Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin 6 (IL-6)/hybridoma growth factor (HGF) has been shown to be the requirement for growth of murine hybridomas in vivo or in vitro. In this paper, two kinds of conditioned media (CM) from the culture supernatants of a human fibroblast cell line CRL1506 and a cloned Epstein-Barr virus (EBV) transformed human lymphoblastoid cell line (LCL) N23 were found to have IL-6 activity by strongly promoting the growth, antibody secretion (increase of one- to three-fold), and cloning efficiencies of heterohybridomas secreting human monoclonal anti-hemorrhagic fever with renal syndrome virus antibodies and LCL. Since these CM contained no detectable IL-2, and IL-4 had no effects on the growth of the cell lines, IL-6 was considered to be the main active component of the CM responsible for promoting hybridoma growth. This effect was further confirmed by IL-6-dependent cell line 7TD1 bioassay (IL-6 activity in the CM ranging from 1,000 to 10,000 units/ml). Moreover, we successfully established four EBV-transformed lymphoblastoid cell lines at single-cell level by adding an equal volume of CRL1506-CM to 10% FCS-RPMI1640 in limiting dilution. Finally, it is worth noting that the sensitivity of the heterohybridomas to the two kinds of CM was not the same and was not consistent with that of their parental myeloma cell lines. Thus, it suggests that the CM might contain more than one factor, and the choice of proper conditioned media should be very useful for human monoclonal antibody production.
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PMID:The effects of hybridoma growth factor in conditioned media upon the growth, cloning, and antibody production of heterohybridoma cell lines. 843 56

A group of 49 multiple myeloma patients, 20 men and 29 women, were evaluated. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17 beta-oestradiol (E) and testosterone (T) serum concentrations have been detected by radioimmunoassay. Peripheral blood lymphocyte proliferation in response to phytohaemagglutinin (PHA), concanavalin A (ConA), recombinant interleukin-2 (rIL-2) and dextran sulphate (DxS) was investigated. Our findings provide evidence for two different patterns of sex hormone changes and immune dysfunctions presented differently by male and female multiple myeloma patients. In men increased FSH, LH and E concentrations and an augmented E to T ratio were associated with decreased lymphocyte blastogenic response to PHA, ConA and increased proliferation to rIL-2 and DxS. Female patients with multiple myeloma demonstrated normal values of FSH, LH and T, but a diminished E level and decreased E to T ratio correlated with a lymphocyte normal response to PHA and ConA and augmented blastogenesis to IL-2 and DxS. Our data, while admittedly preliminary, suffice to provide an indication of sex hormone changes in multiple myeloma patients, which could be responsible, at least in part, for the immune dysfunction observed in multiple myeloma.
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PMID:Sex hormones and immune dysregulation in multiple myeloma. 843 82

Although the hairy cells (HCs) of hairy cell leukaemia (HCL) are now thought to be a form of activated B cell, they have long been known to possess certain monocytoid characteristics. Since the proto-oncogene c-fms is a feature of cells of the monocyte/macrophage lineage, we examined HCs for c-fms expression. We found that approximately 80% of peripheral blood HCs expressed the c-fms protein (8/8 cases). Expression of the 150 kD protein by HCs was shown using three different techniques, APAAP, immunofluorescence and immunoprecipitation, using two different antibodies. Other mature B cell lymphoproliferative disorders examined (PLL, CLL and multiple myeloma) did not express c-fms. We also examined the c-fms expression of normal B-cells: both the in vivo activated (low density) fraction of tonsil B cells and tonsil B cells activated in vitro with SAC plus IL-2 expressed the c-fms protein. As in the case of monocytes c-fms expression by HCs was shown to be down regulated by its ligand M-CSF, and by TNF alpha, both caused a decrease in the receptor expression from 80% to 30% and in the intensity of staining from 6 to 3 x 10(4) molecules/cell. However, as for monocytes, GM-CSF treatment of HCs had no effect on the expression of c-fms; alpha IFN also had no effect. M-CSF treatment of HCs also induced phosphorylation of c-fms, and a number of other proteins, on tyrosine. However, M-CSF was unable to induce HC proliferation either alone or in combination with IL-2, IL-4 or IL-6; in addition it had no effect on HC proliferation induced by SAC, anti-mu or TNF alpha. In addition, M-CSF either alone, or in combination with the above cytokines, had no effect on the differentiated state of HCs as shown by both immunoglobulin secretion and surface antigen expression. M-CSF also had no effect on the morphology or long-term survival of HCs in culture. This study therefore demonstrates that both HCs and activated B-cells express c-fms, and that M-CSF binds to and activates its receptor on HCs. Although c-fms and several other proteins were shown to be phosphorylated in response to M-CSF, the functional consequences of this phosphorylation remain unclear.
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PMID:C-fms protein expression by B-cells, with particular reference to the hairy cells of hairy-cell leukaemia. 830 20

In order to assess cytokine-producing cells at the single cell level, the cytokine-specific ELISPOT assay has proven to be an important and sensitive method. The purpose of this study was to adapt this method to elucidate individual cells producing murine IL-2, IL-4 or IL-6. In order to establish these cytokine-specific ELISPOT assays, IL-2-, IL-4- and IL-6-specific cDNA transfected myeloma cell lines, e.g., X63-Ag8-653 X2, X63-Ag8-653 X4 and X63-Ag8-653 X6, respectively, were used as specific cytokine-producing cells. In the IL-2 ELISPOT assay, the coating reagent, monoclonal antibody (mAb) rat IgG2a anti-mouse IL-2 (CR #40014) was used while rabbit IgG polyclonal anti-mouse IL-2 was employed for detection of IL-2 spot forming cells (SFC). The mAbs anti-mouse IL-4, BVD4-1D11 and BVD6-24G2 were selected as capture and detection antibodies for enumeration of IL-4 SFC. For the IL-6 ELISPOT assay, anti-mouse IL-6 (MP5-20F3) mAb was used for coating and MP5-32C11 mAb was used for detection of IL-6 SFC. When IL-2 producing X63-Ag8-653 X2 cells were subjected to these three different ELISPOT assays, IL-2-specific SFC were only noted with the IL-2 ELISPOT system. In the case of IL-4 SFC, only X63-Ag8-653 X4 cells formed specific spots using the tandem of BVD4-1D11 and BVD6-24G2 mAbs. IL-6-specific spots developed in MP5-20F3 mAb pre-coated wells containing X63-Ag8-653 X6 cells, when developed with mAb anti-IL-6 (MP5-32C11). Addition of cycloheximide (50 micrograms/ml) inhibited formation of IL-2, IL-4 and IL-6 SFC by approximately 90%. When an unrelated mAb was used as detection antibody in these three different cytokine-specific ELISPOT assays, IL-2-, IL-4- and IL-6-specific SFC were not detected. Further, when concanavalin A stimulated T cells from Peyer's patch of normal mice were subjected to the respective cytokine-specific ELISPOT assay, IL-2, IL-4 and IL-6 SFC were enumerated. These results have shown that cytokine-specific IL-2, IL-4 and IL-6 ELISPOT assays have now been established and will allow analysis of the frequency of cytokine-secreting cells at the single cell level.
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PMID:Cytokine-specific ELISPOT assay. Single cell analysis of IL-2, IL-4 and IL-6 producing cells. 845 5

Freshly isolated human peripheral blood mononuclear cells (PBMC) were immunomagnetically depleted of CD56+ cells. When these CD56- PBMC populations were cultured in the presence of autologous donor serum, polyclonal activation with IL-2 and pokeweed mitogen (PWM) generally resulted in exclusive production of IgG antibodies. Fusion with SP2/O-Ag14 mouse myeloma cells was highly efficient and yielded a great number of IgG-producing heterohybridomas. These conditions were used for in vitro immunization with viable human HT29 tumor cells. After fusion, an increase in hybridoma clones producing IgG monoclonal antibodies (MAb) with HT29 specificity showing a higher portion of MAb binding to the surface of viable HT29 cells was recorded. This immunizing efficiency was not observed with HT29 membrane protein fractions or HT29 proteins integrated into ISCOM particles. Investigations with human anti-alpha Gal antibodies showed that the IgG antibodies produced by the human/mouse heterohybridomas did not contain the mouse-specific Gal alpha 1-3Gal epitope.
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PMID:Optimizing production of human monoclonal IgG antibodies by in vitro-primed human PBMC: influence of CD56+ NK cell depletion. 852 52

The recovery of immunoregulatory cells in the peripheral blood of patients with multiple myeloma receiving maintenance therapy with interferon alpha 2 beta (IFN-alpha 2 beta) after intensive therapy with high-dose melphalan and autologous bone marrow or peripheral blood stem cell rescue was studied. IFN-alpha 2 beta significantly inhibited the recovery of CD3+, CD4+, CD8+, CD56+/CD3- and CD16+/CD3- lymphocytes compared with numbers found in patients who had no further post-transplant treatment, but had no effect on the recovery of CD19+ cells. Among patients who did not receive IFN-alpha 2 beta, the number of CD8+, CD56+/CD3- and CD16+CD3- lymphocytes recovered to values similar to normal volunteers with increasing time after intensive therapy, however the number of CD4+ cells remained significantly below levels found in normal volunteers. Although CD16+/CD3- and CD56+/CD3- cell numbers were reduced in patients receiving IFN-alpha 2 beta, natural killer (NK) activity was not affected. The levels of soluble interleukin 2 receptor (sIL-2R) were similar in all patients and IL-2 was not detected in any patient. At the time of writing, of the total of 69 patients, seven have relapsed, of whom three were receiving IFN-alpha 2 beta, however there was no correlation between the absolute numbers of any lymphocyte subset with imminent relapse. The data suggest that the recovery of a specific lymphocyte subset(s) in peripheral blood is unlikely to be associated with the maintenance of response after intensive therapy.
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PMID:Lymphocyte recovery and clinical response in multiple myeloma patients receiving interferon alpha 2 beta after intensive therapy. 854 12

Severe bronchial hyperresponsiveness to methacholine developed after intravenous therapy with OK-T3 and IL-2 in a patient with multiple myeloma, in whom no factors known to be associated with bronchial hyperresponsiveness were present. A substantial increase and activation of peripheral T-lymphocytes was observed after immunotherapy. Bronchial responsiveness and lymphocyte subsets both returned to normal baseline values 2 months after the patient was shifted to subcutaneous low dose administration of IL-2. The strict association between peripheral T-lymphocytes activation and the development of bronchial hyperresponsiveness suggests a causal relationship.
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PMID:Reversible bronchial hyperresponsiveness induced by OK-T3/IL-2 administration in a patient with multiple myeloma. 857 20

The polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS) syndrome is a rare multisystem disorder of obscure pathogenesis associated with osteosclerotic myeloma. Circulating levels of proinflammatory cytokines (tumor necrosis factor-alpha (TNF-alpha) interleukin-1 beta [IL-1 beta], IL-2, IL-6, and interferon-gamma [IFN-gamma]), anti-inflammatory cytokines (transforming growth factor beta 1 [TGF beta 1], IL-4, IL-10, and IL-13), the cytokine carrier protein alpha 2 macroglobulin, IL-1 receptor antagonist (IL-1ra), soluble TNF receptors (sTNFr) p55 and p75, and soluble IL-6 receptor (sIL-6r) were determined in 15 patients with POEMS syndrome and 15 with multiple myeloma. Patients with POEMS syndrome had higher serum levels of IL-1 beta, TNF-alpha, and IL-6 and lower serum levels of TGF beta 1 than did patients with multiple myeloma. Serum levels of IL-2, IL-4, IL-10, IL-13, IFN-gamma, alpha 2 macroglobulin, and sIL-6r were similar in both groups. IL-1ra and sTNFrs were increased in POEMS syndrome, but out of proportion to the increase of IL-1 beta and TNF-alpha. Serial evaluations in 1 patient showed that proinflammatory cytokine serum levels paralleled disease activity assessed by platelet count and neurologic involvement. Our results suggest that the manifestations of POEMS syndrome might be regarded as the result of a marked activation of the proinflammatory cytokine network (IL-1 beta, IL-6, and TNF-alpha) associated with a weak or even decreased (TGF beta 1) antagonistic reaction insufficient to counteract the noxious effects of cytokines.
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PMID:Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome. 860 36

CD3 engagement has been used as a surrogate for antigen-specific stimulation to trigger T cell effector functions. Exogenous IL-2 has been used to prolong and amplify CD3-induced T cell activation. Previous studies have been shown that CD3 reactivity is increased in cancer patients with preactivated (> 10% HLA-DR+) T cells in the peripheral blood. In this study, we report 9 courses of a single infusion of anti-CD3 mAb (OKT3) followed by continuous infusion of intermediate dose IL-2 in 4 cancer patients [2 multiple myeloma (MM), 1 B-cell lymphoma (NHL), 1 metastatic melanoma (ME)] with advanced disease and > 10% HLA-DR+ T cells in the peripheral blood. An increase of lymphocytes, equally distributed between CD4+ and CD8+ subsets, was observed during treatment. Activation was phenotypically documented by the emergence of CD25+ cells in the peripheral blood. Unexpectedly, functional studies [including proliferation to mitogens (PHA, OKT3) and cytotoxicity assays (NK and LAK activities)] did not parallel phenotypic data and a slight decrease of all functions was observed after OKT3 and IL-2 treatment. OKT3 and IL-2 infusions were well tolerated and no limiting toxicity was observed. The treatment did not revert tumor progression in the 2 patients with progressive disease (NHL, ME) and had only minimal effects in the 2 MM patients with stable disease. These data indicate that the sequential administration of OKT3 and IL-2 had no anti-tumor activity in this small series of patients with advanced cancer who were selected for treatment because of an increased number of HLA-DR+ T cells in the peripheral blood. A discrepancy was observed between the emergence of CD25+ T cells and the clinical outcome.
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PMID:Clinical and immunological studies in advanced cancer patients sequentially treated with anti CD3 monoclonal antibody (OKT3) and interleukin-2. 872 15

The monoclonal antibody (MAb) G250 binds to a tumour-associated antigen, expressed in renal cell carcinoma (RCC), which has been demonstrated to be a suitable target for antibody-mediated immunotherapy. A bispecific antibody having both G250 and anti-CD3 specificity can cross-link G250 antigen-expressing RCC target cells with T cells and can mediate lysis of such targets. Therapy studies with murine antibodies are limited by immune responses to the antibodies injected (HAMA response), which can be decreased by using chimeric antibodies. We generated a chimeric bispecific G250/anti CD3 MAb by transfecting chimeric genes of heavy and light chains for both the G250 MAb and the anti-CD3 MAb into a myeloma cell line. Cytotoxicity assays revealed that the chimeric bispecific MAb was capable of mediating lysis of RCC cell lines by cloned human CD8+T cells or by IL-2-stimulated peripheral blood lymphocytes (PBLs). Lysis mediated by the MAb was specific for target cells that expressed the G250 antigen and was effective at concentrations as low as 0.01 microgram ml-1. The chimeric bispecific G250/anti-CD3 MAb produced may be an effective adjuvant to the currently used IL-2-based therapy of advanced renal cell arcinoma.
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PMID:Generation of chimeric bispecific G250/anti-CD3 monoclonal antibody, a tool to combat renal cell carcinoma. 879 76


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