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At least 163 records · Page 9Linked to original sources
PubMed1992

Correlation between interferon (IFN) alpha resistance and deletion of the IFN alpha/beta genes in acute leukemia cell lines suggests selection against the IFN system.

Homozygous and hemizygous deletions of the interferon A (IFNA) and IFNB genes have been frequently observed in acute leukemia cell lines, primary acute leukemia cases, and gliomas. Because IFNs have an antiproliferative effect, selection against the IFN alpha/beta system could play a role or accompany the development of the malignant phenotype. Although the deletion of the IFNA/B genes could interrupt an autocrine loop that controls cell proliferation, cells would still respond to exogenous IFN alpha/beta and, thus, lesions at the receptor or signal transduction level should also be present to render cells resistant to exogenous IFN alpha/beta. To test if selection against the IFN system was operating in acute leukemias, the sensitivity to the antiproliferative effect of IFN alpha 2 was studied in acute leukemia cell lines with and without alterations of the IFNA/B genes. We found that 10 of 11 acute leukemia cell lines with alterations of the IFNA/B genes were resistant to the antiproliferative effect of IFN alpha 2, whereas only two of eight cell lines with normal IFNA/B genes were IFN-resistant. We then examined the possibility that an alteration of the receptor expression could account for the lack of response to IFN alpha 2. No significant alteration in the expression or structure of the IFN alpha receptor was observed. We also studied the downmodulation of the alpha subunit of the IFN alpha receptor upon IFN alpha 2 binding. One cell line with deletion of the IFNA/B genes showed impaired downmodulation of the IFN alpha receptor. The data presented here suggest that selection against the IFN alpha/beta system could play a role or accompany the development of the malignant phenotype.

Acute Disease↗
PubMedDate not supplied

The effects of interferon-alpha/beta in a model of rat heart transplantation.

Interferons have multiple immunologic effects. One such effect is the activation of expression of cell surface antigens. Interferon alpha/beta enhance expression of class I but not class II histocompatibility antigens. Contradictory information has been published regarding the effect of interferon-alpha/beta administration in patients with kidney transplantation. In a model of rat heart transplantation we demonstrated that administration of interferon-alpha/beta accelerated rejection in a dose-dependent fashion in the absence of maintenance cyclosporine. Animals treated with maintenance cyclosporine had evidence of increased rejection at 20 days that was resolved completely at 45 days with cyclosporine alone.

Animals↗
PubMed1992

Variations of lymphocyte sub-populations in vulvar condylomata during therapy with beta-interferon.

Several experiences induced us to consider genital HPV infection as an expression of a local immunodeficiency. The aim of our study was to research the effect of immunotherapy on the lymphocyte subpopulations and Langerhans cells in vulvar condyloma. Twenty women with persistent vulvar condylomata, treated with 2,000,000 IU/die of beta-interferon for 15 days, were submitted to vulvar biopsy before and 2-5 months after medical treatment. The frozen sections obtained were assayed with the following monoclonal antibodies: OKT4 (T helper lymphocytes), OKT8 (T suppressor lymphocytes), OKB7 (B lymphocytes) and S-100 protein (Langerhans cells). Using a morphometric evaluation, the average number of both intraepithelial and stromal lymphocyte subsets and of the intraepithelial Langerhans cells was assessed. In all the biopsies preceding the medical treatment we found a low number of T helper lymphocytes both in the epithelium and stroma, with inversion of T4/T8 lymphocyte ratio and rare presence of Langerhans cells. In patients with a good therapeutic response (50-100% of condyloma reduction) we observed an increase in intraepithelial T4 lymphocytes and a decrease in both intraepithelial and stromal T8 lymphocytes. In cases with persistent disease after therapy, the histological pattern was similar to that observed in the first biopsy, with the exception of a significant increase in the average number of Langerhans cells. Our data correlate the clinical response to the immunotherapy with the histology of lymphocyte subsets in the vulvar condylomata. The increase in Langerhans cells observed in patients with negative response may be interpreted with a probable inability of these cells to promote the immune reaction.

Adult↗
PubMed1992

[Detection of the deletion of interferon-alpha and beta genes in lymphoblastoid cells by PCR].

The HuIFN-alpha and beta genes were examined by the PCR method in the 11 human lymphoblastoid cell lines. The results showed that the homozygous deletion of HuIFN-alpha and beta genes was detected in 5 of 11 cell lines and in 5 of 11 cell lines, respectively. The deletions of both the HuIFN-alpha and beta genes were observed in 4 of 11 cell lines. One T cell leukemia cell line deleted only HuIFN-alpha gene, while the other T cell leukemia line deleted only HuIFN-beta gene. This suggests that the deletions of HuIFN-alpha and beta genes may be related the development of leukemia or lymphoma.

Burkitt Lymphoma↗
PubMed1992

Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes.

The promoter regions of many interferon-inducible genes share a short DNA sequence motif, termed the interferon consensus sequence (ICS) to which several regulatory proteins bind. A murine cDNA which encodes an ICS binding protein has been reported (M-ICSBP). The cloning of the human homologue of ICSBP (H-ICSBP) is described. H-ICSBP shares high sequence homology with its murine cognate. The derived sequence of H-ICSBP reveals restricted homology within the first 120 amino acids to three other interferon regulatory factors, IRF-1, IRF-2, and ISGF3 gamma. Truncated ICSBP lacking the first 33 amino-terminal amino acids fails to bind to the ICS, indicating that at least part of the DNA binding domain is located within the well conserved amino terminus. H-ICSBP is expressed exclusively in cell lines of hematopoietic origin. The results of transient transfection assays carried out either in hematopoietic or nonhematopoietic cells suggest that ICSBP acts as a negative regulatory factor on ICS-containing promoters. Furthermore, either interferon-gamma (IFN-gamma) or IFN-beta can alleviate the repression mediated by ICSBP. Therefore, ICSBP may be involved in maintaining submaximal transcriptional activity of IFN-inducible genes in hematopoietic cells. IFN treatment would then alleviate repression allowing maximal transcriptional activity of these genes.

Amino Acid Sequence↗
PubMed1992

Interferon regulatory factor-1 (IRF-1) activates the synthetic IRF-1-responsive sequence (GAAAGT)4 in Saccharomyces cerevisiae.

In appropriate mammalian cells, interferon regulatory factor-1 (IRF-1) can activate the virus-responsive element of the IFN-beta promoter (VRE beta") or the synthetic oligonucleotide (GAAAGT)4. The latter contains two copies of the functional equivalent of PRDI, one of the regulatory domains of VRE beta". We prepared yeast strains containing an IRF-1 expression plasmid under the control of the galactose-inducible Gal1 promoter and a reporter plasmid with either (GAAAGT)4, VRE beta", or other test sequences placed upstream of a minimal promoter linked to the beta-galactosidase coding sequence. Upon induction of IRF-1 expression, the (GAAAGT)4-containing promoter was activated, but VRE beta" and all other sequences tested were inactive. Our results showed that IRF-1 belongs to a class of higher eukaryotic transcription factors that can interact with the yeast transcriptional machinery. Our findings also raised the question why the duplicate PRDI-like sequences in (GAAAGT)4 can be activated by IRF-1 synthesized in yeast, but not VRE beta", which also contains at least two PRDI-like sequences.

Base Sequence↗
PubMed1992

Variations of lymphocyte sub-populations in vulvar condylomata during therapy with beta-interferon.

Several experiences induced us to consider genital HPV infection as an expression of a local immunodeficiency. The aim of our study was to research the effect of immunotherapy on the lymphocyte subpopulations and Langerhans cells in vulvar condyloma. Twenty women with persistent vulvar condylomata, treated with 2,000,000 IU/die of beta-interferon for 15 days, were submitted to vulvar biopsy before and 2-5 months after medical treatment. The frozen sections obtained were assayed with the following monoclonal antibodies: OKT 4 (T helper lymphocytes), OKT 8 (T suppressor lymphocytes), OKB 7 (B lymphocytes) and S-100 protein (Langerhans cells). Using a morphometric evaluation, the average number of both intraepithelial and stromal lymphocyte subsets and of the intraepithelial Langerhans cells was assessed. In all the biopsies preceeding the medical treatment we found a low number of T helper lymphocytes both in the epithelium and stroma, with inversion of T4/T8 lymphocyte ratio and rare presence of Langerhans cells. In patients with a good therapeutic response (50-100% of condyloma reduction) we observed an increase in intraepithelial T4 lymphocytes and a decrease in both intraepithelial and stromal T8 lymphocytes. In cases with persistent disease after therapy, the histological pattern was similar to that observed in the first biopsy, with the exception of a significant increase in the average number of Langerhans cells. Our data correlate the clinical response to the immunotherapy with the histology of lymphocyte subsets in the vulvar condylomata. The increase in Langerhans cells observed in patients with negative response may be interpreted with a probable inability of these cells to promote the immune reaction.

Adult↗
PubMed1992

Lack of expression of tumor-suppressor genes in human malignant glioma cell lines.

Human malignant gliomas (glioblastomas and anaplastic astrocytomas) are the most frequent brain tumors and are associated with a variety of genetic alterations including retinoblastoma (RB) and p53 gene mutations, loss of interferon alpha and beta (IFNA, IFNB) genes and lack of O6-methylguanine-DNA methyltransferase (MGMT) expression. Yet, in the studies performed to date, the relationship between these alterations has not been addressed. In this report, we have studied gene expression in 29 malignant glioma cell lines and have determined that, although loss of the interferon genes and loss of RB, p53 and MGMT mRNAs are frequent events, combinations of genetic alterations involving these four proven or putative tumor-suppressor genes are relatively infrequent. The exception was loss of RB mRNA, which may be associated with lack of MGMT mRNA.

Chromosome Deletion↗
PubMed1992

Lipopolysaccharide induces DNA binding activity specific for the IFN-stimulated response element in murine peritoneal macrophages.

Several murine macrophage genes that exhibit transcriptional response to LPS (e.g., IP-10, D3) have IFN-stimulated response element (ISRE) sequences present in regions flanking the transcription start sites. In the present study, the ability of LPS to activate proteins in murine peritoneal macrophages capable of binding to the ISRE has been investigated. Nuclear extracts from both LPS-treated and untreated macrophages are capable of forming four distinct complexes with a radiolabeled oligonucleotide containing the ISRE sequence as detected by electrophoretic mobility shift assays. LPS-treated nuclei contained an additional ISRE binding activity (complex I) that was not found in unstimulated cells. The induction of the latter activity by LPS was sensitive to polymyxin B sulfate, a lipid A antagonist, demonstrating that LPS was the primary inducing activity. All five retarded protein-DNA complexes formed were specific for the ISRE sequence as shown by competition with a series of oligonucleotides containing either ISRE-related or -unrelated sequences. Complex I binding activity was dependent upon the concentration of LPS and the time of LPS treatment. Furthermore, complex I was similar to that induced in response to treatment with IFN-beta in terms of electrophoretic mobility and specificity for the ISRE. LPS-induced complex I formation was partially independent of protein synthesis and could not be blocked by including neutralizing antibody to IFN-alpha/beta in the culture medium. Thus, even though LPS is a potent inducer of IFN-beta in murine macrophages, class I IFN expression may not be an obligatory intermediate event in the LPS-driven activation of ISRE binding activity. These results suggest that induction of ISRE binding activity may be an important part of the signaling process initiated by LPS.

Animals↗
PubMed1992

Interferon system in primary acute lymphocytic leukemia cells with or without deletions of the alpha-/beta-interferon genes.

Various aspects of the interferon (IFN) system were studied in malignant cells from 37 unselected patients with acute lymphocytic leukemia (ALL). It was found that leukemic cells from two of 37 patients had a complete loss of alpha- and beta-IFN genes, whereas cells from four of 37 had lost one of the alpha-/beta-IFN alleles. In 25 cases, viable cells were also available for functional studies. Cell clones with loss of one of the alpha-/beta-IFN alleles produced low amounts of IFN after virus induction in vitro. Some clones with an apparently normal set of IFN genes were unable to produce detectable amounts of IFN. All clones studied were found to carry high-affinity alpha-IFN receptors. In clones carrying deletions of IFN genes, the cells were sensitive to IFN in vitro as measured by alpha-IFN-induced enhancement of 2',5'-oligoadenylate synthetase (2',5'-A synthetase). Cells from four patients with an apparently normal set of IFN genes were insensitive to this effect of IFN. We conclude that of the 17 patients in which IFN genes, IFN production, alpha-IFN receptors, and IFN-induced enhancement of 2',5'-A synthetase were studied, nine (53%) showed some abnormality in their IFN system. This finding may add some support to the hypothesis that defects in the IFN system could be a step on the path to malignant transformation in ALL. Moreover, patients whose malignant cells carry IFN gene deletions or other defects in their IFN-producing capacity, but are still sensitive to exogenous IFN, could represent a subgroup of ALL with a greater likelihood of responding to IFN therapy.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Induction of intracellular and plasma 2',5'-oligoadenylate synthetase by pentostatin.

Similar to interferon alpha, pentostatin is highly effective in hairy cell leukemia and moderately active in other chronic lymphoid malignancies. In ten patients with hairy cell leukemia (HCL) and seven patients with other B-cell chronic leukemias (BCL), we have studied the intracellular 2',5'-oligoadenylate synthetase (2,5OAS) activity of the mononuclear cells before, 4 h, 24 h, and 48 h after pentostatin administration. In patients with HCL the median level of intracellular 2,5OAS increased 4.6-fold at 4 h and 11.5-fold at 24 h compared to the pretreatment value. Among the other seven patients, the median intracellular 2,5OAS remained unchanged in three patients and rose slightly by 2 to 14 times in four patients. Eleven patients (eight with HCL and two with BCL) responded to pentostatin. The median increase in 2,5OAS among the responders was 13.0-fold (range 4.8-30.0) whereas that among non-responders was 2.2-fold (range 0.2-6.3). The difference was highly significant (p less than 0.0001). In five of the total seventeen patients, the plasma levels of 2,5OAS activity were also determined and changes in plasma levels paralleled those measured intracellularly. To determine if the elevation of 2,5OAS is mediated by induction of interferon alpha, the expressions of mRNA for interferon alpha and beta were investigated by means of reverse transcription and polymerase chain reaction using the corresponding sense primers. In none of the five patients thus studied could we find an induction of mRNA for interferon alpha or beta in the leukemic cells during treatment with pentostatin. Thus, response to pentostatin correlates with induction of 2,5OAS directly and the 2',5'-oligoadenylate system seems to be involved in cytotoxicity.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Inhibition of Friend leukemia cell visceral metastases by a new monoclonal antibody and role of the immune system of the host in its action.

We developed a syngeneic mouse IgG2a monoclonal antibody (MAb) A9D41 directed against the Friend leukemia virus envelope gp70 antigen present on the cell surface membranes of virus producer 3C18 Friend leukemia cells (FLC). A9D41 showed a marked antitumor activity in DBA/2 mice given injections of gp70 positive 3C18 FLC, but it was ineffective in mice given injections of gp70 negative 745 FLC or unrelated tumor cells. A9D41 was particularly effective in inhibiting the development of 3C18 FLC liver and spleen metastases. MAb was also effective as adjuvant therapy in inhibiting visceral metastases after excision of an established s.c. FLC tumor, and combined therapy of A9D41 with mouse interferon alpha/beta was more effective than MAb or interferon alpha/beta alone. The immune system of the host played a decisive role in the antimetastatic action of A9D41. Thus, although MAb was cytotoxic for 3C18 FLC in vitro in the presence of rabbit complement, the F(ab')2 fragment was ineffective in vivo, and the antitumor effect of MAb was abolished in mice treated with an antibody to CD4 and diminished in natural killer cell-deficient beige and athymic nude mice. MAb-treated mice surviving injection of FLC developed an immune response to 3C18 FLC.

Animals↗
PubMed1992

[Basic research for interferon gene therapy against malignant glioma].

In order to establish new interferon therapy against malignant glioma by selective transfection of its gene, we developed a novel transfection system using liposomes bearing positive charges on their surface and entrapping plasmids containing the HuIFN- beta gene (pSV2IFN-beta). The liposomes were composed of N-(alpha -trimethylammonioacetyl) -didodecyl-D-glutamate chloride (TMAG), dilauroylphosphatidylcholine (DLPC), and dioleoylphosphatidylethanolamine (DOPE) as a molar ratio of 1:2:3. The liposomes were not observed to have cytotoxicity for human glioma cells, when applied at a rate less than 15nmol/ml. This liposome-mediated transfection of the gene into the cultured glioma cells (U-251-MG) resulted in the secretion of HuIFN- beta into the medium. The HuIFN- beta level in the culture media of glioma cells reached 23 IU/ml after 96h of incubation. When the pSV2IFN-beta containing liposomes were coupled with a monoclonal antibody (G-22 MCA) against glioma-associated antigen (G-22), the level of HuIFN-beta in the medium was 181 IU/ml, resulting in a 7-fold increase. It was indicated that this transfection system was a safe and selective method in the case of TMAG/DLPC/DOPE liposomes.

Brain Neoplasms↗