of at least 5 x 10(8) cells up to 5 x 10(9), 4 to 8 weeks after the initiation of culture. The expanding glioma-derived lymphocytes consisted of 88 +/- 10% CD3+ T cells including both CD4+ and CD8+ subpopulations. CD16 was expressed on 4 +/- 5% of the cells and three cultures studied exhibited 14% +/- 1 of CD56+ cells. After 4 to 8 weeks of the proliferation period, the lymphocytes ceased to grow in all cultures. The glioma-derived effector lymphocytes could lyse almost all the autologous tumor targets as well as allogeneic glioma cells. The cytotoxic activity of the glioma-derived lymphocytes appeared to be similar or inferior to that of interleukin-2-activated peripheral blood lymphocytes obtained from the same patients in killing autologous glioma cells. The glioma-derived effector cells could also lyse three-dimensional glioma targets (spheroids), but this lytis activity was clearly lower than that of the activated peripheral blood lymphocytes. Ability of these effector cells to infiltrate glioma tissue was doubtful, since after 24-hours coculture of effector cells with target spheroids, the effector cells scarcely infiltrated the spheroids. In summary, glioma-derived lymphocytes expanded in bulk culture with interleukin-2 consisted predominantly of T-lymphoblasts with the ability to kill autologous glioma cells and also to lyse glioma spheroids. However a benefit of use of the glioma-derived lymphocyte as a novel effector cells in clinical trail replacing the IL-2-activated peripheral blood lymphocytes could not be found.
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PMID:[Isolation and expansion of glioma-infiltrating lymphocytes in vitro: an analysis of their surface phenotypes and antitumor activities]. 178 72

Tumor-infiltrating lymphocytes (TIL) were generated from 10 glioma specimens by using recombinant interleukin-2 and an anti-CD3 antibody (CD3 + TILs). We obtained more than 1 x 10(9) cells in 5 cases, more than 5 x 10(8) cells in 2 cases, and about 1 x 10(8) cells in 3 cases during three weeks of incubation from small specimens ranging in weight from 0.5 to 2.0 g. In 4 cases, TILs were expanded following stimulation with only rIL-2 (CD3-TILs). The growth rate of CD3-TILs was less than that of CD3 + TILs. Cytotoxicity of CD3 + TILs was lower than that of lymphokine-activated killer (LAK) cells in a standard 4h 51Cr release assay. Cold target inhibition was undertaken in three cases and specific cytotoxicity could be shown in only one case. CD3 + TILs mainly consisted of CD3-positive cells, ranging from 63.2 to 99.9%. The ratio of CD4-positive cells to CD8-positive cells was not constant. The expression of Leu 7 and CD16 was low. The present study did not confirm previous findings that TILs were more tumor-selective and potent than LAK cells. Furthermore, the results on in vitro antitumor activity of those cells were not necessarily consistent with the results on their clinical activity. Further careful work is necessary on the preparation of immunocytes and the subsequent adoptive immunotherapy.
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PMID:Cytological characteristics of human glioma-infiltrating lymphocytes stimulated with recombinant interleukin 2 and an anti-CD3 antibody. 182 92

Lysis of tumor cells by activated cytotoxic lymphocytes requires their recognition of antigens associated with major histocompatibility complex molecules. The authors studied the constitutive expression of Class I and Class II major histocompatibility complex antigens on mouse brain-tumor cells and the capacity of different cytokines and cytokine combinations to alter this expression in vitro. Cells from the murine glioma 26 (GL26), glioma 261 (GL261), and ependymoblastoma A (EpA) cell lines were established in monolayer culture and treated for 48 hours with either alpha interferon, gamma interferon, tumor necrosis factor alpha, tumor necrosis factor alpha plus gamma interferon, or interleukin-2. They were then analyzed by flow cytometry for baseline and cytokine-altered major histocompatibility complex expression. All cell lines had a similar constitutive major histocompatibility complex pattern with low Class I antigen expression and no detectable Class II antigen expression. Alpha interferon substantially induced and up-regulated Class I antigen expression, but had no effect on Class II antigen expression. Gamma interferon also stimulated up-regulation of Class I antigen expression, generally doubling the anti-Class I antigen fluorescence of treated cells. Its effect on Class II antigen expression was more extensive. In the GL26 and GL261 cell lines the expression of Class II antigen determinants increased to 12 x and 14 x control values and as many as 75% of cells that had no detectable constitutive expression of Class II antigen expressed this antigen after priming with gamma interferon. The addition of tumor necrosis factor alpha to gamma interferon further increased Class II antigen expression on EpA tumor cells only. Interleukin-2 and tumor necrosis factor alpha alone had no effect on Class I or Class II antigen expression of any cell lines. It is concluded that Class I and Class II antigen expression in mouse glioma cell lines is induced and enhanced after treatment with certain cytokines in vitro. Use of these cell lines to create in situ primary brain tumors in C57BL/6 mice should provide an excellent animal system to study major histocompatibility complex modulation in brain tumor cells and to examine the potential impact of major histocompatibility complex up-regulation on the response of brain tumors to immunotherapy.
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PMID:Expression and modulation of major histocompatibility antigens on murine primary brain tumor in vitro. 158 18

The homing characteristics and infiltrative capacity of interleukin-2 activated human peripheral blood lymphocytes, the lymphokine activated killer (LAK) cells, were studied. In vitro stimulated 111In-oxine labeled lymphocytes were injected into the hypogastric artery during hysterectomy, performed because of endometrial carcinoma. Scintigrams demonstrated clear homing of the lymphocytes into the area of the malignant tumor. No selective homing was detectable when labeled red blood cells were injected in a similar fashion. To analyze the infiltrative capacity of the activated lymphocytes, they were incubated in vitro with tumor spheroids grown from cultured glioma cell lines. As revealed by antibodies against the leukocyte common antigen and immunoperoxidase techniques, the activated lymphocytes infiltrated the three-dimensional tumor tissue slowly as a frontier. These results show that, in addition to their previously suggested potential role in cancer therapy, interleukin-2 activated lymphocytes may possibly also be useful as tumor tracers.
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PMID:Interleukin-2 activated lymphocytes (LAK cells) as potential tumor tracers. 196 55

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


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