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Biomedical subjects

B Klein

Publications and source records attributed to B Klein.

At least 37 records · Page 2Linked to original sources
PubMed1996

[Use of interferon alpha in multiple myeloma].

Alpha Interferon has been used for fifteen years in the management of patients with multiple myeloma. However this indication remains controversial. Seven multicenter randomized trials have compared alpha Interferon with observation in patients responding to conventional chemotherapy. Three of these studies have given negative results. In the other four, alpha Interferon therapy has prolonged remission duration but in none of them has the overall survival been significantly prolonged. After intensive treatments the results of only one study are available and are in favour of alpha Interferon. Seven randomized studies have tested the impact of a combination chemotherapy plus alpha Interferon as compared to chemotherapy alone. Only one has shown a significant benefit for patients receiving chemotherapy plus natural alpha Interferon. This benefit has been limited of IgA and BJ myelomas and to stage II myelomas. Finally, the combination high dose dexamethasone-alpha Interferon has given promising preliminary results which justify prospective ongoing studies. These clinical results are analyzed in relation to the in vitro data.

Antineoplastic Agents↗
PubMed1996

Molecular cloning and sequencing of trypsin cDNAs from Penaeus vannamei (Crustacea, Decapoda): use in assessing gene expression during the moult cycle.

Trypsin is the most abundant protease in Crustacea. This enzyme was purified from the digestive gland of Penaeus vannamei, revealing three major isoforms (molecular weights 31-32 kDa) and several minor components. Five cDNAs encoding five isoforms of trypsin were detected by two successive screenings of an amplified cDNA library from the digestive gland of P. vannamei. The longest isolated and sequenced cDNA encoded a preproenzyme of 255 amino acids containing a putative precursor peptide of 14 residues and a highly hydrophobic signal sequence of 14 amino acids. Amino acid sequence alignments revealed a high degree of identity between the trypsin from P. vannamei and that from crayfish (74%) and an equal level of sequence similarity to that from mammals and insects (approximately 40). Dot blot hybridization and subsequent analysis of the variation in trypsin-specific activities revealed that mRNA expression is at a maximum during early premoult (D1), declining sharply in late premoult (D2-D3). The specific activity of trypsin also followed this pattern, suggesting the regulation of trypsin biosynthesis is, at least in part, transcriptional. The characterization of trypsin cDNA from P. vannamei provides the first description of a putative zymogen sequence in a crustacean species, enabling us to elucidate the regulatory mechanism of trypsin synthesis in these important marine organisms.

Amino Acid Sequence↗
PubMed1996

A plasmocyte selective monoclonal antibody (B-B4) recognizes syndecan-1.

We developed a new monoclonal antibody. B-B4, which specifically identifies human plasma cells. It strongly reacts with all multiple myeloma cell lines and with malignant plasma cells of all tumour samples of the multiple myeloma patients tested. B-B4 does not react with any peripheral blood, bone marrow or tonsil cells. Cloning of the B-B4 antigen reveals that the monoclonal antibody recognizes syndecan-1. It appears that the monoclonal antibody B-B4 is a suitable marker for human plasmocyte identification among haemopoietic cells and a useful probe for the diagnosis of haematological malignancies. Furthermore, this monoclonal antibody can be used for depletions prior to CD34 grafting.

Antibodies, Monoclonal↗
PubMed1996

Identification of a novel antigenic structure of the human receptor for interleukin-6 involved in the interaction with the glycoprotein 130 chain.

The receptor for interleukin-6 (IL-6) is characterized by a ligand-binding glycoprotein 80 (gp80) transmembrane chain (IL-6R) which associates with a signal-transducer gp130 chain. We previously raised a series of monoclonal antibodies (mAb) recognizing different epitopes of the human IL-6R and interfering with the function of the receptor. One of them, M182, was able to diminish the proliferation of IL-6-dependent plasmacytoma cell lines although it was found unable to inhibit the binding of IL-6 to its receptor. Using an enzyme-linked immunosorbent assay for measuring the binding of IL-6 IL-6R to the gp130 chain, we showed that M182 was directed against a structure directly involved in the IL-6R gp130 interaction. M182 was able to potentiate the inhibitor effect of anti-IL-6R mAB which interfere with the binding of IL-6, leading to complete inhibition of the proliferation of IL-6-dependent cell lines. M182 was also found to synergize with inhibitory anti-IL-6 mAb. Therefore this structure appears to be an important regulatory domain of the IL-6R and a valuable target for inhibiting IL-6 signalling.

Antibodies, Monoclonal↗
PubMed1996

Correlation between tumour and serum beta 2m expression in patients with breast cancer.

HLA class I antigens are composed of a major histocompatibility complex (MHC) encoded heavy chain that is associated non-covalently with a light chain beta-2 microglobulin (beta-2m). When the HLA complex is metabolized, beta-2m is shed into the serum. A large variety of human and experimental tumours have altered MHC class I expression. In a previous study we observed elevated mean beta-2m serum levels in breast cancer patients, as compared to controls. To study the relationship between tumour expression and serum levels, we examined 54 patients with breast cancer. Tumour beta-2m was determined by immunohistochemistry and serum levels by the ELISA technique. Of the 54 patients, 38 had low and 16 had high beta-2m expression on the tumour. There was a significant correlation between tumour beta-2m and serum beta-2m levels (P = 0.02), with patients whose tumours expressed high beta-2m having high serum beta-2m levels. There was an inverse correlation between tumour grade and tumour beta-2m expression which approached statistical significance (P = 0.06). These findings suggest that in a substantial number of patients the high serum levels derive from shedding of beta-2m from tumour cells. These levels may have implications for tumour growth and metastases due to influences on immunological responses.

Adult↗
PubMed1996

Immunohistochemical study of pancreatic neuroendocrine tumor in Panthera tigris tigris.

The histological and immunohistochemical characteristics of a case of pancreatic neuroendocrine tumor are described in a 14-yr-old female Bengal tiger (Panthera tigris tigris) housed at the New Biblical Zoo of Jerusalem, Jerusalem, Israel, 1994. The neoplastic cells were immunohistochemically negative for insulin and glucagon, slightly positive for neuron-specific enolase, moderately positive for serotonin and somatostatin, and markedly positive for chromogranine A and gastrin. This is the first documentation of a pancreatic neuroendocrine tumor in the tiger.

Animals↗
PubMed1996

A ciliary neurotrophic factor-sensitive human myeloma cell line.

We obtained a human myeloma cell line (XG4-CNTF) whose growth was completely dependent on addition of ciliary neurotrophic factor (CNTF). Half-maximal proliferation was induced by adding 20 pg/mL CNTF. Response to CNTF correlated with expression of membrane CNTF receptor alpha-chain (CNTFR alpha), as shown by PCR analysis and immunostaining with anti-CNTFR alpha antibodies. CNTF-induced proliferation was completely inhibited by antibodies to gp130 interleukin-6 (IL-6) transducer, unlike antibodies to IL-6 or IL-6 receptor (IL-6R). Growth of XG4-CNTF cells using the gp130 IL-6 transducer was also supported by other cytokines: IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OM). This cell line should be very useful for studying the interactions of IL-6-related cytokines with their receptors.

Antibodies↗
PubMed1996

HLA class I antigen expression in human solid tumors.

The expression of HLA class I antigens was studied by immunohistochemistry in various tumors in correlation with clinicopathologic characteristics. Reduced expression was observed in germ cell testicular cancer, kidney, prostate, gastric and colon cancer, and was associated with tumor aggressiveness, grade and penetration of the tumor through the organ wall. In bladder cancer reduced expression was associated with poor survival. Irradiation of brain tumors resulted in an increase in class I expression. Soluble class I levels were studied in breast and colon cancer patients and were found to be high in those with metastatic disease. The clinical relevance of reduced class I levels are discussed.

Gene Expression Regulation, Neoplastic↗
PubMed1995

Interleukin-10 induces interleukin-11 responsiveness in human myeloma cell lines.

Interleukin (IL)-6-dependent human myeloma cell lines (HMCL) can be reproducibly obtained from patients with multiple myeloma and terminal disease. The growth of some of these HMCL can also be supported by IL-11. We show that IL-11-responsive, but not -unresponsive, HMCL expressed the gene of human IL-11 receptor (IL-11R) and produced an autocrine IL-10. All HMCL expressed the IL-10 receptor. In addition, IL-10 induced IL-11R gene expression and conferred IL-11 responsiveness on unresponsive HMCL. The ability of HMCL to produce IL-10 was strictly correlated with the capacity of the original patient's myeloma cells to produce IL-10 or not, and with the presence or absence of IL-10 in the patient's plasma.

Cell Line↗
PubMed1995

Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments.

A major limitation on the therapeutic use of cytokine antagonists is that the amount of cytokine to be neutralized in vivo is not presently known. We previously reported that anti-interleukin-6 (IL-6) monoclonal antibody (MoAb) administered to a patient with multiple myeloma (MM) induced high amounts of IL-6 to circulate in the form of monomeric immune complexes. Based on this observation, the present study developed a new methodology to estimate daily IL-6 production in 13 patients with MM or renal cancer who received anti-IL-6 MoAb. Treatment was considered effective when the production of C-reactive protein (CRP) was inhibited. The production of this acute-phase protein by hepatocytes is dependent on the activation of IL-6 gp130 transducer. Inhibition of tumor proliferation was also evaluated in patients with MM. In 7 of 13 patients whose CRP production was completely inhibited (> 96%) and who showed some antitumoral effects, whole-body IL-6 production in vivo was less than 18 micrograms/d (median, 5.7 micrograms/d; range, 0.5 to 17.5 micrograms/d). In the other 6 patients, subtotal inhibition of CRP production and a lack of antitumoral response were associated with high IL-6 production (median, 180 micrograms/d; range, 18 to 358 micrograms/d). These in vivo observations were consistent with mathematical modeling that predicted that anti-IL-6 MoAb treatment would be efficient only in low IL-6 producers. These data indicate the difficulty of neutralizing IL-6 with a single anti-IL-6 MoAb in vivo and call for new strategies to avoid accumulation of IL-6 in the form of stable immune complexes.

Antibodies, Monoclonal↗
PubMed1995

Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma.

In patients with advanced multiple myeloma (MM) there is an excess of production of interleukin-6 (IL-6) in vivo, and elevated serum levels are associated with plasmablastic proliferative activity and short survival. These data prompted us to perform a clinical trial with a murine anti-IL-6 monoclonal antibody (MoAb) to neutralize the excess of this putatively deleterious factor in these patients. Ten MM patients with extramedullary involvement frequently were treated with anti-IL-6 MoAb. The MoAb was administered intravenously to 9 patients; 1 patient with malignant pleural effusion received intrapleural therapy. Of the 3 patients who succumbed to progressive MM after less than 1 week of treatment (including the only 1 treated locally), 2 with evaluable data exhibited marked inhibition of plasmablastic proliferation. Among the 7 patients remaining more homogeneous receiving the anti-IL-6 MoAb for more than 1 week, 3 had objective antiproliferative effect marked by a significant reduction of the myeloma cell labelling index within the bone marrow. One of these 3 patients achieved a 30% regression of tumor mass. However, none of the patients studied achieved remission or improved outcome as judged by standard clinical criteria. Of major interest, objective antiproliferative effects were associated with complete inhibition of C-reactive protein (CRP) synthesis and low daily IL-6 production in vivo. On the other hand, the lack of effect in 4 patients was associated with a higher IL-6 production and inability of the MoAb to neutralize it. Anti-IL-6 was also associated with resolution of low-grade fever in all the patients and with worsening thrombocytopenia and mild neutropenia. The generation of human antibodies to Fc fragment of the murine anti-IL-6 MoAb observed in 1 patient was associated with dramatic progression. These data show that anti-IL-6 MoAb can suppress the proliferation of myeloma cells and underscore the biologic role of IL-6 for myeloma growth in vivo. Furthermore, suppression of CRP and worsening of neutropenia/thrombocytopenia both indicate that IL-6 is critically involved in acute-phase responses and granulopoiesis/thrombopoiesis.

Acute-Phase Reaction↗
PubMed1995

Interleukin-10 is a proliferation factor but not a differentiation factor for human myeloma cells.

Because interleukin-10 (IL-10) is a potent differentiation factor of human B cells into mature plasma cells, we investigated its effect on human malignant plasma cells. IL-10 did not induce any differentiation and increase in Ig synthesis in four human IL-6-dependent malignant plasma cell lines. However, it stimulated the proliferation of two of four cytokine-dependent cell lines in the absence of IL-6 and IL-10-dependent myeloma cell lines have been obtained. The myeloma cell growth activity of IL-10 was unaffected by anti-IL-6 and anti-IL-6R antibodies. Similarly, IL-10 stimulated (P = .001) the proliferation of freshly-explanted myeloma cells in IL-6-deprived cultures of tumor samples from patients with active multiple myeloma (MM) and produced twice as many myeloma cells in these cultures. Again, this cytokine was unable to induce further differentiation (assessed by rate of Ig production) of fresh myeloma cells. A very sensitive enzyme-linked immunosorbent assay (ELISA; 1 pg/mL) only rarely detected IL-10 in the sera of MM patients (3 of 89). On the contrary, serum IL-10 was detected in 60% of patients with plasma cell leukemia (12 of 20). These data show that IL-10 is an IL-6-unrelated growth factor for malignant plasmablastic cells. This cytokine could be involved in the late phase of MM in vivo.

Cell Differentiation↗
PubMed1995

Potent interleukin 3 receptor agonist with selectively enhanced hematopoietic activity relative to recombinant human interleukin 3.

A systematic evaluation of structure-activity information led to the construction of genetically engineered interleukin 3 (IL-3) receptor agonists (synthokines) with enhanced hematopoietic potency. SC-55494, the most extensively characterized member of this series, exhibits 10- to 20-fold greater biological activity than recombinant human IL-3 (rhIL-3) in human hematopoietic cell proliferation and marrow colony-forming-unit assays. In contrast, SC-55494 is only twice as active as rhIL-3 in priming the synthesis of inflammatory mediators such as leukotriene C4 and triggering the release of histamine from peripheral blood leukocytes. The enhanced hematopoietic activity of SC-55494 correlates with a 60-fold increase in IL-3 alpha-subunit binding affinity and a 20-fold greater affinity for binding to alpha/beta receptor complexes on intact cells relative to rhIL-3. SC-55494 demonstrates a 5- to 10-fold enhanced hematopoietic response relative to its ability to activate the priming and release of inflammatory mediators. Therefore, SC-55494 may ameliorate the myeloablation of cancer therapeutic regimens while minimizing dose-limiting inflammatory side effects.

Amino Acid Sequence↗