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)

To study the effects of cytokines on human IgE antibody forming cells (AFCs), log phase U266 myeloma cells (3 x 10(3)/ml), which secrete immunoglobulin E (IgE), were cultured for 0-24 h with and without cytokine or with or without antibodies against various cytokines. The numbers of IgE AFCs were determined in ELISPOT assay. We found that interleukin-6 (IL-6) suppressed (to 95%) whereas anti-IL-6 increased (to 148%) the numbers of IgE AFCs and that both worked in a dose-dependent fashion. IL-4 and interferon-gamma (IFN-gamma) also suppressed IgE AFC responses in a dose-dependent fashion. However, antibodies to these cytokines had no effect. In contrast, IFN-alpha increased (to fourfold) the numbers of IgE AFCs in a dose-dependent fashion. The data are the first to show a suppressive effect of IL-6 on human IgE responses and may also suggest a role for IL-6 in the treatment of atopic disease.
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PMID:Suppression of human IgE antibody forming cell responses by IL-6. 836 May 95

We have recently shown that peripheral blood T cells of multiple myeloma (MM) patients are very susceptible to stimulation of the T-cell receptor/CD3 complex with anti-CD3 monoclonal antibodies (MoAbs). CD3 stimulation is currently under clinical investigation as a nonspecific approach to boost antitumor effector mechanisms. The aim of this study was to determine whether the hyperreactivity of MM T cells to CD3 stimulation could be exploited to generate antitumor activity. Bone marrow mononuclear cells (BMMCs) from 65 MM patients were stimulated with the anti-CD3 MoAb OKT3 and the effect of this stimulation on autologous T cells and plasma cells was evaluated. The number of CD3+ CD25+ cells on day 6 was significantly higher in MM than the controls (30 normal individuals) (P = .001). Kinetic studies showed that 3H-thymidine incorporation peaked on day 3 and that the T-cell expansion peaked on days 5 and 6. In MM, T-cell activation markedly affected the survival of autologous plasma cells; their number in OKT3-treated cultures was significantly lower than in unstimulated cultures (P < .0001). T-cell activation and plasma cell decrease were not observed when T cells were removed from BMMC preparations. MM produced significantly higher levels of interferon-gamma (P = .005) and tumor necrosis factor-beta (P = .001), but lower levels of tumor necrosis factor-alpha (P < .001) than normal individuals. Interferon-gamma only was partially involved in CD3-induced plasma cell killing. Transwell cultures showed that the main mechanism by which CD3+ CD25+ cells affected plasma cells was direct cell-to-cell contact rather than cytokines. In conclusion, T cells in MM BMMCs possess distinct features in terms of susceptibility to CD3 stimulation and cytokine production compared with normal bone marrow T cells that can be exploited to generate antiplasma cell activity.
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PMID:Rapid generation of antiplasma cell activity in the bone marrow of myeloma patients by CD3-activated T cells. 840 Feb 33

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

Multiple myeloma is characterized by a proliferation of clonal B lymphocytes and plasma cells. The idiotypic structure of clonal immunoglobulin (Ig) expressed on the tumour B-cell surface can be regarded as a tumour-specific antigen and, as such, a potential target for anti-idiotypic T and B-cells in an immune regulation of the tumour-cell clone. Active immunization using the autologous mono-clonal Ig as a 'vaccine' was shown to induce tumour-specific immunity in murine B-cell tumours and in human B-cell lymphoma. With the aim to induce or amplify an anti-idiotypic response in multiple myeloma, five stage I-III patients were repeatedly immunized with the autologous monoclonal IgG. Induction of idiotype-specific cellular immunity was analysed in vitro by an enzyme-linked immunospot assay (interferon-gamma and interleukin-4 secreting cells). B cells secreting anti-idiotypic IgM antibodies were also analysed. An anti-idiotypic T-cell response was amplified 1.9-5-fold in three of the five patients during immunization. The number of B cells secreting anti-idiotypic antibodies also increased in these three patients. In two of the patients induction of idiotype-specific immunity was associated with a gradual decrease of blood CD19+ B cells. The induced T-cell response was eliminated during repeated immunization. Further studies are warranted to optimize the immunization schedule in order to achieve a long-lasting T-cell immunity against idiotypic determinants on the tumour clone. A role for immunity in controlling the tumour clone remains to be established.
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PMID:Modulation of anti-idiotypic immune response by immunization with the autologous M-component protein in multiple myeloma patients. 861 76

Interleukin-6 (IL-6) is a growth factor for multiple myeloma (MM) cells and can inhibit MM cell apoptosis. Our recent studies show that IL-6 facilitates MM cell growth via phosphorylation of retinoblastoma protein (pRB); however, the effects of IL-6 on those cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CDIs) that are known to regulate phosphorylation of pRB have not been defined in MM cells. In the present report, we cultured MM cell lines and patient cells with IL-6 and/or dexamethasone (Dex) and characterized changes in cell cycle; expression and association of cyclins, CDKs, and CDIs; and phosphorylation of pRB. Dex induced G1 growth arrest in MM cells, whereas IL-6 facilitated G1 to S phase transition; moreover, the effect of Dex was blocked by IL-6. p21WAF1 (p21) protein was constitutively expressed in the majority of MM cells independent of the status of p53. Its expression was upregulated by Dex and downregulated by IL-6; again, IL-6 inhibited the increase in p21 triggered by Dex. These alterations in p21 expression in MM cells were associated with changes in p21 binding to CDK2, CDK4, and CDK6; CDK2, CDK4, and CDK6 kinase activities; and phosphorylation of pRB. In contrast, expression of G1 cell cycle regulatory proteins, including p27KIP1, cyclin D2, and cyclin E, was not altered in MM cells cultured with Dex and/or IL-6. Finally, interferon-gamma (IFN-gamma) also induced G1 growth arrest and upregulated p21 protein expression; as with Dex, affects of IFN-gamma were inhibited by IL-6. Our results therefore show that changes in cell cycle distribution in MM cells triggered by Dex, IL-6, and IFN-gamma correlate with changes in p21 protein expression and implicate p21 in the coupling of Dex-, IL-6-, and IFN-gamma-related signals to G1 cell cycle regulation in MM cells.
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PMID:Interleukin-6 overcomes p21WAF1 upregulation and G1 growth arrest induced by dexamethasone and interferon-gamma in multiple myeloma cells. 920 63

Cytokines are polypeptides that bind to membrane receptors and may act in an endocrine, paracrine or autocrine way. Several cytokines and growth factors may be produced by bone cells, stored in the matrix or act on them. Osteoclasts derive from the bone marrow stem cell and, as monocytes, belong to the family of tissue macrophages. Their specific function is bone resorption. Interleukin 1, 6 and 11, transforming growth factor and tumor necrosis factor stimulate osteoclast mediated bone resorption. Interleukin 1 is the most potent bone resorption agent and seems to be identical to osteoclast activation factor, identified in multiple myeloma. The role of interleukin 1, 6, 11 and tumor necrosis factors in postmenopausal osteoporosis triggered by the fall in estrogen levels, has not been well defined yet. Cytokines that increase bone formation are insulin like growth factors I and II, transforming growth factor, platelet derived growth factor and bone morphogenic proteins. Probably, tumor necrosis factor and interferon-gamma have a depressor effect on bone formation. Cytokines and growth factors, liberated from bone cells or from the matrix during osteoclastic work, could be the signals responsible for coupling bone formation and resorption.
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PMID:[Cytokines, growth factors, and metabolic bone disease]. 921 95

Peripheral blood T cells from 83 patients with multiple myeloma (MM) were examined for the production of interferon-gamma (INF-gamma) and interleukin-2 (IL-2) using three-colour flow cytometry. Comparisons were made between the percentage of cytokine-positive lymphocytes in normal donors and in patients during remission or relapse. Patients were divided into those who were on maintenance therapy with interferon-alpha2b (intron A) and those who had no further treatment after high-dose melphalan (HDM) with or without autologous bone marrow (ABMR) or peripheral blood stem cell rescue (PBSCR). The percentage of INF gamma+/CD3+, INF gamma+/CD45RO+/CD3+ and IL-2+/CD8+ was higher in patients on INF alpha2b during remission and relapse compared with normal donors (P<0.005). During remission INF gamma+/CD45RO+/CD3+ and IL-2+/CD8+ lymphocytes were higher in patients not on INF alpha2b (P<0.05 and P<0.005, respectively). In relapsed patients INF gamma+/CD3+ and INF gamma+/CD45RO+/CD3+ were increased in patients not taking INF alpha2b (P<0.005). There was no significant difference between the percentages of cytokine-positive lymphocytes in patients taking or not taking INF alpha2b either during remission or relapse. Plasma IL-6 levels were similar in both groups of patients during remission. The data suggest that if maintenance therapy with INF alpha2b induces the synthesis of INF gamma and IL-2 in vivo, the magnitude of the effect is small and may be unimportant in providing an anti-tumour effect in the majority of patients.
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PMID:Interferon-gamma+ and interleukin-2+ T cells in peripheral blood from multiple myeloma patients in relation to disease status and maintenance therapy with interferon-alpha2b (intron A). 923 74

Immunotherapy involving cytotoxic T lymphocytes (CTLs) is an attractive alternative for treatment of various malignancies, including multiple myeloma. For tumour cells to be recognized and killed by CTLs they must express cell surface major histocompatibility complex (MHC) class I molecules and the transporter associated with antigen processing (TAP). However, loss of MHC class I and the TAP protein are common among several types of solid tumours. This study assessed the expression of TAP protein (by intracellular flow cytometry) and cell surface MHC class I molecules in three human myeloma cell lines as well as the plasma cell population (CD38+ bright) in bone marrow specimens from 13 multiple myeloma patients. In all of the patients, 100% of the plasma cell population expressed both the TAP subunits and cell surface MHC class I molecules, but at varying intensities. Both TAP and MHC class I were also expressed in the three myeloma lines. Additionally, the function of the antigen transport machinery was evaluated by a peptide transporter assay in the three myeloma lines. TAP transporter activity was readily detectable in two out of three myeloma lines, whereas the diminished activity in the third cell line was completely restored by co-culturing with recombinant interferon-gamma (rIFN-gamma).
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PMID:Assessment of intracellular TAP-1 and TAP-2 in conjunction with surface MHC class I in plasma cells from patients with multiple myeloma. 926 43

Recurrent bacterial infections due to humoral immunodeficiency are an important cause of death in myeloma patients. Recent data indicate that CD8+ T lymphocytes and a reduction of T helper type 1 cells with disease progression may be involved in the regulation of polyclonal immunoglobulin secretion. In mixed lymphocyte cultures derived from peripheral blood mononuclear cells (PBMC) of 24 myeloma patients with reduced immunoglobulin serum levels we investigated the association of CD4+ and CD8+ T cell subsets and immunoglobulin-secreting B cells (ISC) upon mitogenic stimulation with pokeweed mitogen (PWM) and concanavalin A (Con A). In supernatants of cultured PBMC of myeloma patients the spontaneous secretion of the type 1 cytokine interferon-gamma was reduced. After PWM stimulation reduced numbers of polyclonal ISC were found in 79% of patients, and monoclonal ISC were observed in 12% of patients. After Con A stimulation, again formation of polyclonal ISC was reduced, but monoclonal ISC were found in 41% of patients. Elevation of monoclonal and reduction of polyclonal ISC after stimulation with Con A were associated with an increase of CD8+ CD11b+ Leu-8- T cells (P<0.05). We conclude that the elevated numbers of CD8+ CD11b+ Leu-8- T cells play a role in the stimulation of monoclonal and suppression of polyclonal immunoglobulin secretion in myeloma patients.
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PMID:Elevation of CD8+ CD11b+ Leu-8- T cells is associated with the humoral immunodeficiency in myeloma patients. 927 27

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.
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PMID:Myeloma bone marrow plasma cells: evidence for their capacity as antigen-presenting cells. 929 30

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