UMLS:C0026764 - FACTA Search

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Query: UMLS:C0026764 (multiple myeloma)
36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have suggested that interleukin-6 (IL-6) may mediate growth of multiple myeloma (MM) in either an autocrine or paracrine growth mechanism. However, those molecules which can trigger IL-6 secretion either by tumor cells or non-MM marrow cells are not well characterized. In the present study, we have examined the expression and functional significance of CD40 on MM and plasma cell leukemia (PCL) cells and derived cell lines, as well as long-term bone marrow stromal cells (BMSCs) and derived cell lines. CD40 was expressed on the majority of MM cells (> 90%) and BMSCs (> 70%). Triggering via CD40 using NIH3T3 CD40 ligand transfectant (CD40LT) cells increased (> 30%) cell surface CD80, CD18, CD11a, CD11b, and CD11c expression on MM cell lines. Culture with either fresh or paraformaldehyde fixed NIH3T3 CD40LT cells upregulates IL-6 secretion in MM cells and MM-derived cell lines, as well as normal and MM bone marrow mononuclear cells (BMMCs), BMSCs, and BMSC lines; this effect can be specifically blocked by anti-CD40 monoclonal antibody (MoAb). BMMCs and BMSCs from patients with MM secreted significantly more IL-6 than those from healthy donors (n = 3, P < .001); moreover, after stimulation using CD40L, IL-6 secretion was fourfold greater (n = 3, P < .001) from MM BMMCs and BMSCs than from normal BMMCs and BMSCs. Myeloma (CD38+CD45RA-) cells and non-MM (CD38+CD45RA+, CD38-CD45RA+, and CD38-CD45RA-) BMMCs were separated by dual fluorescence cell sorting. The latter secreted fourfold more IL-6 than the former (n = 2, P < .001). Increased IL-6 secretion (up to 28-fold) and proliferation (Stimulation index 10) by CD38+CD45RA-MM cells was triggered by culture with NIH3T3 CD40LT cells. Finally, anti-CD40MoAb partially (30%) blocked tumor cell to BMSC adhesion-induced IL-6 secretion. These studies support the view that CD40L may trigger IL-6 secretion by both MM cells and BMSCs and that IL-6-mediated autocrine and paracrine growth mechanisms may be possible in MM.
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PMID:CD40 ligand triggered interleukin-6 secretion in multiple myeloma. 753 94

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.
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PMID:CD40 and the effect of anti-CD40-binding on human multiple myeloma clonogenicity. 890 62

We and others previously demonstrated that human multiple myeloma (MM) cells express CD40 and have an active CD40-growth regulatory pathway. This study characterizes the growth outcome of soluble (gp39) or membrane-bound recombinant human CD40-ligand (rCD40L) and its relationship with Fas-dependent apoptosis. Contrary to the moderate growth-stimulatory effect of the CD40-MAb G28.5, gp39 inhibited 3H-thymidine uptake of the plasma dyscrasia lines ARH-77, U266, and HS-Sultan in a dose-dependent fashion by up to 82%. By comparison, RPMI 8226 cells were resistant to CD40L-growth modulation, which may be attributable to a single base substitution (TCA-->TTA, serine-->leucine) at the 3rd cysteine-rich extramembrane region of CD40. Gp39 similarly reduced myeloma clonogenic colony (MCC) formation in patient primary bone marrow cultures by 50% (40-76%; n=6). Studies using transfectant L cells that constitutively expressed CD40L showed that membrane-bound CD40L inhibited the growth of ARH-77, U266, and HS-Sultan cells (66%, 63%, and 32%, respectively), whereas untransfected L cells did not. Growth inhibition by gp39 or CD40L+ L cells was neutralized by coincubation with the CD40L antibodies 5c8 or LL48. CD40L-treatment increased apoptotic activity of MM cells, as defined by oligonucleosomal DNA fragmentation and an increased binding to annexin V (16-28%). All three untreated CD40-responsive MM lines expressed the Fas/Apo-1/CD95 antigen (65-92% CD95+). However, only ARH-77 cells responded to the growth inhibitory effect of the CD95-agonistic antibody CH-11. CD95 expression was not affected significantly by gp39 treatment, and growth inhibition by CH-11 was additive to gp39 (from 42% to 64% decrease in 3H-thmidine uptake). Conversely, the CD95 antagonist antibody ZB4 reversed the Fas-dependent growth inhibitory process but did not significantly alter gp39-mediated growth outcome. Gp39 treatment lowered the expression of TNFR-associated factors TRAF4 and TRAF6 by 38% and 32%, respectively, whereas detectable levels of TRAF1,2,3, and 5 levels remained unchanged. Our observations indicate that the CD40L-binding inhibits human MM cell growth and increases its apoptotic activity. This growth inhibitory effect corresponds to lower levels of cytoplasmic TRAF signaling elements, and appears independent of the Fas-signaling pathway. CD40 receptor mutation may lead to unresponsiveness to CD40 growth modulation in multiple myeloma cells.
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PMID:CD40 ligand-induced apoptosis is Fas-independent in human multiple myeloma cells. 1078

Ligation of CD40 is essential for primary B-cell activation and expansion and yet has suppressive or apoptotic effects on some CD40-expressing neoplasia. SGN-14 is a monoclonal antibody that binds to the human CD40 receptor. Here we report that SGN-14, in the presence of interleukin 4, provided a modest level of stimulation of peripheral blood B cells, as measured by proliferation. Stimulation was greatly enhanced in the presence of nonproliferating CD40 ligand-expressing cells. The enhanced agonistic activity could be attributed to a dose-dependent increase in CD40L binding to CD40 in the presence of SGN-14. In contrast to its proliferative effect on primary B cells, SGN-14 inhibited the growth of B-cell-derived tumor lines in vitro, and this growth inhibition was enhanced in the presence of CD40L-expressing cells. In vivo, SGN-14 showed significant antitumor activity in treating human B-cell lymphoma and multiple myeloma xenografted severe combined immunodeficient mice. Antitumor activity was not diminished by blunting murine natural killer activity, suggesting that CD40 ligation contributes to the antitumor efficacy of SGN-14. On the basis of these activities, SGN-14 is being pursued for therapeutic use in treating patients with CD40-expressing hematological malignancies.
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PMID:Agonistic properties and in vivo antitumor activity of the anti-CD40 antibody SGN-14. 1086 15

Neoplastic plasma cells from patients with myeloma fail to stimulate an effective anti-myeloma immune response, which may be in part due to their deficient expression of immune accessory molecules. Attempting to alter this, we infected myeloma cell lines and patient-derived primary myeloma cells with an adenovirus encoding CD154 (Ad-CD154). Myeloma cells were made to express the CD154 transgene at multiplicity of infection (MOI) between 10 and 1000. Furthermore, infection of CD40(positive) myeloma cells with Ad-CD154, but not an adenovirus encoding an irrelevant transgene, beta-galactosidase (Ad-LacZ), induced enhanced expression of immune accessory molecules, such as CD54, HLA-DR and CD70. In addition, Ad-CD154-infected myeloma cells could activate bystander CD40(positive) antigen-presenting cells to express immune accessory molecules. Consequently, Ad-CD154 infected myeloma cells stimulated proliferation in allogeneic mixed lymphocyte reactions (MLR). Finally, co-infection of CD40(negative) myeloma cells with Ad-CD154 and an adenovirus encoding CD40 (Ad-CD40) induced expression of immune accessory molecules and enhanced the MLR stimulatory capacity of transduced myeloma cells. Collectively, these results indicate that infection of myeloma cells with Ad-CD154 or Ad-CD154/Ad-CD40 can induce changes in myeloma cells that enhance their ability to induce cellular immune activation. As such, this approach may have potential application for immune therapy of patients with this disease.
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PMID:Adenovirus transduction to effect CD40 signalling improves the immune stimulatory activity of myeloma cells. 1213 39

In the peripheral blood (PB) of multiple myeloma (MM) patients, clonotypic B cells are present that express the identical V(D)J rearrangements as the malignant plasma cells in the bone marrow. In the present study, the proliferative capacity of clonotypic B cells from MM patients (n = 10) and the ability to differentiate in vitro was determined using the CD40-culturing system. For six patients, the presence of clonotypic B cells expressing variant immunoglobulin (Ig) isotypes was assessed by Ig isotype-specific allele-specific oligonucleotide reverse transcription polymerase chain reaction (ASO-RT-PCR) after culturing with CD40L and interleukin 4 (IL-4). In three out of six patients, clonotypic B cells expressing variant isotypes were detected both before and after culturing. The ability of clonotypic B cells to undergo B-cell differentiation was studied by abrogating CD40 signalling accompanied by IL-10 and IL-2 stimulation, enhancing differentiation towards Ig-secreting cells. The numbers of clonotypic B cells were determined by quantitative ASO-PCR. An increase in cell number was observed upon CD40L and IL-4 stimulation, whereas the relative number of clonotypic B cells was unaltered. In contrast, upon B-cell differentiation the relative number of clonotypic B cells decreased. In conclusion, clonotypic B cells can be cultured and isolated in vitro using the CD40 system. Clonotypic B cells responded to CD40 triggering in a similar fashion as to non-clonotypic normal B cells. However, the ability of clonotypic B cells to undergo in vitro activation and differentiation into Ig-secreting cells is hampered.
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PMID:Myeloma clonotypic B cells are hampered in their ability to undergo B-cell differentiation in vitro. 1235 3

Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells in the bone marrow and their egress into peripheral blood with progression to plasma cell leukemia. Our previous study defined a functional role of CD40 activation in MM cell homing and migration. In this study, we examine signaling events mediating CD40-induced MM cell migration. We show that cross-linking CD40, using either soluble CD40L (sCD40L) or anti-CD40 monoclonal antibody (mAb), induces phosphatidylinositol 3-kinase (PI3K) activity and activates its downstream effector AKT in MM.1S cells. CD40 activation also activates the MAP kinase (MEK) pathway, evidenced by phosphorylation of extracellular signal-regulated mitogen-activated protein kinase (ERK), but not c-jun amino-terminal kinase (JNK) or p38, in a dose- and time-dependent manner. Using pharmacologic inhibitors of PI3K and MEK, as well as adenoviruses expressing dominant-negative and constitutively expressed AKT, we demonstrate that PI3K and AKT activities are required for CD40-induced MM cell migration. In contrast, inhibition of ERK/MEK phosphorylation only partially (10%-15%) prevents migration, suggesting only a minor role in regulation of CD40-mediated MM migration. We further demonstrate that CD40 induces nuclear factor (NF)-kappa B activation as a downstream target of PI3K/AKT signaling, and that inhibition of NF-kappa B signaling using specific inhibitors PS1145 and SN50 completely abrogates CD40-induced MM migration. Finally, we demonstrate that urokinase plasminogen activator (uPA), an NF-kappa B target gene, is induced by CD40; and conversely, that uPA induction via CD40 is blocked by PI3K and NF-kappa B inhibitors. Our data therefore indicate that CD40-induced MM cell migration is primarily mediated via activation of PI3K/AKT/NF-kappa B signaling, and further suggest that novel therapies targeting this pathway may inhibit MM cell migration associated with progressive MM.
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PMID:CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF-kappa B signaling. 1243 78

CD40, a member of the tumor necrosis factor receptor (TNF-R) family, is a surface receptor best known for its capacity to initiate multifaceted activation signals in normal B cells and dendritic cells (DCs). CD40-related treatment approaches have been considered for the experimental therapy of human leukemias, lymphomas, and multiple myeloma, based on findings that CD40 binding by its natural ligand (CD40L), CD154, led to growth modulation of malignant B cells. Recent studies also exploited the selective expression of the CD40 receptor on human epithelial and mesenchymal tumors but not on most normal, nonproliferating epithelial tissues. Ligation of CD40 on human breast, ovarian, cervical, bladder, non small cell lung, and squamous epithelial carcinoma cells was found to produce a direct growth-inhibitory effect through cell cycle blockage and/or apoptotic induction with no overt side effects on their normal counterparts. CD154 treatment also heightened tumor rejection immune responses through DC activation, and by increasing tumor immunogenicity through up-regulation of costimulatory molecule expression and cytokine production of epithelial cancer cells. These immunopotentiating features can produce a "bystander effect" through which the CD40-negative tumor subset is eliminated by activated tumor-reactive cytotoxic T cells. However, the potential risk of systemic inflammation and autoimmune consequences remains a concern for systemic CD154-based experimental therapy. The promise of CD154 as a tumor therapeutic agent to directly modulate tumor cell growth, and indirectly activate antitumor immune response, may depend on selective and/or restricted CD154 expression within the tumor microenvironment. This may be achieved by inoculating cancer vaccines of autologous cancer cells that have been transduced ex vivo with CD154, as documented by recently clinical trials. This review summarizes recent findings on CD154 recombinant protein- and gene therapy-based tumor treatment approaches, and examines our understanding of the multifaceted molecular mechanisms of CD154-CD40 interactions.
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PMID:Prospects for CD40-directed experimental therapy of human cancer. 1248 23

Dendritic cells (DCs) are antigen-presenting cells that play a critical role in the induction of cytotoxic T-lymphocytes. An optimal method for the generation of DC for clinical use remains to be established. The aim of our study was to find an optimal cytokine combination for DC generation from peripheral blood stem cells (PBSC) and peripheral blood mononuclear cells (PBMC) in serum-free conditions. Serial immunophenotyping enabled us to observe changes in DC content during the culture as well as the development of maturation and activation markers. As a source for DC culture, we used PBSC from patients with multiple myeloma after stem cell mobilization using cyclophosphamide and G-CSF, or PBMC from healthy donors without mobilization. The cells were cultured in a serum-free medium with different cytokine combinations including GM-CSF, TNF-alpha, Flt-3, CD40L, IFN-gamma, IL-1alpha, IL-6, PGE1, and IL-4. The cell cultures were evaluated by immunophenotyping. For PBMC, interleukin-12 assay was performed. For PBSC, the yield of DC as determined by CD83+ cell count ranged from 0. 6 x 10(5) to 30.1 x 10(4) (mean: 9.4 x 10(4)) of DC generated per 1 x 10(6) of initially plated nucleated cells from apheresis. This yield corresponded to (0.3-19.1) x 10(5) (mean: 4.3 x 10(5)) per 1 x 10(6) of CD34+ cells in the apheresis products. For PBMC, the yield was (0.4-24.8) x 10(4) (mean: 2.4 x 10(4)) of DC generated per 1 x 10(6) of initially plated mononuclear cells from venous blood. The cultured cells expressed the mature immunophenotype. No significant differences in cell yield or immunophenotype were detected when comparing different cytokine combinations.
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PMID:Generation of antigen-loaded dendritic cells in a serum-free medium using different cytokine combinations. 1254 97

T-cell immune dysfunction in patients with malignant tumours has been attributed to the altered expression of components of the T-cell receptor (TCR)/CD3 complex and their associated intracellular protein tyrosine kinases. In this study, four-colour flow cytometry was applied to study the surface bound molecules TCRalphabeta, CD28, CD152 and CD154 involved in T-cell signalling and the signal transduction molecules CD3zeta, p56lck, p59fyn, ZAP-70 and phosphatidyl-inositol-3 kinase (PI3-k) as well as the intracellular cytokines interferon-gamma (IFN-gamma), interleukin (IL)-4 and IL-2 as a functional read-out of non-stimulated and superantigen (staphylococcus enterotoxin B)-stimulated blood T cells of multiple myeloma (MM) patients at different stages of the disease. Multiple abnormalities were demonstrated in the CD4 and CD8 populations, both under non-stimulated and superantigen-stimulated conditions. There was a marked reduction, particular in advanced stage MM, in the proportion of CD4 and CD8 cells expressing CD28, CD152, CD3zeta, p56lck, ZAP-70 and PI3-k. The level of intracellular T-cell cytokines (IFN-gamma, IL-2 and IL-4) was normal or increased in non-stimulated cells but activation-induced cytokine production was impaired. These results illustrated profound and multiple T-cell signalling defects, from the surface and down-stream, consistent with involvement of a master T-cell function, especially in advanced stage MM. These data should be taken into consideration when developing immune-based therapeutic approaches and when applying new emerging technologies that aim to restore T-cell functions.
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PMID:Signalling molecules and cytokine production in T cells of multiple myeloma-increased abnormalities with advancing stage. 1471 78

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