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

An increasing amount of literature has been published concerning the interaction of the CD40 antigen and its ligand with regard to normal B cell ontogeny. In this review, an overview of the CD40 antigen and the CD40 ligand is given, focussing on their possible role in B cell malignancies. Data on the expression of the CD40 antigen on various B cell malignancies (acute and chronic leukemias, non-Hodgkin's lymphoma and multiple myeloma) are presented. The recently developed novel culture "CD40 system" is described. This system is a powerful tool used to culture normal B cells, but also most malignant B cells. We demonstrate in addition a more prominent role of the human Fc receptor presenting murine fibroblasts in the "CD40 system", especially in relation to cultured plasma cells. Finally, some important applications of the "CD40 system" are also summarized.
 ...
PMID:The role of the CD40 antigen on malignant B cells. 881 71

CD40 is a 48 kDa glycosylated phospoprotein that is a member of the tumor necrosis factor receptor (TNF-R) superfamily. CD40 was originally identified in B lymphocytes, and is found on monocytes, dendritic cells, some carcinoma cell lines, and the thymic epithelium. CD40 is expressed on normal pre-B through mature B stages of differentiation. For normal B cells, the cross-linking of CD40 induces cell cycle progression, long-term proliferation in vitro, IgE secretion, increased adhesion molecule (LFA-1) expression, and low level IL-6 secretion. The natural ligand of CD40 (CD40L, gp39, or T-BAM, for T-B cell activating molecule) was recently identified as an inducible molecule expressed transitionally on activated T cells. Although originally believed to be absent in normal and malignant plasma cells, CD40 has been demonstrated on the majority of myeloma cell lines and myeloma cells from plasma cell dyscrasia (PCD) patient specimens tested. CD40 activation modulated myeloma cell proliferation and clonogenicity in vitro, suggesting that the CD40 pathway is active in myeloma cell growth. For the IL-6 dependent cell line ANBL-6, CD40 activation was associated with autocrine IL-6 production. However, the IL-6 pathway does not appear to play a predominant role in CD40 activation of non-IL-6-dependent MM cell lines and patient primary bone marrow cultures. The possible pathophysiologic role of the CD40 receptor in human multiple myeloma is discussed.
 ...
PMID:CD40 and the effect of anti-CD40-binding on human multiple myeloma clonogenicity. 890 62

G28-5 sFv-PE40 is a single-chain immunotoxin targeted to CD40, which is highly expressed on human hematologic malignancies, including non-Hodgkin's lymphoma, B-lineage leukemias, multiple myeloma, and Hodgkin's disease, as well as certain carcinomas. In vitro analysis showed that this monovalent immunotoxin had a binding affinity of 3 nmol/L, within 15-fold of the bivalent parental monoclonal antibody. G28-5 sFv-PE40 was stable when incubated in mouse serum at 37 degrees C for 6 hours and cleared from the circulation of mice with a half-life of 16.7 minutes. This immunotoxin was effective in treating human Burkitt's lymphoma xenografted SCID mice with complete responses, defined by an asymptomatic phenotype for greater than 120 days, obtained at doses of 0.13 to 0.26 mg/kg. The efficacy of treatment was dependent on the schedule used, with every three days for five injections being the most effective tested. The toxicity of G28-5 sFv-PE40 was examined in SCID mice, rats, and monkeys, with the maximum tolerated dose being 0.48, 1.0, and 1.67 mg/kg, respectively. Comparative immunohistology showed that the G28-5 specificity was qualitatively similar between human and monkey tissue. In summary, G28-5 sFv-PE40 was effective at inducing complete antitumor responses in lymphoma xenografted mice at doses that were well tolerated in mice, rats, and monkeys.
 ...
PMID:In vivo efficacy and toxicity of a single-chain immunotoxin targeted to CD40. 919 73

We have previously demonstrated that CD40 stimulation induced a cellular growth arrest of the highly CD40-positive myeloma cell line XG2. To further characterize this inhibition of proliferation, we looked for a possible induction of apoptosis. Since no DNA fragmentation could be detected, we used newly described techniques that enable detection of apoptosis independently of DNA degradation, i.e. supravital exposure to propidium iodide (PI) and Annexin V labelling. We demonstrated that CD40 effectively induced programmed cell death. Furthermore, we have shown that CD95 (Fas) stimulation significantly enhanced the CD40-induced apoptosis.
 ...
PMID:CD40 and CD95 induce programmed cell death in the human myeloma cell line XG2. 920 15

Myeloma plasma cells constitute 10% to 90% of the total bone marrow cell count in patients with multiple myeloma (MM). These cells express a variety of cell surface markers, such as HLA-ABC and HLA-DR, and surface antigens that are necessary for professional antigen-presenting cells, including adhesion and costimulatory molecules. In this study, we examined the expression of major histocompatability complex (MHC) and costimulatory molecules on CD38(bright,++) plasma cells in bone marrow aspirates from eight MM patients. Small percentages of plasma cells expressed weak but detectable levels of HLA-DR, HLA-DQ, CD40, CD80, and CD86, which could be upregulated by interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha. CD38++ plasma cell and CD38(dim,+) cells were sorted from freshly isolated bone marrow mononuclear cells and tested for their capacity to act as antigen-presenting cells. Indeed, both CD38++ plasma cells and CD38+ cells were able to stimulate allogeneic T cells and present the soluble antigens purified protein derivative and tetanus toxoid to autologous T cells. Recognition of the antigens led to T-cell proliferation and secretion of IFN-gamma and was MHC class-I and -II restricted. Antigen processing and presentation by CD38++ and CD38+ cells were abolished by treatment of the cells with chloroquine. Hence, our study provides for the first time evidence that myeloma plasma cells may act as antigen-presenting cells. Further studies are warranted to examine in detail the molecules required for inducing T-cell stimulation.
 ...
PMID:Myeloma bone marrow plasma cells: evidence for their capacity as antigen-presenting cells. 929 30

The major limitation to the use of immunotoxins in the clinic is the toxicity associated with the toxin moiety. BD1-G28-5 single-chain Fv (sFv) is a single-chain immunotoxin targeted to human CD40 and consists of bryodin 1 (BD1), a plant ribosome-inactivating protein that is 20-30-fold less toxic in animals than commonly used toxins, fused to the sFv region of the anti-CD40 monoclonal antibody G28-5. This immunotoxin was expressed in Escherichia coli and purified from refolded inclusion bodies. BD1-G28-5 sFv retained the full protein synthesis inhibition activity of recombinant BD1 and specifically bound to CD40 with a binding affinity, kd, of 1.5 nM, within 10-fold of the bivalent parental monoclonal antibody. BD1-G28-5 sFv was potently cytotoxic against CD40-expressing B lineage non-Hodgkin's lymphoma and multiple myeloma cell lines, with EC50 values in the ng/ml range, but not against a CD40-negative T cell line. Interestingly, BD1-G28-5 sFv was not cytotoxic against CD40-expressing carcinoma cell lines that were sensitive to a BD1-based immunotoxin conjugate targeted to the Ley carbohydrate antigen. These data represent the first report indicating that BD1 can be used in the construction of potent single-chain immunotoxins. Additionally, although BD1-G28-5 sFv effectively killed CD40-expressing hematologic malignancies, its lack of activity against CD40-expressing carcinomas suggests that CD40-mediated trafficking of BD1 differs in the two cancer types.
 ...
PMID:Construction, expression, and characterization of BD1-G28-5 sFv, a single-chain anti-CD40 immunotoxin containing the ribosome-inactivating protein bryodin 1. 930 66

Eight myeloma cell lines with variable expression of bcl-2 were screened for the expression of the FAS antigen and for sensitivity to anti-FAS-induced apoptosis. Anti-FAS-induced apoptosis correlated positively (R = 0.89) with the level of expression of the FAS antigen, and was independent of the expression of bcl-2. Forced expression of bcl-2 in 8226 and ARP-1 multiple myeloma (MM) cell lines expressing relatively low levels of bcl-2, resulted in 1-2 log increase in resistance to dexamethasone (DEX)-induced apoptosis. However, sensitivity to anti-FAS-induced apoptosis was unchanged in ARP-1 cells or was increased in 8226 cells, compared to the parental cell lines. The increased sensitivity to anti-FAS-induced apoptosis in 8226 cells was due to the increase in FAS expression in the bcl-2 transfected cells and was proportionate to the increase in FAS expression. Furthermore, we observed manyfold increase in the expression of Fas, CD40, CD45 and CD19 antigens, in 8226 cells, concomitant with a significant decrease in the expression of CD38 antigen. Thus, 8226 cells overexpressing bcl-2 appear to have an immature myeloma cell phenotype, have higher growth-rate and increased sensitivity to anti-FAS-induced apoptosis.
 ...
PMID:Fas (APO-1/CD95)-mediated apoptosis is independent of bcl-2: a study with cell lines overexpressing bcl-2 and with bcl-2 transfected cell lines. 945 7

In mice, Pax5 gene is indispensable for B cell development. Pax5-deficient mice fail to produce mature B cells owing to complete arrest of B cell development at a precursor stage. However, the lineage and stage of human Pax5 gene expression have remained elusive. In this investigation expression of the human Pax5 gene was studied. Pax5 gene expression was detected in B cell lines but not in myeloma cell lines. CD19 expression was correlated with Pax5 gene expression. Adult spleen and bone marrow and fetal spleen and liver showed strong Pax5 gene expression, as did the corresponding mouse tissues, as reported previously. In common variable immunodeficiency (CVID) peripheral blood lymphocytes (PBL) with a decreased number of B cells, no Pax5 gene expression was detected. Some CVID PBL stimulated with IL-2, IL-10 and anti-CD40 monoclonal antibody, expressed the Pax5 gene. Defect of Pax5 gene expression in CVID may be caused by regulatory T cell disorder.
 ...
PMID:Expression of Pax5 gene in human haematopoietic cells and tissues: comparison with immunodeficient donors. 948 1

Previous studies have shown that triggering multiple myeloma (MM) cells via CD40 induces IL-6-mediated autocrine growth as well as increased expression of cell surface adhesion molecules including CD11a, CD11b, CD11c, and CD18. In this study, we generated the 5E2 mAb which targets an antigen that is induced upon CD40 ligand (CD40L) activation of MM cells. Immunofluorescence, immunoprecipitation, and protein sequencing studies identified the target antigen of 5E2 mAb as the 86-kD subunit of the Ku autoantigen. We demonstrate that increased cell surface expression of Ku on CD40L-treated cells is due to migration of Ku from the cytoplasm to the cell surface membrane. Moreover, cell surface Ku on CD40L-treated MM cells mediates homotypic adhesion of tumor cells, as well as heterotypic adhesion of tumor cells to bone marrow stromal cells and to human fibronectin; and 5E2 mAb abrogates IL-6 secretion triggered by tumor cell adherence to bone marrow stromal cells. These data suggest that CD40L treatment induces a shift of Ku from the cytoplasm to the cell surface, and are the first to show that Ku functions as an adhesion molecule. They further suggest that cell surface Ku may play a role in both autocrine and paracrine IL-6-mediated MM cell growth and survival.
 ...
PMID:The 86-kD subunit of Ku autoantigen mediates homotypic and heterotypic adhesion of multiple myeloma cells. 950 80

Human hybridomas that secrete monoclonal antibodies (MAbs) in a stable manner are technically difficult to obtain. The problems limiting their production are the low numbers of sensitized B cells in peripheral blood, the limited choice of techniques for B cell immortalization, the limited number of suitable human myeloma or lymphoblastoid fusion partners, and the inability to immunize humans with most antigens. In order to circumvent these problems, we have compared the efficiency of different methods for production of B cell lines secreting human MAbs against the nuclear antigens dsDNA, ssDNA, and Sm/RNP from patients with the autoimmune disease systemic lupus erythematosus (SLE). We have tested various combinations of the following procedures: (1) EBV infection for immortalization of activated B lymphocytes, (2) activation of human resting B lymphocytes by anti-CD40, and (3) direct fusion of lymphocytes with a myeloma cell line using PBL or splenocytes from SLE patients. The methodological aspects of this investigation include optimization of the CD40 system and the generation of human hybridomas specific for nuclear antigens by fusion between sensitized lymphocytes and the human/mouse heteromyeloma cell line CBF7. The most efficient method for producing stable, IgG autoantibody-secreting human hybridomas was fusion of lymphocytes with cell line CBF7; human spleen was the best source of lymphocytes.
 ...
PMID:A comparison of three methods for production of human hybridomas secreting autoantibodies. 970 33


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>