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)

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.
 ...
PMID:CD40 ligand-induced apoptosis is Fas-independent in human multiple myeloma cells. 1078

The novel multiple myeloma (MM) cell line MOLP-5 and its homologous sister cell line B407, a lymphoblastoid cell line (LCL), were established from the peripheral blood of a 71-year-old Japanese patient with Bence-Jones kappa-type multiple myeloma (stage IIIB with hyperammonaemia and hypercalcaemia). The growth of MOLP-5 cells is constitutively dependent on bone marrow stroma (BST) cells; none of the cytokines tested nor the culture supernatant of the bone marrow stroma cells could support the growth of MOLP-5. Wright-Giemsa-stained MOLP-5 cells showed typical plasma cell morphology with abundant cytoplasm and one to three nuclei. The immunoprofile of MOLP-5 corresponds to that seen typically in primary MM cells: positive for cytoplasmic immunoglobulin (Ig) kappa light chain, CD28, CD29, CD38, CD40, CD44, CD49d, CD54, CD56, CD58, CD71, CD138 and PCA-1; the cells were negative for surface Ig and various other B-cell, T-cell and myelomonocyte-associated immunomarkers. Interleukin 6 (IL-6) receptor mRNA was found in the reverse transcriptase polymerase chain reaction (RT-PCR) analysis. IL-6 and IL-10 could induce cellular proliferation in short-term induction experiments. IL-6 or IL-10 production was not detected by specific enzyme-linked immunoabsorbent assay (ELISA). MOLP-5 cells expressed parathyroid hormone-related protein (PTHrP) at the mRNA level. Cytogenetic analysis showed the typical t(11; 14) chromosome abnormality. The novel MOLP-5 cell line together with the B407 B-LCL sister line will be useful model systems in the investigation of the biology of MM.
 ...
PMID:Human bone marrow stroma-dependent cell line MOLP-5 derived from a patient in leukaemic phase of multiple myeloma. 1084 82

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.
 ...
PMID:Agonistic properties and in vivo antitumor activity of the anti-CD40 antibody SGN-14. 1086 15

Human bone marrow stroma (BST)-dependent myeloma sister cell lines MOLP-6 and MOLP-7 were established from the peripheral blood of a multiple myeloma (MM) patient with IgA kappa type MM (stage IIIB). The growth of the cell lines is constitutively dependent on BST cells; none of the cytokines tested nor the culture supernatant of the BST cells could support the growth. Both cell lines showed typical plasma cell morphology with abundant cytoplasm and one to four nuclei under Wright staining. The immunoprofiles of MOLP-6 and MOLP-7 correspond to that seen typically in primary MM cells: positive for cytoplasmic immunoglobulin (Ig) chains, a heavy and kappa light chains, CD9, CD28, CD40, CD44, CD45, CD56, and PCA-1; the cells were negative for surface Igs and various other B-cell, T-cell and myelomonocyte associated markers. Both cell lines also expressed adhesion molecules including HCAM (CD44), VLA-4 (CD49d/CD29), VLA-6 (CD49f/CD29), ICAM-1 (CD54), NCAM (CD56), LFA-3 (CD58) and L-selectin (CD62L). The doubling time of MOLP-6 and MOLP-7 was 48 and 168 hours, respectively. In addition to this growth characteristic, the maximum cell density of each cell line was obtained at 1.7 x 10(6) cells/ml and 9.7 x 10(5) cells/ml, respectively. The characteristics of each cell line may reflect intraclonal variation of the proliferative capacity. The MOLP-6 together with the MOLP-7 sister will be useful model systems for the investigation of the biology of myeloma.
 ...
PMID:Human bone marrow stroma-dependent myeloma sister cell lines MOLP-6 and MOLP-7 derived from a patient with multiple myeloma. 1093 46

Deficiencies in B7:CD28 costimulation are considered to be one of the major causes of the failure to generate a tumor-specific immune response. Up-regulating the expression of the B7 molecules on malignant B cells has been shown to stimulate cytotoxic T cells. Plasma cells from patients with myeloma express a tumor-specific idiotype but lack CD80 (B7-1) and have a variable expression of CD86 (B7-2). This study has identified the incidence and clinical significance of high CD86 expression on plasma cells at diagnosis and studied the ability of trimeric human CD40 ligand (huCD40LT) to up-regulate the expression of the B7 family on malignant plasma cells. CD86 expression on plasma cells was increased in 54% of the patients studied at diagnosis (n = 35) and was associated with a significantly shorter survival (median, 28 versus 57 months; chi(2) = 4.6; P =.03) and a higher tumor load (patients with more than 50% bone marrow plasma cells, 47% versus 6%; chi(2) = 7.2; P =.005). CD86 expression was highest on immature and primitive plasma cells (CD38(++), CD45(+)) of both patients and controls and was associated with a CD40(+), CD20(+), CD19(-), CD138(+) phenotype. The shortened survival was associated with high CD86 only on mature (CD38(++), CD45(-)) plasma cells (chi(2) = 7.6; P =.006). There was no significant correlation between high CD86 and other known prognostic markers, including serum beta(2)-microglobulin, serum thymidine kinase, and labeling index. The addition of huCD40LT to short-term cultures up-regulated both CD80 and CD86 expression on B cells (CD19(+)) and CD80 on plasma cells (CD38(++)), but did not up-regulate CD86 expression on plasma cells. Thus, B7-2-positive myeloma consists of a subgroup of patients with a relatively poor prognosis, and CD40LT may be useful in immunotherapy protocols because it up-regulates CD80 expression on malignant plasma cells without inducing B7-2-positive myeloma. (Blood. 2000;96:1274-1279)
 ...
PMID:B7-2-positive myeloma: incidence, clinical characteristics, prognostic significance, and implications for tumor immunotherapy. 1094 68

It was previously demonstrated that p53 status in human multiple myeloma (MM) cells regulates distinct cell cycle responses to CD40 activation. In this study, the production of vascular endothelial growth factor (VEGF) and migration in MM cells triggered by CD40 activation was examined, and the influence of p53 status in regulating this process was determined. Two human MM cell lines that express wild-type p53 at permissive (28 degrees C) and mutant p53 at restrictive (37 degrees C) temperatures were used as a model system. CD40 activation induces a 4-fold (RPMI 8226) and a 6-fold (SV) increase in VEGF transcripts, respectively, under restrictive, but not permissive, temperatures. VEGF expression is significantly induced after CD40 activation in patient MM cells expressing mutant p53. Increased VEGF transcripts result in increased protein and secretion levels, as evidenced by immunoblotting and enzyme-linked immunosorbent assay. In a double-chamber transmigration assay, CD40 activation of MM cells induced a 3-fold (RPMI 8226) and a 5-fold (SV) increase in migration under restrictive, but not permissive, conditions. A 2- to 8-fold induction in migration of patient MM cells expressing mutant p53 was similarly observed. Transduction of MM cells with a luciferase reporter under the control of a human VEGF promoter further indicated that CD40-induced VEGF expression was mediated through a transcriptional control mechanism. Finally, adenovirus-mediated wild-type p53 overexpression down-regulated CD40-induced VEGF expression and transmigration in MM cells expressing mutant p53. These studies demonstrate that CD40 induces VEGF secretion and MM cell migration, suggesting a role for CD40 in regulating MM homing and angiogenesis.
 ...
PMID:CD40 activation induces p53-dependent vascular endothelial growth factor secretion in human multiple myeloma cells. 1183 Apr 95

CD40 ligand (CD40L) is a member of the tumor necrosis factor (TNF) superfamily and is expressed primarily on the activated CD4( )T lymphocytes. The CD40 molecule, the cognate receptor of CD40L presents on many immunocytes such as B lymphocytes, dendritic cells (DCs) as well as on some neoplastic cells. Triggering of CD40 through CD40L plays a central role in the initiation and regulation of the human immune response. In order to further investigate the possible biological roles of CD40 signaling triggered by CD40L, we subcloned the DNA fragment encoding the extracellular region of human CD40L into the pSK plasmid. After being sequenced, the target fragment was introduced into the pPICZalphaA plasmid to construct the pPICZalphaA-sCD40L expressing vector which was then transduced into Pichia pastoris GS115 cells by electroporation. The tansformant expressed sCD40L in culture supernatants with a maximum yield of about 35 mg/L. Furthermore, we found that the recombinant human soluble CD40 ligand (rhsCD40L) could effectively induced human peripheral blood monocytes(PBMCs) in vitro in the absence of TNFalpha into dendritic cells (DCs) with the typical morphology and special surface markers of dendritic cells including CD1a, CD80, CD83, and HLA-DR etc. To our surprise, the rhsCD40L also could inhibit directly in vitro proliferation of the CD40-positive multiple myeloma cell line XG-2 and the B lymphoma cell line Daudi significantly at an optimal concentration from 2.5 to 15.0 mg/L, while CD40 negative ovarian carcinoma cell lines, SKB and SKR, were not effected by either high or low concentration of rhsCD40L. Moreover, rhsCD40L had the same effects as CD40L-transfected cell in inducing XG2 cell apoptosis. Our results demonstrated that functional human soluble CD40L could be successfully expressed in the Pichia pastoris system and that the recombinant human soluble CD40L might be a potential immune adjuvant and a new powerful molecule for tumor bio-therapy.
 ...
PMID:Expression of Human Soluble CD40 Ligand in Pichia pastoris and Its Effects on Dendritic Cells and Malignant B Cells. 1205 65

Because tumor-specific antigens have been identified in multiple myeloma (MM), immunotherapy might provide an additional treatment modality for the disease. Expression of CD40 ligand (CD40L) proximate to the MM cells might serve this purpose, either by increasing their capacity to present self-antigens by activation through their CD40 receptor or by the recruitment of professional antigen-presenting cells (APCs) able to take up and present tumor-associated antigens. To distinguish between these possibilities and predict whether human CD40(-) myeloma might respond to this approach, we examined 3 murine plasmacytoma cell lines, 2 (MPC-11 and S107) expressing the CD40 molecule and 1 (X-24) lacking such expression. Syngeneic BALB/CBYJ mice were inoculated subcutaneously with tumor cells mixed with CL7.1 fibroblasts, retrovirally transduced to express either the mCD40L or the neo gene. For all 3 plasmacytoma cell lines, coinjection with CL7.1/mCD40L significantly reduced local tumor growth compared with controls. This effect was mediated by a systemic antitumor immune response, since mice immunized with tumor and CL7.1/mCD40L were resistant to subsequent challenge with tumor, and tumor growth inhibition was abolished when CD8(+) or CD4(+) lymphocytes were depleted. Because expression of CD40L gave equivalent protection from CD40(+) and CD40(-) tumors and transgenic-CD40L failed to up-regulate costimulatory molecules in either tumor, the protective effects of CD40L probably resulted from recruitment/activation of professional APCs rather than from CD40 activation of plasmacytoma cells. As further support of this concept, we found that mice were also well protected if CL7.1 and CD40L were injected together with apoptotic plasmacytoma cells from these tumors. Hence, transgenic CD40L expression may produce an antimyeloma immune response against either CD40(+) or CD40(-) tumors and may be of therapeutic value for both types of myeloma in humans.
 ...
PMID:Transgenic expression of CD40 ligand produces an in vivo antitumor immune response against both CD40(+) and CD40(-) plasmacytoma cells. 1207 28

We studied concentration, phenotype, and function of peripheral blood (PB) dendritic cells (DCs) from patients with multiple myeloma (MM). The absolute number of circulating precursors of myeloid and plasmacytoid DCs was significantly lower in MM patients than in healthy subjects. After maturation, PBDCs from MM patients showed significantly lower expression of HLA-DR, CD40, and CD80 antigens and impaired induction of allogeneic T-cell proliferation compared with controls. Remarkably, they were not capable of presenting the patient-specific tumor idiotype to autologous T cells. Conversely, DCs generated in vitro from CD14(+) monocytes from the same patients, and PBDCs freshly isolated from healthy donors efficiently stimulated allogeneic and autologous T cells. To clarify the mechanism of PBDC deficiency in MM, we investigated the effects of the main plasma cell growth factor, interleukin-6 (IL-6), on the development of DCs from CD34(+) cells. IL-6 inhibited the colony growth of CD34(+) DC progenitors and switched the commitment of CD34(+) cells from DCs to CD14(+) CD1a(-) CD86(-)CD80(-) CD40(+/-)HLA-DR +/- monocytic cells exerting potent phagocytic activity but no antigen-presentation capacity. This effect was reversed by anti-IL-6 antibodies. Growing CD34(+) cells in the presence of autologous serum (without IL-6) also suppressed the development of functional DCs. This study demonstrates that PBDCs from MM patients are functionally defective, partially because of IL-6-mediated inhibition of development. This brings into question the advisability of using PBDCs as antigen carriers for immunotherapy trials in MM. The results also suggest a novel mechanism whereby myeloma cells escape immune recognition.
 ...
PMID:Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. 1207 32

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.
 ...
PMID:Adenovirus transduction to effect CD40 signalling improves the immune stimulatory activity of myeloma cells. 1213 39


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