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)

Studies with human myeloma-derived IgD have demonstrated the existence of IgD-R on peripheral blood T cells. These receptors, which are detected by rosetting with IgD-coated ox E (IgD-rosette-forming cells), are competitively inhibited by IgD, but not by IgM or IgG. Similar results were obtained with human T cell clones and T hybridomas derived from such clones either by rosetting assays or by staining with biotinylated-IgD. In agreement with studies of murine IgD-R+ cells, human IgD-R can be up-regulated by exposure of peripheral blood T cells, T cell clones, and hybridomas derived from such clones, to oligomeric IgD, but not monomeric IgD. Human IgD-R can also be induced by IL-2, IL-4, and IFN-gamma. In contrast with studies of murine IgD-R, which are expressed primarily by CD4+ cells, phenotyping studies show that both the CD4+ and CD8+ human T cell subsets are capable of expressing IgD-R.
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PMID:IgD-receptor-positive human T lymphocytes. I. Modulation of receptor expression by oligomeric IgD and lymphokines. 212 22

The t(14;18) of human follicular B cell lymphoma translocates the Bcl-2 gene into the Ig H chain locus and markedly deregulates Bcl-2 expression. We sought to determine if Bcl-2 could be directly implicated in a growth-factor pathway. Consequently, we introduced a retrovirus containing the murine Bcl-2 gene (N2-M-Bcl-2) or the parental retrovirus (N2) into a series of factor-dependent hemopoietic cell lines. Overexpressed Bcl-2 resulted in no long term IL-2, IL-3, or IL-6 independent clones, indicating that Bcl-2 could not spare the need for a specific ligand-receptor interaction. However, Bcl-2 did extend the short term survival of IL-3-dependent cell lines after factor deprivation. Although viable, IL-3-deprived pro B lymphocytes (FL5.12) bearing N2-M-Bcl-2 were in Go, and deregulated Bcl-2 did not obviously influence cell-cycle progression. Bcl-2 predominant effects were to delay the onset of cell death and to modestly augment viable cell growth in the first 48 h after IL-3 deprivation. This death sparing was associated with increased levels of Bcl-2 RNA and protein in factor-deprived cells possessing N2-M-Bcl-2. This result was not restricted to prolymphocytes because an IL-3-dependent mast cell line (32D) as well as a promyeloid line (FDC-P1) demonstrated the same response to Bcl-2. Moreover, the effect was not limited to the IL-3/IL-3R signal transduction pathway in that promyeloid cells maintained in granulocyte-macrophage-CSF or IL-4 displayed a similar response. Yet, Bcl-2-enhanced cell survival was not universal as an IL-2-dependent T cell line, and an IL-6-dependent myeloma line demonstrated no consistent effect upon IL withdrawal. Thus, Bcl-2 appears to interfere with cell death but in a cell type and/or factor-restricted fashion.
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PMID:Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. 218 93

Recently, the failure of interleukin 4 (IL4) autocrine growing CT4S cells to grow in vivo has been demonstrated. Because it could not be excluded that the cells produce insufficient amounts of IL4 to support their growth in vivo, subclones were established which are unresponsive to exogenous IL4 and therefore have acquired full growth autonomy. From the fact that the subclones likewise did not give rise to tumors when injected into nude mice, one may conclude that the IL4 production of autocrine growing CT4S prevents their growth in vivo. To test this hypothesis, a retroviral vector containing the IL4 gene under the control of the immunoglobulin heavy chain (Igh) enhancer/promoter was constructed and used to infect the myeloma cell line J558L. An IL4 producing clone was established (J558L-XEPIL4) and the tumor progression in comparison to the parental clone J558L was monitored in nude mice. The IL4 production significantly delayed the growth of J558L-XEPIL4 in vivo. Tumor suppression was much more evident when J558L-XEPIL4 cells were injected into syngeneic BALB/c mice. These results may explain why autocrine growing CT4S do not grow in vivo and suggest the involvement of functional T lymphocytes in the effectiveness of the host dependent anti-tumor action of IL4.
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PMID:Lack of tumorigenicity of interleukin 4 autocrine growing cells seems related to the anti-tumor function of interleukin 4. 227 62

A number of antigens (Ags) are expressed on normal and malignant terminal B (plasma) cells, including plasma-cell, earlier B-cell, and non-B cell-Ags. These Ags, coupled with indirect and dual fluorochrome labelling techniques, permit characterization of normal and malignant in vitro and in vivo terminal B-cell differentiation. The majority (90%) of B cells within spleen bear Bl and lack PCA-1 Ags. As B cells differentiate to pokeweed mitogen in vitro, immunoglobulin (Ig) secretion precedes the appearance of cell surface PCA-1 and plasmacytoid morphology. Dual fluorescence cell sorting permits characterization of in vivo B-cell differentiation: Bl + PCA-1 + cells are more "differentiated" since they are more prevalent in lymph node than spleen, exhibit plasmacytoid morphology and maximal Ig secretion, and no longer respond to triggers of B-cell proliferation; in contrast, Bl + PCA-1-cells are lymphoid in morphology and may respond to triggers of B-cell proliferation as "resting" B cells. Similar studies of myeloma cells demonstrated that they may also include cells expressing plasma-cell, earlier B, and non-B cell Ags. Although they neither proliferated nor secreted Ig in vitro to G/M-CSF, G-CSF, M-CSF, IL-1, IL-1B, IL-2, or IL-4, proliferation without Ig secretion (Stimulation Index greater than or equal to 3.0) was induced to IL-6 in 6 of 10 patients (pts); to IL-3 (2 pts) and to IL-5 (2 pts).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phenotypic and functional characterization of normal and malignant terminal B (plasma) cells. 262 90

The content of peripheral blood B cells (B1+) was reduced in patients of multiple myeloma (MM) and not in those with benign monoclonal gammopathy (BMG) compared to normal donors (P less than 0.01). This observation correlated with the suppression of synthesis of normal immunoglobulin (Ig) in MM. Thus, cytokine activities regulating the proliferation of normal mature B cells, such as B cell stimulatory factor 1 (BSF-1)/interleukin 4 (IL-4), B cell growth inhibitory factor (BIF) and IL-2 in peripheral blood T cells, and IL-1 in peripheral blood adherent cells, were investigated in patients with BMG (n = 7) and MM (n = 28). All patients of MM having a marked suppression of synthesis of all other normal Ig, had significantly lower levels of BSF-1 activity and inversely higher levels of BIF activity than those of normal donors. However, patients with BMG having no suppression of synthesis of normal Ig had BSF-1 and BIF activities similar to normal donors. There was no significant difference in IL-1 and IL-2 activities between both normal donors and BMG versus MM patients. These data show that in MM altered cytokine activities correlate with suppression of synthesis of normal Ig.
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PMID:Altered cytokine activities are related to the suppression of synthesis of normal immunoglobulin in multiple myeloma. 264 60

By using the reverse transcriptase (RT)-PCR and in situ hybridization we have studied the expression of mRNA for IL-5 and IL-4 in human lung mast cells induced by cross-linkage of high affinity Fc epsilon Rs. Lung mast cells were purified using affinity magnetic selection with mAb YB5.B8 against c-kit to achieve a final mast cell purity > 93%. Purified mast cells were precultured with stem cell factor (SCF) (10 ng/ml) and myeloma IgE (3 micrograms/ml) for 16 h before challenge with anti-IgE (1 or 10 micrograms/ml). IgE-dependent activation of lung mast cells caused expression of IL-5 mRNA, which was evident by 2 h and persisted for up to 48-72 h in all of 12 experiments, whereas IL-4 mRNA expression was of a shorter duration and was demonstrable in 6 of 13 experiments. We confirmed that mast cells, and not T cells, were the source of these cytokine messages by using reverse transcriptase-PCR in cell preparations containing known numbers of mast cells and T cells, in situ hybridization in enriched mast cell preparations, and double in situ hybridization-immunocytochemical staining. IL-5 mRNA expression did not require the pretreatment of cells with SCF, whereas expression of IL-4 mRNA seemed to require both anti-IgE and SCF. The strength of IL-5 mRNA signal was related to anti-IgE concentration. Immunoreactive IL-5 was detectable 8 h after anti-IgE challenge, and 10(6) mast cells generated a mean of 731 +/- 400 pg of IL-5 into the supernatant during 48-h culture, but no IL-4 product was detectable. These findings demonstrate the capacity of human lung mast cells to transcribe IL-4 and IL-5 after IgE-dependent activation and to synthesize and release immunoreactive IL-5.
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PMID:IgE-dependent expression of mRNA for IL-4 and IL-5 in human lung mast cells. 754 33

The presence of idiotype-reactive T-cell subsets and their relation to the tumor load were analyzed in 9 patients with monoclonal gammopathy of undetermined significance (MGUS), in 12 patients with multiple myeloma (MM) clinical stage I, and in 9 patients with MM stage II/III. An enzyme-linked immunospot assay was used to identify interferon-gamma (IFN-gamma)-, interleukin-2 (IL-2)-, or IL-4-secreting T cells after stimulation by F(ab')2 fragments of monoclonal IgG. The response to autologous IgG was significantly higher than that induced by isotypic monoclonal IgG. Comparable results were obtained in a proliferation assay (3H-thymidine incorporation). A total of 8 of 9 patients with MGUS, 7 of 12 patients with MM stage I, and 3 of 9 with MM stage II/III had T cells secreting IFN-gamma and/or IL-2 (T helper [Th1] type-1 cells), whereas cells secreting both Th1 and Th2 or Th0 types of cytokines were more frequent in patients with MM, particularly in those with MM stage II/III. The number and frequency of Th1-type cells were significantly higher in MGUS patients as compared with those of MM stage II/III. The results indicate that idiotype-reactive T cells of the Th1 and Th2 or Th0 subsets were present in MGs and might provide indirect evidence that idiotype-reactive Th1-type cells may have a regulatory impact on the human tumor B cells.
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PMID:Idiotype-reactive T-cell subsets and tumor load in monoclonal gammopathies. 757 98

A large expansion of activated T cells (CD3+CD25+) with the potential to act as anti-tumour effector cells is inducible in multiple myeloma (MM) patients by culturing bone marrow mononuclear cells (BMMCs) with the anti-CD3 monoclonal antibody (mAb) OKT3. The aim of this study was to provide a greater characterization of CD3-activated T cells. On day 6, most T cells coexpressed the CD11a, CD18, CD54, CD45R0 antigens and consisted of activated (CD25+) CD4+ and CD8+ cells in nearly equal proportions. Kinetics studies showed that CD4+CD25+ cells proliferated more rapidly and peaked earlier than CD8+CD25+ cells. When experiments were performed with purified subpopulations by removing CD4+ cells (resulting in CD8+ BMMCs) or by removing CD8+ cells (resulting in CD4+ BMMCs). T-cell activation and autologous plasma cell decrease were observed in CD4+ BMMCs only. Transwell cultures showed that CD4 help was necessary to make CD8+ BMMCs susceptible to CD3 stimulation. Relevant amounts of IL-2 were found in the supernatants of CD4+ BMMCs cultures, whereas no secretion of IL-4 was detected, indicating a Th1-like profile of CD3-activated CD4+ cells. These data indicate that CD4+ cells proliferate earlier and provide optimal help to induce the subsequent expansion of CD8+ cells after CD3 stimulation of MM BMMCs. Adequate stimulation of CD4+ cells is therefore essential in any strategy aiming to recover T-cell-mediated immunity in MM.
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PMID:CD3-induced T-cell activation in the bone marrow of myeloma patients: major role of CD4+ cells. 764 4

Multiple myeloma (MM) is a slow-growing malignancy whose plasma cells express the BCL-2 antiapoptosis gene. It is also associated with high levels of interleukin-6 (IL-6), a cytokine that prevents programmed cell death (PCD) in other target cell types. We thus investigated the ability of MM cells to undergo PCD and the possible regulatory effects of IL-6. Four MM cell lines underwent PCD when exposed to serum starvation, doxorubicin (dox), etoposide (VP-16), or dexamethasone (dex). Apoptosis was confirmed by morphologic criteria and/or detection of endonucleosomal DNA fragmentation. The concentrations of dox, VP-16, and dex required for PCD were at least 10-fold greater than that required to inhibit proliferation. Addition of IL-6 (but not IL-1 beta, IL-4, IL-7, or IL-10) inhibited PCD of 8226 targets induced by serum starvation or dexamethasone in a concentration-dependent fashion. In contrast, it had no effect on PCD induced by dox or VP-16. Exposure of targets to IL-6 did not increase BCL-2 expression (it actually consistently decreased expression), suggesting IL-6's protection against apoptosis was not mediated by direct effects on BCL-2. Targets protected from PCD by IL-6 were still sensitive to serum starvation and dex-induced cytostasis, but, after reculturing in drug-free complete media, they reinitiated normal proliferation. These data suggest that high levels of IL-6 may contribute to expansion of myeloma clones by inhibiting apoptotic death.
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PMID:Interleukin-6 inhibits apoptosis of malignant plasma cells. 774 52

The effects of tumour necrosis factor-alpha (TNF-alpha) and interleukin 4 (IL-4) on peripheral blood mononuclear cells (PBMC) from 36 patients with multiple myeloma (MM), 12 with monoclonal gammopathy of undetermined significance (MGUS) and 21 normal controls, were investigated. In 16/36 patients with MM, monoclonal plasma cells appeared after 4d in cultures containing TNF-alpha and IL-4. These changes were not observed in PBMC from patients with MGUS or from normal controls. These findings suggest that myeloma cell precursors do exist in the peripheral blood of MM patients and differentiate into plasma cells in the presence of TNF-alpha and IL-4. Based on these observations, we think that the variation in the number of myeloma cell precursors in peripheral blood could be used as a prognostic parameter of response to chemotherapy in myeloma patients. In addition, this assay may be useful to distinguish early-stage MM from MGUS.
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PMID:Tumour necrosis factor-alpha and interleukin 4 promote the differentiation of myeloma cell precursors in multiple myeloma. 780 39


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