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)

Expression of T cell receptor (TCR) V alpha and V beta genes in tumor infiltrating lymphocytes (TILs) within human malignant brain tumor was examined. Primers for 18 different human TCR V alpha and 21 V beta families were used to analyze TCRV-(D)-J-C gene rearrangements in TILs in 8 human malignant glioma specimens obtained at surgery. Using the polymerase chain reaction (PCR) method, we detected limited TCR variable region, V alpha gene expression in malignant glial tumors and also V alpha 7 and V alpha 12 TCR genes were preferentially expressed. Usage of TCR V beta gene was not as restricted as in TCR V alpha. These TILs expressing a limited repertoire of TCRs might be isolated, expanded, and used therapeutically for treatment of malignant brain tumors.
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PMID:[T-cell receptor repertoire in tumor infiltrating lymphocytes within malignant brain tumors]. 131 45

Two monoclonal antibodies (mAb), termed ED6 and LD6, were obtained by immunizing mice with cytotoxic T cell lines expressing the T cell receptor (TcR) gamma/delta. These mAb were selected according to their ability to trigger the cytolytic program of the immunizing cell lines in a redirected killing assay. Both mAb recognized molecule(s) expressed on the surface of most long-term cultured TcR gamma/delta +, TcR alpha/beta + and CD3-CD16+ lymphocytes, while it was absent on resting peripheral blood lymphocytes. In addition both mAb reacted with neoplastic B cell lines, Epstein-Barr virus-transformed B cell lines, small cell lung cancer and glioma cell lines, while no surface reactivity was detected on ovarian, breast, colon and non-small cell lung cancer lines. The functional activity of these mAb was studied by two cytolytic assays. Both mAb were able to trigger the cytolytic program of CD3+TcR gamma/delta + polyclonal cell lines and of a CD3-CD16+ NK cell clone against the murine mastocytoma target cell line P815 (Fc receptor+) in a 4-h 51Cr-release assay. In addition, ED6 and LD6 hybridomas were lysed by TcR gamma/delta + effector cells while other hybridomas (obtained from the same fusion) were not lysed. ED6 and LD6 mAb (in the presence of submitogenic doses of the phorbol 12-myristate 13-acetate) also induced the secretion of interleukin 2 by ED6/LD6+ T cell clones expressing TcR gamma/delta or alpha/beta. mAb-induced surface antigen modulation experiments showed that the antigenic determinant recognized by ED6 and LD6 co-modulated, thus indicating that the two mAb probably recognize the same or closely associated molecules. The molecular characteristics of the antigen recognized by the mAb were investigated by Western blot analysis. The LD6 mAb recognized a major band of approximately 65 kDa, both under nonreducing and reducing conditions. These data indicate that ED6 and LD6 mAb recognize a novel non-lineage-specific activation antigen which is involved in the induction of the functional program of long-term cultured T or natural killer cells.
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PMID:A novel surface molecule expressed by long-term cultured T and natural killer cells is involved in cell activation. 183 83

The purpose of this study was to assess the V-(D)-J junctional region of the T cell receptor (TCR), the CDR3 region, which is responsible for glioma-specific antigen contact in alpha beta TCR-mediated recognition. We sequenced the TCR alpha and beta chains of V alpha 7, and V beta 13.1 cDNA derived from tumor-infiltrating lymphocytes (TIL) of 12 glioma patients and also the corresponding clones from the patients' peripheral blood lymphocytes (PBL). A shared V beta 13.1 DJ sequence of the CDR3 region, ND beta N, was demonstrated in 49 of 66 V beta 13.1+ clones (74.2%) from the glioma TIL, whereas only 4 of 33 clones (12.1%) were observed in the V beta 13.1+ clones from the PBL (p < 0.001). A common VDJ sequence, FCASS (V beta 13.1)-YRLPWGTSDS (ND beta N)-GELFF (J beta 2.2), was observed not only in the gliomas from each patient, but also among all the patients with a preference for V beta 13.1. In contrast, the amino acid sequences of the V beta 13.1+ PBL clones were diverse and random. Next, we sequenced subclones from other V beta subfamilies randomly selected to compare their VDJ region rearrangements (V beta 3 and V beta 5.1). In contrast to V beta 13.1, the amino acid sequences of these junctional regions were completely different in these subclones. The V-J junctional region of the alpha chain is dominated by a few clones in some patients, and no shared amino acid sequences were detected in the TCR V alpha junctional region. However, in the N alpha region of the V alpha 7-bearing TIL clones, arginine was used in 27 of 44 clones (61.4%) compared to only 3 of 12 clones from the PBL (p < 0.05). These results are consistent with the hypothesis that a clonal expansion/accumulation of glioma lineage-specific T cells occurred in vivo at the tumor site and that these T cells may be recognizing glioma-specific antigens.
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PMID:Shared amino acid sequences in the ND beta N and N alpha regions of the T cell receptors of tumor-infiltrating lymphocytes within malignant glioma. 780 26

We previously demonstrated that intratumoral administration of liposomes containing the murine interferon beta (IFN-beta) gene [lip(pSV2muIFN-beta)] resulted in stronger growth-inhibitory effect on GL261 (H-2b) mouse glioma inoculated in brains of syngeneic C57BL/6 mice than conventional exogenous IFN-beta administration, and histologic evaluation revealed the massive infiltration of T lymphocytes (CD8 > CD4) within the residual tumor. The present study was aimed at determining whether such tumor-infiltrating lymphocytes (TIL) have any tumor-specific cytotoxic effects. Intratumoral administration of lip(pSV2muIFN-beta) resulted in prolonged survival time and a 50% tumor-free incidence in the mice treated. The surviving animals were subsequently re-challenged with either subcutaneous or intracranial injection of GL261 cells, and no tumors were found to develop over a 50-day period. In vivo depletion of CD8, but not CD4 cells decreased the efficacy of lip(pSV2muIFN-beta). Specific cytotoxic T lymphocytes (CTL) against GL261 cells were generated from both TIL and spleen cells of the mice treated. The results of flow cytometric analysis and antibody blocking test revealed that the bulk CTL lines thus prepared were T cell receptor (TCR) alphabeta, CD8 T lymphocytes with H-2b restriction. These findings suggest that, in addition to direct growth-inhibitory effects by the IFN-beta gene on the tumor cells, activation of systemic cellular immunity may participate in antitumor effects in vivo, despite the fact that central nervous system is generally regarded as an immunologically privileged site.
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PMID:IFN-beta gene therapy induces systemic antitumor immunity against malignant glioma. 1098 52

Mammalian cells are capable of committing "active suicide" or apoptosis in response to specialized pathological mechanisms employing a phylogenetically developed intrinsic program of death, triggered by signal transduction through specific receptors. Changes in cellular structure such as: 1) condensation of the nuclear (chromatin) and cytoplasmic structures (especially the mitochondria); 2) blebbing of the cell membrane; 3) characteristic swelling of the endoplasmic reticulum; and 4) fragmentation of the cells in membrane bound apoptotic bodies, are the dramatic signs of total cell destruction. Apoptosis requires energy in the from of ATP, indicating that programmed cell death (PCD), as opposed to necrosis, is an energy dependent, active physiological and pathophysiological phenomenon. During this immunocytochemical study, we observed the presence of PCD in the prenatal thymus and various human neoplastically transformed tissues. During the intrauterine ontogenesis, in thymocytes or resting T lymphocytes, p53 tumor suppressor protein was identified to be a critical mediator of PCD in response to DNA damage. The cellular interaction of immature, cortical thymocytes (characterized by a double positive CD4+CD8+TCRlow immunophenotype-IP) with thymic RE cells induces positive selection of T lymphocytes that recognize, but are not activated, by self-MHC molecules (tolerance induction). Double positive CD4+CD8+CD3- thymocytes undergo FasL-mediated apoptosis, while CD4+CD8+CD3+ cells use the CD3 mediated pathway of PCD. Two step, apoptotic cell death is mainly restricted to the CD4+CD8+TCR dull thymocyte subpopulation. T-lymphocytes which do not undergo positive selection are killed by apoptosis in response to a number of intrinsic and extrinsic factors, such as chemical toxins, viral infections, X- and UV irradiation, mild hyperthermia, the actions of various hormones, extracellular survival factors, calcium ionophores (such as A23187), various chemotherapeutic drugs (adriamycin, actinomycin D, etc) and antibodies directed to the CD3-TCR (T cell receptor) complex. Immature thymocytes also undergo a second selective process, so-called negative selection, when thymic stromal cells eliminate autoreactive T lymphocytes. As a typical model of embryonal neoplasms, we observed 34 childhood PNET/MED tissues samples. A systematic observation for the presence of apoptosis related markers (especially FasR) and cells in PCD was carried out. A strong expression (intensity of staining: "A"--the highest possible; number of stained neoplastic cells: +++ to ++++, between 50% to 90%) of FasR was detected. We also observed 42 childhood glial tumors, divided as follows: 6 pilocytic ASTRs; 14 low grade ASTRs; 16 anaplastic ASTRs; and 6 GBMs. The GBMs represent an end-stage brain tumor IP dedifferentiation of glial origin. During the immunocytochemical screening of these 42 childhood ASTRs, we detected strong expression (intensity of staining: "A"--the highest possible; number of stained cells: ++ to ++++, between 20% to 90%) of FasR, employing 4 microns thick, formalin fixed, paraffin-wax embedded tissue slides. FasR expression was rated high, 70% to 90% on the tumor cells in pylocytic ASTRs, lowered to 50% to 60% on the neoplastic cells in low grade ASTRs, even lower between 30% to 40% in anaplastic ASTRs and significantly lower, between 20% to 35% on the neoplastically transformed cells of GBM tissues. The presence of apoptotic neoplastic cells was also regularly detected in other human adult neoplasms, such as thyroid, pancreatic, hepatocellular, gastric, colon, breast, ovarian, prostata, and renal cell carcinomas, as well as, in Hodgkin and non-Hodgkin lymphomas and some sarcomas. The expression of apoptosis related cell surface molecules on the surface of both neoplastically transformed cells and on tumor cell specific, cytotoxic T lymphocyte (CTL) surfaces (FasR-FasL system) raises a distinct possibility of active PCD induction in CTL by tumor cells. Juxtacrine interactions between CTL and neoplastically transformed cells, coupled with observations that tumor cells can modulate the intracellular, signaling domains of cell surface receptors to elicit responses quite often contrary to the expected, may even provide a way for CTL to enhance the proliferation and dedifferentiation of cancer cells. Adoptive cellular immunotherapies employing CTL raised against autologous neoplastically transformed cells in vitro should be employed in the control of minimal residual disease following surgical resection of the primary malignant growth.
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PMID:The role of apoptosis in normal ontogenesis and solid human neoplasms. 1120 98

In this study, we report on novel alterations found in rat intracranial (i.c.) tumor-infiltrating T lymphocytes (TIL) that are indicative of T cell defects and death. FACS analysis showed that the cytotoxic T cells (CTL) infiltrating rat T9.F gliomas were CD3epsilon+, alphabetaTCR+, CD8alpha+, but CD8beta-. These lymphocytes also stained positive for the B cell-specific marker, CD45RA, as well as Annexin-V, signifying apoptotic changes. Functional and biochemical analyses were performed to assess whether the aberrant phenotype was linked to other defects. When CD8alpha+ TIL were purified and stimulated in vitro, their proliferative capacity was markedly diminished in comparison with CD3+CD8alpha+CD8beta+ T cells isolated from the spleens of naive, non tumor-bearing rats. Furthermore, the mean fluorescence intensity of surface CD3epsilon was dramatically reduced in the CD3+CD8alpha+CD8beta- TIL population as compared with CD3-CD8alpha+CD8beta+ TIL from the same tumor-bearing animal. Biochemical studies revealed that the expression of TCRzeta and LAT were reduced in lysates generated from CD8alpha-purified TIL with respect to CD8alpha-purified T cells from naive spleen. We believe that these degenerative changes are reflective of chronic T cell receptor ligation, because in vitro culture of rat splenocytes or purified T cells with ConA or anti-CD3 mAb induced the same alterations. In vitro, the downregulation of CD8beta could be inhibited by the caspase inhibitor, z-VAD. These results suggest that the aberrant CTL phenotype found in the TIL of glioma-bearing rats may be novel signals for their impending death and degenerating anti-tumor immune function.
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PMID:Cytotoxic T cells infiltrating a glioma express an aberrant phenotype that is associated with decreased function and apoptosis. 1157 May 81

These studies report the identification of a population of myeloid suppressor cells (MSC) that are preferentially enriched in the spleens and tumor-infiltrating mononuclear cells (TIMC) from T9.F-vaccinated animals. In this model designed to mimic immunotherapy for an established intracranial (i.c.) glioma, animals were given an i.c. inoculum with 5 x 10(4) T9 glioma cells at day 0, followed by a subcutaneous (s.c.) injection of 5 x 10(6) irradiated T9.F glioma cells 5 days later. Unexpectedly, we found that the survival of these T9.F-vaccinated animals was dramatically shorter than their age-matched counterparts who received only saline injections. Since MSC have previously been demonstrated to be associated with tumor progression, the question arose of whether MSC might play a role in the rapid tumor progression observed in this model. Analysis of the spleen cells and TIMC revealed an increase in the population of myeloid cells expressing granulocytic and monocytic markers. Both the polyclonal and tumor-specific proliferation of splenic T cells and tumor-infiltrating T lymphocytes (T-TIL) from T9.F-vaccinated animals were significantly inhibited in the presence of these myeloid cells. Furthermore, the adoptive transfer of MSC into animals bearing a 5-day T9 glioma caused rapid tumor progression. Reduced survival of the glioma-bearing vaccinated rats was associated with enhanced tumor growth, as well as with an increased density of T-TIL. However, purified T-TIL did not show any discernable signs of inherent defects in terms of their effector functions and T cell receptor (TCR) signal transduction protein levels. Therefore, we believe that an MSC population is responsible for inhibiting the anti-tumor T cell response, resulting in the enhanced growth of the i.c. glioma, and may represent a significant obstacle to immune-based therapies.
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PMID:Irradiated tumor cell vaccine for treatment of an established glioma. II. Expansion of myeloid suppressor cells that promote tumor progression. 1201 6

To enhance the efficacy of cellular immunotherapy for gliomas, we tested the concept of using proinflammatory cytokine treatment with interferon-gamma (IFN-gamma) or interleukin-1beta (IL-1beta) or both to render glioma cells more susceptible to cytolysis by alloreactive cytotoxic T lymphocytes (aCTL). The cytokines, separately or in combination, were able to upregulate major histocompatibility complex (MHC) class I antigen or intercellular adhesion molecule-1 (ICAM-1) on Fischer rat 9L gliosarcoma cells. 9L cells were incubated in vitro for 24, 48, or 72 h with varying concentrations of rat IFN-gamma (0-2000 U/ml) or recombinant human IL-1 (rHUIL-1) (0-1000 U/ml) or both. By 48 h, IFN-gamma (500 U/ml) maximally induced the percentage of positive expressing cells and the relative antigen density of MHC class I and ICAM-1 on 9L cells, whereas IL-1 induced only ICAM-1 expression. Simultaneous incubation of IL-1 with IFN-gamma did not further affect the induction of class I on 9L cells more than that achieved with IFN-gamma alone. 9L cells with upregulated MHC class I and ICAM-1 expression were more sensitive to lysis by aCTL in in vitro cytotoxicity assays, regardless of whether the precursor aCTL came from naive or from 9L-immunized rats. Furthermore, inhibition of 9L cytotoxicity in assays that included blocking antibodies to MHC class I or to ICAM-1 revealed that T cell receptor (TCR) interactions with MHC class I and that ICAM-1 interactions with lymphocyte function-associated-1 (LFA-1) antigen account for a portion of the glioma lysis by aCTL.
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PMID:Effects of IFN-gamma and interleukin-1beta on major histocompatibility complex antigen and intercellular adhesion molecule-1 expression by 9L gliosarcoma: relevance to its cytolysis by alloreactive cytotoxic T lymphocytes. 1258 94

By flow cytometry, a panel of 18 primary glioma cell explants exhibited high expression of class I HLA-A, B, C, but class II HLA-DR expression was absent. Freshly isolated normal brain cells displayed little or no HLA antigens. Alloreactive cytotoxic T lymphocytes (aCTL), sensitized to the HLA of the patient, were generated in a one-way mixed lymphocyte response (MLR). The specificity of aCTL was confirmed to be to target cells (patient glioma cells or lymphoblasts) expressing the relevant HLA antigens. However, nontumor patient-specific aCTL did not lyse normal brain cells. Titration of antibodies to HLA class I into cytotoxicity assays blocked lysis of gliomas by aCTL, confirming aCTL T cell receptor (TCR) interactions with the class I antigen on gliomas. Furthermore, aCTL interactions with glioma cells caused their apoptosis. Coincubations of aCTL with gliomas resulted in upregulated cytokine secretion. Importantly, dexamethasone, an immunosuppressive steroid used for brain edema, did not affect aCTL lytic function against tumor, indicating that steroid-dependent patients may benefit from the immunotherapy. We also explored the use of interferon-gamma (IFN-gamma) to increase aCTL tumor recognition. Coincubation of gliomas with exogenous IFN-gamma (500 U/ml, 48 h) caused a 3-fold upregulation of HLA class I and a slight induction of class II antigen expression. Gene-modified glioma cells producing IFN-gamma similarly displayed upregulated HLA expression. Glioma cells incubated with exogenous IFN-gamma or IFN-gamma-transduced glioma cells were more susceptible to lysis by aCTL than their parental counterparts, thus supporting the concept of combining IFN-gamma cytokine gene therapy with adoptive aCTL immunotherapy for brain tumor treatment.
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PMID:Human alloreactive CTL interactions with gliomas and with those having upregulated HLA expression from exogenous IFN-gamma or IFN-gamma gene modification. 1451 64

A CD8+ cytotoxic T lymphocyte (CTL) line was derived from the peripheral blood mononuclear cells of a patient with primary melanoma. The CD8+ CTL line specifically lysed the autologous primary melanoma cells and not the natural killer cell-sensitive K562 cells or lymphokine activated killer cell-sensitive DAUDI cells. When a large panel of human leukocyte antigen (HLA)-matched and -unmatched allogeneic melanoma, glioma, breast and colorectal carcinoma cells was tested as targets in cytolysis assays, 4 HLA-matched and two HLA-unmatched allogeneic metastatic melanoma lines were lysed by the CD8+ CTL. Lysis of autologous and allogeneic melanoma cells was dependent on the effector-to-target cell ratio. Lysis of autologous melanoma cells was not blocked by anti-HLA class I or class II antibodies, confirming that the cytolytic activity of the CD8+ CTL was HLA-unrestricted. CTL lysis of autologous melanoma cells was CD3 (T cell receptor) dependent and FAS-FAS-L, and CD1 independent. Identification of the melanoma-associated antigen recognized by the HLA-unrestricted CTL may provide a vaccine for a broad population of melanoma patients.
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PMID:CD8+, HLA-unrestricted, cytotoxic T-lymphocyte line against malignant melanoma. 1628 81


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