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PubMed1992

Multiple myeloma complicated by congestive heart failure following first administration of recombinant alpha-interferon.

A 59-year-old female was admitted to Tsukuba University Hospital and diagnosed as IgA-lambda multiple myeloma (stage IIIA). No cardiovascular disorder with the exception of minor ischemic changes in ECG was revealed before treatment. Recombinant human alpha-interferon (IFN) at a dose of 3 million units combined with melphalan and prednisolone was administrated. Sixteen hours after the first administration of IFN, IFN was suspended by the symptoms of congestive heart failure (CHF). Treatment with diuretics and catecholamine products showed almost complete recovery from CHF in 3 weeks. An adverse reaction to IFN was strongly suspected as the cause of CHF.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1989

Cloning and expression of cDNA encoding ovine trophoblastin: its identity with a class-II alpha interferon.

The cDNAs encoding ovine trophoblastin (oTP) were isolated from an ovine embryo cDNA lambda gt 11 library by screening with a synthetic 29-mer oligodeoxynucleotide corresponding to amino acid (aa) residues 34 to 43 of oTP. The cDNA contained an open reading frame of 595 bp and the deduced amino acid sequence indicates a protein precursor of 195 aa. Nucleotide and amino acid sequence comparisons establish that oTP shares extensive homology with alpha-interferon (IFN-alpha) but is more closely related to the IFN-alpha sII subfamily. When the oTP cDNA was cloned into an eukaryotic expression vector and transfected in monkey COS cells, a high level of antiviral activity was detected. RNA blot analyses of total RNA reveal that the oTP-coding gene is expressed during a relatively short period (eleven to 21 days). The abundant expression of oTP mRNA corresponds closely to the time at which the embryo acts to extend luteal lifespan. RNAs homologous to oTP were also detected in goat and cow embryos at equivalent periods of their development, but not in the pig.

Amino Acid Sequence↗

PubMed1991

Genotypic and phenotypic evidence of T-cell leukemia in a patient successfully treated by interferon-alpha for typical hairy cell leukemia.

A 53-year-old man was diagnosed to have typical hairy cell leukemia. Immunophenotyping of frozen splenic tissue showed clonality of hairy cells for mu lambda, confirmed by the corresponding immunoglobulin gene rearrangements. The patient was successfully treated with interferon-alpha (IF-alpha). In the fifth year of treatment with IF-alpha the morphology of peripheral blood mononuclear cells (PBMC) and of bone marrow infiltration changed with the appearance of numerous small to intermediate shaped lymphocytes of a T-helper phenotype. Frank leukemia, resistant to IF-alpha treatment and ultimately aggressive chemotherapy, developed. Emergence of this second clonal disease was confirmed by rearrangement studies performed on PBMC; rearrangements of both alleles of the TCR beta were identified, whereas the JH and lambda IVS genes were in germline configuration. The outgrowth of a second, malignant T-cell clone paralleled by the disappearance (down-regulation?) of the initial B-cell clone while under cytokine treatment is consistent with the possibility that IF-alpha favoured the emergence of this second clone.

Bone Marrow↗

PubMedDate not supplied

Effect of preinduction specific growth rate on recombinant alpha consensus interferon synthesis in Escherichia coli.

The effect of preinduction specific growth rate on the yield of recombinant alpha consensus interferon in Escherichia coli K-12 was investigated. The cells used in the investigation contain a temperature-sensitive, walkaway plasmid bearing an insert that codes for alpha consensus interferon. Transcription of the recombinant gene is controlled by a lambda repressor/pL promoter system. The lambda promoter is regulated by the temperature-sensitive gene cI857 at 30 degrees C, but at 42 degrees C the promoter is derepressed. The cells were grown under glucose-limited conditions in a chemostat at pH 7 and 30 degrees C. Once steady state was achieved, the vessel temperature was raised to 42 degrees C and a fed-batch mode was initiated. Six dilution rates ranging from 0.025/h to 0.2/h were investigated. Cell dry weight, alpha consensus interferon content, glucose concentration, acetate concentration, and plasmid stability were measured. At each dilution rate, the expression level of alpha consensus interferon (g/g of cell dry wt) reached its maximum value approximately 3 h after induction. In addition, the expression level of alpha consensus interferon increases 4-fold as the dilution rate prior to induction is increased from 0.025/h to 0.2/h. Consequently, the expression of recombinant protein produced by E. coli is dependent on the preinduction specific growth rate.

Acetates↗

PubMedDate not supplied

Construction of a modified murine interferon alpha with increased stability.

The mutant [Ser86] murine interferon alpha A was constructed by oligodeoxyribonucleotide-directed site-specific mutagenesis and expressed under the control of lambda phage PL promoter in Escherichia coli. The effect of the substitution of serine for the cysteine residue at position 86 in the murine interferon alpha A was studied. It was observed that the mutant Ser86 murine interferon alpha A which does not contain the free cysteine residue in the peptide was inactivated more slowly than its parent with a free cysteine residue at position 86. Heat-inactivated murine interferon alpha A cannot be reactivated, but the heat-inactivated Ser86 derivative can be reactivated significantly to about 27.5 per cent of the original activity in the presence of sodium dodecylsulfate. These results suggest that the free cysteine in the peptide is a factor contributing to the instability of the protein.

Bacteriophage lambda↗

PubMed1989

Cloning of murine interferon gamma receptor cDNA: expression in human cells mediates high-affinity binding but is not sufficient to confer sensitivity to murine interferon gamma.

A full-length cDNA encoding the murine interferon gamma (IFN-gamma) receptor was isolated from a lambda gt11 library using a human IFN-gamma receptor cDNA probe. The deduced amino acid sequence of the murine IFN-gamma receptor shows approximately 53% homology to its human counterpart but no homology to other known proteins. Murine IFN-gamma receptor cDNA was expressed in human HEp-2 cells, which do not bind murine IFN-gamma and are insensitive to its action. Transfectants displayed the same binding properties as mouse cells. The biological responsiveness of such transfectants to various biological effects of both human and murine IFN-gamma was investigated, including modulation of major histocompatibility complex class I and class II antigen expression, inhibition of cell growth, and antiviral activity. Like parental HEp-2 cells, these transfectants responded only to human, but not to murine, IFN-gamma. Inversely, mouse L929 cells transfected with human IFN-gamma receptor cDNA were insensitive to human IFN-gamma. These results confirm and extend previous findings, suggesting that species-specific cofactors are needed for IFN-gamma-mediated signal transduction.

Amino Acid Sequence↗

PubMed1992

[Rapid disappearance of M-protein in multiple myeloma complicated by pneumonia during treatment with HLBI].

A 64-year-old female was admitted for treatment of refractory myeloma (IgG-lambda). Because of severe liver cirrhosis, the patient was treated with interferon (IFN) alone (natural IFN 6 x 10(6) IR/day i.m. for 28 days). Pneumonia developed during IFN therapy. The IFN therapy was completed, restoring suppressed IgM and IgA to their normal ranges, while pneumonia was cured by antibiotics. Because the M-component remained, an additional IFN therapy was resumed and M-protein disappeared. As the period within which the M-component disappeared in this case was shorter than that reported previously, we supposed that the pneumonia might have enhance the effects of IFN. To verify this, we administered OK-432 for 4 weeks as a model of immunoactivation by pneumonia between two successive courses of IFN therapy when M-protein reappeared. To monitor the immune state, natural killer (NK) and lymphokine activated killer (LAK) activities were measured: NK activity suppressed by IFN was restored by OK-432 and was suppressed less by subsequent IFN administration. LAK activity was increased by IFN and OK-432. These observations suggested synergic effects of OK-432 on IFN-activated immunity. This case suggests that IFN combined with immunotherapy may be effective in some cases of myeloma.

Drug Administration Schedule↗

PubMed1992

Genes for beta-thromboglobulin and platelet factor 4 are closely linked and form part of a cluster of related genes on chromosome 4.

The small inducible gene (SIG) family encodes related proteins that are involved in the overlapping processes of coagulation, inflammation, immune response, and wound repair. This family contains two branches, termed CXC and CC, which are distinguished by whether or not the first two of four conserved cysteine residues are separated by an additional amino acid residue. All of the CXC SIGs map to chromosome 4, including those encoding beta-thromboglobulin (beta TG) and platelet factor 4 (PF4), both of which are expressed by megakaryocytes in a tissue-specific fashion. Both of these latter two genes have been previously reported to be duplicated, there being a PF4 and a PF4alt gene, and a beta TG1 and beta TG2 gene. We now show by pulse-field gel electrophoresis (PFGE) that the beta TG genes are closely linked to the PF4 genes and to other previously mapped CXC SIGs, namely IL8 (encoding interleukin-8), GRO1 (encoding a cytokine also called melanoma growth-stimulatory activity), and two related genes GRO2 and GRO3, on a single 700-kb Sfil fragment localized to chromosome bands 4q12-q13. The only CXC SIG not linked to this cluster is that encoding gamma-interferon-induced 10-Kd protein (INP10), which has been previously localized to 4q21. Analysis of lambda genomic clones demonstrate that the beta TG1 and PF4 genes are separated by less than 7 kb, and the beta TG2 and PF4alt genes by approximately 5 kb. Within each beta TG/PF4 duplication, the beta TG-like gene is upstream of its linked PF4-like gene. Thus, the beta TG/PF4 genes appear to form a close-linked complex expressed in a megakaryocyte-specific fashion. Further genomic studies may provide additional insights into the regulation of the tissue-specific expression of the beta TG/PF4 gene complex, while further analysis of the linked CXC SIG cytokine family may provide further understanding of their evolutionary history.

Autoradiography↗

PubMed1988

Depression in gene expression for poly(ADP-ribose) synthetase during the interferon-gamma-induced activation process of murine macrophage tumor cells.

A 2.7-kb cDNA clone coding for bovine poly(ADP-ribose) synthetase was isolated from a lambda gt11 expression library by direct immunological screening with an antiserum to the enzyme. The cDNA hybridizes to an approximately 3.8-kb bovine thymus polyadenylated RNA, which translates an immunoprecipitable 120-kDa protein with the antibody to the enzyme. The partial DNA sequence of the cDNA was determined and portions of the predicted amino acid sequence matched the sequence of 26 amino acids at the N terminal of the 41-kDa alpha-chymotryptic fragment and two cyanogen-bromide-cleaved peptides of the enzyme. A subcloned fragment from the coding region of the cDNA was used as a probe to estimate the level of mRNA for the enzyme during the interferon-gamma-induced activation process of the murine macrophage tumor P388D1 cell line. The amount of mRNA for the enzyme decreased nearly completely within 24 h after incubation in a medium containing interferon-gamma, while mRNA of the Ia antigen, one of the major histocompatibility gene products, was increased in the macrophage tumor cells by interferon-gamma as confirmed by the I-A beta cDNA as a probe. These results suggest that the gene expression for poly(ADP-ribose) synthetase is depressed during the interferon-gamma-induced activation process of macrophage tumor cells.

Amino Acid Sequence↗

PubMed1992

Molecular cloning of a cDNA coding for mouse liver xanthine dehydrogenase. Regulation of its transcript by interferons in vivo.

The cDNA coding for xanthine dehydrogenase (XD) is isolated from mouse liver mRNA by cross-hybridization with a DNA fragment of the Drosophila melanogaster homologue. Two lambda bacteriophage overlapping clones represent the copy of a 4538-nucleotide-residue-long transcript with an open reading frame of 4005 nucleotide residues, coding for a putative polypeptide of 1335 amino acid residues. Comparison of the deduced amino acid sequence of the mouse XD with those of the Drosophila and the rat homologues shows a high conservation of this protein (55% identity between mouse and Drosophila, and 94% identity between mouse and rat). RNA blotting analysis demonstrates that interferon-alpha (IFN-alpha) and its inducers, i.e. poly(I).poly(C), bacterial lipopolysaccharide (LPS) and tilorone (2,7-bis-[2-(diethylamino)ethoxy]fluoren-9-one), increase the expression of XD mRNA in liver. Poly(I).poly(C) also induces XD mRNA in several other tissues in vivo. Protein synthesis de novo is not required for the elevation of XD mRNA after IFN-alpha treatment, since cycloheximide does not block the induction. The elevation of XD mRNA concentration is relatively fast and precedes the induction of both XD and xanthine oxidase (XO) enzymic activities.

Amino Acid Sequence↗

PubMed1989

Establishment and characterization of a new human Burkitt's lymphoma cell line (WSU-BL).

A new human cell line, WSU-BL, was established from a malignant ascitic fluid occurring in a patient with Burkitt's lymphoma. The established line grows in a single-cell suspension with a doubling time of 19 hours and expresses L3 morphologic features by the French-American-British classification. Immunologic study revealed that WSU-BL cells express IgM-lambda both in the cytoplasm and on the surface and react with monoclonal antibodies to B-cell antigens (B1, B4, BL3, BL4, HLA-DR, and common acute lymphoblastic leukemia antigen [CALLA]). These cells are negative for T-cell and myeloid/monocyte antigens as well as Epstein-Barr virus nuclear antigen (EBNA). These results suggest that WSU-BL corresponds to an intermediate stage of B-cell differentiation. Both fresh tumor and WSU-BL cells had a hyperdiploid karyotype carrying the 8;14 chromosome translocation. Molecular studies showed that WSU-BL has a rearrangement of c-myc proto-oncogene and expresses c-myc RNA. Phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA) and interferon-gamma (IFN-gamma) were able to induce several phenotypic changes on WSU-BL cells. Two-dimensional gel electrophoresis of total cellular protein showed that either TPA or IFN-gamma induced both the synthesis or loss of several proteins. Analysis of the protein patterns indicated that some proteins were uniquely responsive to either TPA or IFN-gamma and others were common to both. This cell line should be valuable for future studies of cell proliferation, differentiation, and oncogenesis concerning this neoplasm.

Adult↗

PubMed1989

Cloning and expression of the cDNA for the murine interferon gamma receptor.

A murine interferon gamma (IFN-gamma) receptor cDNA was isolated by screening a murine T-cell hybridoma library prepared in lambda gt10 with probes prepared from a human IFN-gamma receptor cDNA. The 2.1-kilobase (kb) cDNA encoded a serine-rich polypeptide of 477 amino acids that was 52% identical to the human protein. Southern and Northern (RNA) blot analyses indicated the presence of a single receptor gene and a single predominant 2.3-kb receptor transcript. Human embryonic kidney fibroblasts, stably transfected with the murine IFN-gamma receptor cDNA, expressed murine IFN-gamma receptors as detected by flow cytometry with either ligand or a receptor-specific monoclonal antibody. Nontransfected cells bound neither ligand nor antibody. Radioligand-binding analysis demonstrated that the transfectants expressed 530,000 murine IFN-gamma receptors per cell and bound murine IFN-gamma with a Ka of 1 x 10(9) M-1. However, despite high-level expression of murine IFN-gamma receptors, the transfected human cells responded only to human and not to murine IFN-gamma as detected by enhancement of major histocompatibility class I antigen expression and induction of antiviral activity. These results thus document the isolation and expression of a full-length murine IFN-gamma receptor cDNA and suggest that additional species-specific components may be necessary to form a biologically active IFN-gamma receptor.

Amino Acid Sequence↗

PubMed1991

[IgG lambda-type multiple myeloma associated with myelofibrosis accompanied by thrombocytosis].

A 72-year-old male had complained of right back pain and bleeding from his tongue. He was admitted to our department on May 18, 1989. Physical examination revealed hepatosplenomegaly. Peripheral blood findings were as follows: RBC was 3.80 x 10(6)/microliters. Hb 12.2 g/dl, Ht 36.5%, platelet count 735 x 10(3)/microliters, WBC 22,100/microliters, leukoerythroblastosis present. Neutrophil alkaline phosphatase score was normal. Serum vitamin B12 and plasma platelet-derived growth factor level were elevated. Skeletal X-ray revealed multiple punched-out lesions at the 8th thoracic vertebra, and 6th and 8th ribs. Serum IgG level was 3,900 mg/dl. Serum immunoelectrophoresis revealed IgG lambda-type M-protein. Because he complained of severe cervical pain, and skeletal X-ray examination revealed the fracture of 6th cervical vertebra, the operation was performed to remove the lesion. Biopsy of cervical lesion revealed plasmacytoma. M-protein was decreased and the size of the tumor was reduced after treatment with VCAP (vincristine, cyclophosphamide, adriamycin, prednisolone) regimen and interferon-alpha for multiple myeloma.

Aged↗

PubMed1991

RNase E cleavage in the atpE leader region of atpE/interferon-beta hybrid transcripts in Escherichia coli causes enhanced rates of mRNA decay.

Chimeric transcripts containing the ribosome binding site of the Escherichia coli atpE gene and variants of the human structural interferon-beta gene are subject to RNase E processing in the 5'-untranslated atpE part of the transcripts. The absence of processing at two sites in the atpE leader-sequence caused by the RNase E deficiency in E. coli host N3431 leads to a considerable stabilization of the mRNA moiety. RNase E has originally been described as a processing enzyme for non-mRNAs such as precursor 5 S rRNA and RNA1, but cleavage mRNA substrates have also been reported. RNase E processing of the atpE gene leader sequence-containing transcripts leads to an increased rate of mRNA breakdown. The two RNase E-dependent processing sites in the atpE part of the mRNA transcripts exhibit some similarity to the other known RNase E processing sites. The influence of RNase E cleavage upon post-transcriptional regulation such as RNA stability and the efficiency of translational initiation is discussed.

Bacteriophage lambda↗

PubMed1989

Molecular cloning and characterization of complementary deoxyribonucleic acids corresponding to bovine trophoblast protein-1: a comparison with ovine trophoblast protein-1 and bovine interferon-alpha II.

Bovine trophoblast protein-1 (bTP-1) is a secreted glycoprotein that consists of several forms differing slightly in mol wt and isoelectric point. It is produced by bovine conceptuses after about day 15 of pregnancy and is believed to play a key role in signalling the presence of an embryo to the mother. In this study, a series of recombinant cDNA clones corresponding to the mRNA for bTP-1 have been isolated from cDNA libraries representing day 18-19 bovine conceptus poly(A)+ mRNA. Base sequencing of several cDNAs indicated that multiple mRNAs for bTP-1 exist. Northern blotting and primer extension experiments showed that the mRNAs average about 1 kilobase in length. One apparently full-length cDNA clone consisted of 1035 bases up to the beginning of the poly(A) tail. It contained an open reading frame of 195 codons which began at a position 79 bases from the 5' end. Its entire sequence was 85% identical to that of a cDNA for the immunologically related ovine trophoblast protein-1 (oTP-1) and about 79% identical to that for a bovine interferon-alpha II (IFN alpha II). The highest conservation of sequence (greater than 90%) was noted in the 3'-untranslated sequences of the bTP-1 and oTP-1 cDNAs. The deduced amino acid sequence of bTP-1 shared 80% identity with oTP-1, between 45-55% with human, rodent, porcine, and bovine IFNs of the alpha 1 subfamily and about 70% with a bovine IFN alpha II. A single potential site for N-glycosylation was noted at Asn78. These results show that bTP-1, like its ovine counterpart oTP-1, is structurally related to the IFN alpha S. We suggest that these embryonic IFNs play a role in controlling immunoreactions at the trophoblast-uterus interface as well as triggering other maternal responses to pregnancy.

Amino Acid Sequence↗

PubMed1987

Bacteriophage lambda cloning system for the construction of directional cDNA libraries.

We have developed a bacteriophage lambda cloning vector, lambda ORF8, that can be used for the construction of cDNA libraries. The wild-type lambda genome contains five BamHI, five EcoRI, and seven HindIII restriction sites that have all been removed from the genome of lambda ORF8. Sites for these endonucleases are present within the multiple cloning site of lambda ORF8. We report a method for preparing cDNAs that can be cloned in a single orientation in our phage vector. The method utilizes the synthesis of double-stranded cDNA, including priming of first-strand synthesis by oligo(dT). After completion of second-strand synthesis, a bifunctional oligodeoxynucleotide linker is ligated to the cDNA fragments. This linker, which contains a BamHI restriction site, will create a HindIII restriction site when ligated to the 3' end of cDNA fragments. Subsequent treatment of methylated cDNA with HindIII and BamHI endonucleases allows these fragments to be cloned directionally into lambda ORF8. To demonstrate the utility of this cloning system, we prepared a library from 5 micrograms of mRNA isolated from phytohemagglutinin-stimulated human peripheral blood lymphocytes. The primary library contained 2 X 10(8) plaque-forming phage, at least 80% of which contain inserts. A portion of the library was examined for the presence of gamma-interferon-related clones to verify the method had generated a library that was representative of phytohemagglutinin-stimulated peripheral blood lymphocytes. This simple and efficient cDNA cloning system significantly reduces the amount of RNA and effort required for the preparation of large directionally cloned libraries.

Bacteriophage lambda↗

PubMed1990

Characterization of new IgG lambda myeloma plasma cell line (EJM): a further tool in the investigation of the biology of multiple myeloma.

A new IgG lambda myeloma plasma cell line known as EJM was established from a peritoneal effusion from a patient with extramedullary myeloma. The EJM cells have a plasmablastic morphology with abundant rough endoplasmic reticulum and grow in liquid culture with a doubling time of 72 h and a labelling index of 36%. In addition to cytoplasmic IgG lambda, the cells are positive for CD9, 20, 32, 38, 44, 54, 71, 78, MHC Class II DR, DP and DQ. Studies on the control of the cell line proliferation by cytokines have demonstrated stimulation with interleukin 6. In contrast interferon alpha produces marked inhibition of proliferation in doses of greater than 100 units/ml. The culture conditions and the importance of accessory cells and cytokines in supporting myeloma plasma cell growth in vitro are discussed.

Ascitic Fluid↗

PubMed1990

A stimulatory monoclonal antibody detecting T cell receptor diversity among idiotype-specific, major histocompatibility complex-restricted T cell clones.

A panel of independent BALB/c T cell clones responding to a peptide of the lambda 2(315) immunoglobulin light chain (residues 91-101), in the context of I-Ed, has previously been described. A monoclonal antibody (mAb; GB113) to the T cell receptor (TcR) of one of the clones, 4B2A1 (V alpha 1, J alpha 19; V beta 8.2, D beta 1.1, J beta 1.2) precipitates the alpha/beta heterodimer from 4B2A1. However, GB113 does not bind DO11-10.2 cells bearing a similar alpha/beta heterodimer (V alpha 1.1, J alpha TT11; V beta 8.2, D beta 1.1, J beta 1.1). GB113 does not cross-react with the TcR of the six other clones in the panel. Furthermore, the mAb does not bind polyclonal lambda 2(315)-specific T cell lines except 4.4% of cells of line 4 from which 4B2A1 was cloned. The mAb only binds a negligible number (0.5%) of BALB/c thymocytes and peripheral T cells. Therefore, the epitope detected by GB113 is very rarely expressed on 91-101. lambda 2(315)-specific TcR or on TcR of normal T cells. Soluble GB113 induces T cell activation [measured as proliferation and interleukin (IL) 2, IL3 and interferon-gamma production]. GB113-induced T cell activation is enhanced by soluble anti-CD4 and anti-Thy-1 mAb.

Animals↗