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)

We examined proliferation of natural killer (NK) cells in 10 day mixed culture of peripheral blood mononuclear cells (PBMC) from healthy subjects with irradiated bone marrow mononuclear cells (BMMC) with multiple myeloma. In culture, NK cells increased with 9.5-fold. However, no increase was observed in T cells. The NK cell proliferating activity of PBMC stimulated with BMMC was higher than that of IL-2. NK cells at a purity of 90% or higher purity were collected from 10 day culture. Proliferation of these NK cells was stimulated by the addition of IL-2 but was suppressed by the addition of antibody coated erythrocyte (EA). IFN-gamma production was negligible in cultures of these NK cells alone but was marked in cultures with EA stimulate IFN-gamma production. Next, the NK cell obtained as above showed marked NK activity against K 562 cells, and this activity was further enhanced by the addition of IL-2. Also, while NK cells, these NK cells had some activity against Daudi cells and it was enhanced by the addition of IL-2. These results also suggest the presence of unknown cytokines with NK cell proliferating activities in the bone marrow of patients with multiple myeloma.
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PMID:[Preferential proliferation of natural killer cells with bone marrow mononuclear cells in multiple myeloma]. 755 40

After treatment with human normal IgM, 78 +/- 8% of purified CD3-CD56+ resting human NK cells and 93 +/- 6% of IL-2-activated NK cells selected by adherence to plastic reacted with FITC-goat anti-human IgM. Binding of IgM to the FcR for IgM (Fc mu R) on human NK cells was not species specific because mouse myeloma IgM also bound to these cells. The percentage of CD56+ cells binding IgM after incubation with anti-CD16 mAb was similar to that of cells incubated with medium alone (95 +/- 1% vs 93 +/- 4%). Binding of anti-CD16 mAb to Fc gamma RIII on NK cells was unaffected by pretreatment with IgM (65 +/- 12% vs 69 +/- 4%). The CD7 molecule has been reported to be the Fc mu R on the surface of T cells. Two-color flow cytometry showed that 94 +/- 3% of CD3-CD56+ resting NK cells and 71 +/- 16% of activated NK cells were CD7+. Preincubation of NK cells with three anti-CD7 mAb (Leu-9, 8H8-1, and LAU-A1) failed to block the binding of IgM to the Fc mu R. Modulation of the CD7 molecule off the cell surface (CD7+ = 1.5% +/- 0.3) did not reduce IgM binding, thus excluding the possibility that IgM anti-CD7 might bind to different epitopes of the same molecule. These data indicate that the Fc mu R is a specific Ig-binding structure, distinct from the Fc gamma RIII (CD16) or CD7. The Fc mu R on NK cells functions as a signal-transducing molecule because the addition of 0.2 mg/ml IgM to R-NK cells caused a rapid increase in [Ca2+]i (delta = 40 nM). One of the early events that followed signaling through the Fc mu R was the down-modulation of IFN-gamma gene expression and IFN gamma production in NK cells. The presence of IgM during culture of NK cells consistently decreased the expression of HLA-DR (16% vs 40% in control). Thus, the Fc mu R, a constitutively-expressed receptor on human NK cells, seems to be an important functional molecule, which delivers negative regulatory signals to NK cells.
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PMID:Characterization of the Fc mu receptor on human natural killer cells. Interaction with its physiologic ligand, human normal IgM, specificity of binding, and functional effects. 769 Jul 92

Idiotype-specific T cells were characterized in patients with multiple myeloma stage I by analysing idiotype-induced DNA synthesis (3H-thymidine incorporation), IL-2 and IFN-gamma production at the single cell level (ELISPOT) (in vitro tests) and delayed type hypersensitivity (DTH) skin reaction (in vivo test). In seven out of eight patients at least one of the four tests was positive. In five patients three or more tests were positive. One patient was negative in all four tests. Six patients had both IL-2 and IFN-gamma-secreting cells and three of them also a DTH response. Furthermore, those three patients with a proliferative response also had IL-2 and IFN-gamma-secreting cells induced by the idiotype. The data indicate that part of the idiotype-specific T cell fraction belongs to the CD4 Th1 cell population. Whether CD8-specific T cells also were present could not be ruled out. The present study provides further support for the existence of idiotype-specific T cells in multiple myeloma. Such cells might be an important target for an immune-mediated therapeutic approach.
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PMID:Idiotype-specific T cells in multiple myeloma stage I: an evaluation by four different functional tests. 783 49

There are three types of interferons (IFN), alpha, beta and gamma. IFN-alpha is produced in the leukocytes infected with virus, while IFN-beta is from fibroblasts infected with virus. IFN-gamma is induced by the stimulation of sensitized lymphocytes with antigen or non-sensitized lymphocytes with mitogens. It is believed that IFN-alpha and beta originated from the same ancestral gene, whereas IFN-gamma did not. IFN has not only an antiviral activity, but also various kinds of biological activities including cell growth inhibition, immunosuppressive effects, enhancement of macrophage, natural killer (NK) cell, killer (K) cell and neutrophil functions, and cell differentiation-inducing activity. IFN also shows the antitumor activity resulting from the integration of the above-mentioned biological activities. IFN is also deeply involved in the pathogenesis of various diseases, e.g., collagen diseases such as SLE and rheumatoid arthritis, insulin-dependent diabetes mellitus, fulminant hepatitis, severe pancreatitis, nephritis, multiple sclerosis, allergic diseases, and atherosclerosis. At present, IFN is clinically used in therapy against virus infections such as hepatitis B and C, and for malignancies such as renal cell carcinoma, multiple myeloma, malignant melanoma, glioblastoma, skin cancers, malignant lymphoma and chronic myelogenous leukemia.
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PMID:[Interferon-alpha, beta, gamma]. 799 28

T cells in multiple myeloma (MM) patients are highly susceptible to activation with the anti-CD3 monoclonal antibody (mAb) OKT3. When short-term OKT3 stimulation is carried out on bone marrow mononuclear cells (BMMC), large numbers of CD3+ CD25+ HLA-DR+ cells are rapidly generated and autologous malignant plasma cells are killed. OKT3 may thus be exploited in autologous bone marrow transplantation (ABMT) to purge residual plasma cells and simultaneously activate T cells to induce graft-versus-leukemia-like (GVL-like) activity upon reinfusion. However, the possible impact of ex-vivo short-term OKT3 stimulation on haematological recovery is unknown. The aim of this work was to investigate the effect of OKT3 stimulation in vitro on autologous haemopoietic progenitor cells (HPC) of MM patients. Colony formation by granulocyte-macrophage progenitor cells (granulocyte-macrophage colony-forming units, CFU-GM) was highly suppressed, although supernatants of OKT3-activated T cells contained up to 2,500 pg/ml of granulocyte-macrophage colony-stimulating factor (GM-CSF). T cell depletion completely prevented this suppression. Neutralizing antibodies against TNF-alpha, TNF-beta and IFN-gamma (which are also produced by OKT3-activated MM T cells) did not prevent it, and Transwell cultures showed that cell-to-cell contact was the main mechanism involved. OKT3-activated T cells also suppressed erythroid burst-forming units (BFU-E) and CFU-GM generation from HPC responsible for long-term maintenance of in vitro myelopoiesis. When tested on normal allogeneic BM, MM supernatants of OKT3-stimulated BMMC partially suppressed the generation of day 7 CFU-GM, but had no effect on day 14 CFU-GM. These data indicate that short-term stimulation of BMMC with OKT3 can be used to generate anti-tumour effector T cells for autologous adoptive immunotherapy. It is not a feasable approach for ex-vivo purging and activation procedures in ABMT because of its potent inhibition of autologous haemopoiesis.
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PMID:Generation of anti-tumour activity by OKT3-stimulation in multiple myeloma: in vitro inhibition of autologous haemopoiesis. 799 89

Interleukin-6 (IL-6) mediates pleiotropic functions through specific receptors (IL-6R) composed of an 80-kDa binding protein, associated with a non-ligand binding protein (gp130) which transduces the signal. Because IL-6 is the major tumor growth factor in multiple myeloma, we investigated the regulation of IL-6R in two human multiple myeloma cell lines. Binding experiments with 125I-labeled IL-6 showed that IL-6R were expressed at a high density on RPMI-8226 cells (15 000 receptors/cell), but no specific binding was detected on XG-1 cells, whose growth depends on the presence of exogenous IL-6. However, when IL-6 was removed from the culture medium, high-affinity IL-6R appeared on the surface of XG-1 cells (5300 sites/cell). Treatment of RPMI-8226 cells with IL-6 reduced the number of IL-6R without changing their affinity. This reduction was dose dependent and was not affected by acid treatment which dissociates ligand-receptor complexes. Cross-linking experiments showed that the formation of one IL-6/receptor complex of 160 kDa markedly decreased upon IL-6 treatment, while the other complex of 190 kDa became undetectable. These data provide evidence for ligand-induced down-regulation of membrane IL-6R expression in myeloma cells. Treatment of RPMI-8226 cells with interferon-alpha (IFN-alpha), which inhibits the growth of these cells, stimulated IL-6R expression and increased the formation of the 160-kDa IL-6/receptor complex. This stimulation was specific for IFN-alpha, since IFN-gamma reduced the number of IL-6R. These data indicate that, in myeloma cells, IL-6R are differentially regulated by IL-6 and IFN-alpha.
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PMID:Differential regulation of interleukin-6 receptors by interleukin-6 and interferons in multiple myeloma cell lines. 802 May 47

The stimulation of peripheral blood mononuclear cells by purified autologous and/or allogeneic monoclonal IgG was studied in five patients with multiple myeloma (MM), nine patients with monoclonal gammopathy of undetermined significance (MGUS) and six healthy individuals. Single cells secreting IFN-gamma or IL-2 were identified using an enzyme-linked immunospot assay. Patients' cells were preferentially stimulated by autologous monoclonal IgG at low concentrations (1-100 pg/ml), while 100 ng/ml or higher stimulated T cells both from patients and, to a lesser degree, healthy individuals. This biphasic dose-response of T-cell stimulation by autologous monoclonal IgG was reproduced in all patients. The numbers of cells secreting IFN-gamma and IL-2 in response to allogeneic IgG were significantly lower than the numbers obtained using autologous IgG in patients with MM and MGUS. Cells from healthy individuals were stimulated by allogeneic monoclonal IgG, but to a lesser extent. The results of this study support the presence of idiotype-reactive T cells in patients with MM and MGUS and also may suggest a general but less pronounced T-cell reactivity to monoclonal IgG among these patients.
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PMID:T-cell stimulation induced by idiotypes on monoclonal immunoglobulins in patients with monoclonal gammopathies. 825 10

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

A consensus regarding myeloma cell growth factor responsiveness and ability to produce autocrine interleukin (IL)-6 has not yet been obtained. In this study, we have established three new human myeloma cell lines (DP-6, KAS-6/1 and KP-6) from patients with aggressive disease. Extensive characterization of these cell lines revealed considerable heterogeneity at several levels. Growth factor responsiveness was initially addressed. Although the potent myeloma cell growth factor, IL-6, induced the proliferation and allowed for the expansion of all three cell lines, a panel of other cytokines elicited heterogeneous responses in each cell line. IL-3, IL-10, IL-11, insulin-like growth factor-I and tumor necrosis factor-alpha also stimulated DNA synthesis in all three cell lines; however, the magnitude of the response was generally lower than that observed in cultures containing IL-6. Transforming growth factor-beta, by contrast, uniformly inhibited the growth of all three cell lines. IL-1alpha and IL-1beta induced the proliferation of the DP-6 cells, but had minimal effects on the KAS-6/1 and KP-6 cells. Interferon (IFN)-alpha stimulated DNA synthesis in the KAS-6/1 cells, but inhibited the proliferation of the DP-6 and KP-6 cells. By comparison, IFN-gamma induced the growth of the KAS-6/1 and DP-6 cells, but inhibited the KP-6 cells. The gp130-associated cytokines, IL-11, leukemia inhibitory factor and oncostatin M, stimulated the growth of the KAS-6/1 cells, but had minimal effects on the DP-6 and KP-6 cells. The cell lines were also analyzed for IL-6 expression. RT-PCR analysis demonstrated that all three cell lines expressed IL-6 mRNA. However, when culture supernatants were tested using a sensitive IL-6 ELISA or IL-6 bioassay only the DP-6 and KP-6 cells were shown to be secreting biologically active IL-6. In summary, although all three of these cell lines were established from myeloma patients, the heterogeneity observed between these cell lines was considerable and may reflect, as well as provide tools to study, the heterogeneity observed in clinical disease.
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PMID:Establishment and characterization of three myeloma cell lines that demonstrate variable cytokine responses and abilities to produce autocrine interleukin-6. 865 85

Mouse myeloma cell line VKCK/RM4-IFN-gamma secreting the bifunctional fusion protein RM4/IFN-gamma was used to study the relationship between IFN-gamma secretion of tumor cells and its tumorigenicity and to study the potential mechanism responsible for the immune response. IFN-gamma secretion of VKCK/RM4-IFN-gamma tumor cells was estimated at 90 U/ml using an antiviral assay. To evaluate tumorigenicity, 5 x 10(5) viable IFN-gamma-secreting VKCK/RM4-IFN-gamma and non-IFN-gamma-secreting VKCK tumor cells were injected s.c. into syngeneic BALB/c mice and VKCK/RM4-IFN-gamma-immunized or T cell subset-depleted BALB/c mice, respectively. Tumor progression or regression was evaluated 2 weeks after tumor inoculation. Our animal studies showed that RM4/IFN-gamma secretion by VKCK/RM4-IFN-gamma tumor cells curtailed its tumorigenicity in BALB/c mice and induced a persistant protective immune response against a subsequent graft of parental VKCK tumor. This protective immunity is long term and tumor specific as measured in a 51Cr-release assay. In addition, our animal studies in T cell subset-depleted BALB/c mice showed that CD8 CTL play a major role in the reduction of tumorigenicity. This study thus highlights the potential advantages of localized IFN-gamma in tumors to induce potent antitumor immunity and further suggests that the bifunctional fusion protein RM4/IFN-gamma may be useful in cancer immunotherapy because of its capacity of targeting IFN-gamma to human tumors expressing the human tumor-associated TAG72 antigen [corrected].
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PMID:Mouse myeloma cell line secreting bifunctional fusion protein RM4/IFN-gamma [corrected] elicits antitumor CD8 MHC class I-restricted T cells that are cytolytic in vitro and tumoricidal in vivo. 891 Jul 61


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