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

Spleen cells from rats which had been hyperimmunized with mouse lymphokine-activated killer (LAK) cells, were fused with the mouse myeloma cell line, P3 X 63 Ag8.653. Antibodies secreted by 1500 cultures were selected by their blocking effect on LAK cell-mediated cytotoxicity in the absence of complement. Two monoclonal antibodies (KBA4 and KBA6) greatly inhibited the cytotoxic activity of LAK cells, which were induced from mouse spleen cells by culture with recombinant human interleukin 2 (r-IL-2). These antibodies also blocked the cytotoxic activity of natural killer (NK) cells, but activated macrophages (A-M phi) were only slightly sensitive to them. However, no effect of the antibodies on the cytotoxic activity of cytotoxic T lymphocytes (CTL) was detected. These data suggest that the specific antigen, lymphokine-activated cell-associated (LAA) antigen, defined by these monoclonal antibodies may be associated with the recognition mechanisms of broad-reactive killer (BRK) cell-mediated cytotoxicity. The observation that low levels of LAA antigen are distributed in all lymphoid cells and that it was significantly enhanced by treatment of the cells with r-IL-2 suggests that the antigen may be involved in lymphocyte-activation mechanisms. We also found that the LAA antigen consists of two distinct polypeptides with Mr of 180,000 and 95,000 Da, which are similar to that of LFA 1 antigen. However, the biological characteristics of LAA antigen did not coincide with those of LFA 1. Therefore, KBA MAb may recognize a carbohydrate epitope distinct from that of LFA 1.
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PMID:Lymphokine-activated cell-associated antigen involved in broad-reactive killer cell-mediated cytotoxicity. 387 1

In attempts to generate monoclonal antibodies with reactivity directed against the lymphokine Interleukin 2 (IL-2, T cell growth factor), spleen cells harvested from BALB/c mice previously immunized with rat IL-2 were fused with the BALB/c myeloma SP2. Several of the resultant hybrid cell lines secreted a product that significantly neutralized (greater than 50%) IL-2--dependent T cell proliferation. Several lines of evidence suggested that the inhibitory activity was associated with a monoclonal IgG antibody directed against IL-2 determinants. First, passage of cloned hybrid cell culture supernatants through a protein A-coupled Sepharose column yielded purified immunoglobulin G fractions that inhibited mouse, rat, and human IL-2 activity. Secondly, hybridoma-derived IgG, in concert with lyophilized Staphylococcus aureus, was capable of precipitating both "cold" and intrinsically labeled IL-2 activity. Finally, Sepharose conjugated with purified IgG fractions provided on extremely reactive IL-2 absorption matrix. These results suggest that monoclonal antibodies directed against IL-2 determinants may eventually provide new detection assays for IL-2 and allow affinity chromatography to be employed for the isolation of this lymphokine.
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PMID:The biochemical and biological characterization of lymphocyte regulatory molecules. VI. Generation of a B cell hybridoma whose antibody product inhibits interleukin 2 activity. 697 16

In a group of 111 patients with multiple myeloma (MM) comprising a group of 34 patients examined when the diagnosis was established and a group of 77 patients evaluated in different stages of the disease, the author examined the relationship between the interleukin-6 serum level (IL-6), assessed by the method of enzyme immunoanalysis and selected laboratory indicators of the disease. Elevated IL-6 values were recorded in 38% of the patients. In neither of the groups significant relations were found between IL-6 and calcium, urea, creatinine levels, the amount and type of monoclonal immunoglobulin, lacticode dehydrogenase, beta 2-microglobulin, ferritin, IL-2 and its soluble receptor in serum and the incidence of myeloma plasmocytes in bone marrow. In the second (but not in the first) group a significant relationship was recorded between IL-6 levels and the red cell sedimentation rate, the Hb value, the CRP level and serum albumin and the value of thymidinekinase in serum of patients with a value beyond the normal range. From the investigation ensues that examination of IL-6 serum levels in MM contributes so far mainly to improvement of the diagnosis and expedient classification of this disease in clinical practice.
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PMID:[Serum interleukin-6 in multiple myeloma: I. Relation to selected laboratory indicators of disease]. 748 49

In the present study the gene expression of cytokines promoting in vitro myeloma-cell growth was investigated by Northern blot analysis using total RNA of 36 tumour samples of patients with multiple myeloma (MM) or plasma cell leukaemia and poly(A)+ RNA of 10 human myeloma cell lines (HMCL). These cytokines included interleukin (IL)-1 alpha, IL-1 beta, IL-3, IL-6, granulocyte-macrophage (GM)-colony-stimulating factor (CSF) and granulocyte (G)-CSF. IL-1 beta, IL-6 and G-CSF genes were coexpressed in most patients, although at variable levels. IL-1 alpha transcripts were detected in 32% of patients in whom coexpression of IL-1 beta gene was found. IL-3 gene was not expressed in patients' cells and GM-CSF mRNA was detected in only 1/32 patients. No detectable transcripts for the above cytokines were present in HMCL, whereas IL-6 gene was expressed in 2/10 HMCL. We also looked for the presence of transcripts for IL-2, leukaemia inhibitory factor (LIF) and transforming growth factor (TGF)beta in cells of tumour samples from the same patients and in HMCL. IL-2 gene was not expressed in MM patients and HMCL. Weak expression of LIF gene was detected in three patients (9%), and transforming growth factor beta (TGF beta) mRNA was observed in 12/12 tumour samples analysed and all HMCL. These results suggest that, among cytokines shown to control myeloma-cell growth in vitro, IL-1, IL-6 and G-CSF could play a role in the development of myeloma disease in vivo.
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PMID:Cytokine gene expression in human multiple myeloma. 751 Sep 89

We have previously reported the presence of activated (HLA-DR+) T cells in multiple myeloma (MM) patients. These cells produce high amounts of interleukin (IL)-2 and interferon (IFN)-gamma and generate a potent antiplasma cell activity after appropriate in vitro stimulation, but they are unable in vivo to hold in check the disease. Activated T cells are highly susceptible to apoptosis, a form of programmed cell death involved in the modulation of immune responses and regulated by molecules such as Fas (CD95) and bcl-2. The aim of this study was to determine the expression of Fas and bcl-2 antigens and the susceptibility to apoptosis in T cells of MM patients. Fas+ cells were significantly higher, whereas bcl-2+ cells were significantly lower in MM patients than in the controls. MM patients with the highest number of HLA-DR+ T cells showed the highest Fas and the lowest bcl-2 expression. Two-color cytofluorometric analysis confirmed in individual cells that HLA-DR+ T cells coexpressed Fas and lacked bcl-2. Susceptibility to apoptosis was then investigated to evaluate the consequence of dysregulated Fas and bcl-2 expression. The percentage of apoptotic cells after incubation in medium alone (spontaneous apoptosis) or in the presence of methylprednisolone (MP) or anti-Fas monoclonal antibody (triggered apoptosis) was significantly higher in MM and mainly restricted to HLA-DR+ T cells. Spontaneous apoptotosis was reverted by exogenous IL-2. In conclusion, MM T cells have a dysregulated expression of Fas and bcl-2 antigens that is associated with an enhanced susceptibility to apoptosis. These data may unravel a novel mechanism by which activated MM T cells are weakened in their ability to exert an effective antitumor activity in vivo.
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PMID:Dysregulated Fas and Bcl-2 expression leading to enhanced apoptosis in T cells of multiple myeloma patients. 754 69

In 1994, an estimated 12,700 new cases of multiple myeloma (MM) will be diagnosed in the USA and 9,800 patients will die from this disease. At present, a cure for MM has not been achieved with any chemotherapeutic regimen. Therefore, it is important to develop novel therapeutic approaches to treat this fatal disease. This review focuses on new concepts in the immunotherapy of MM. Thus far, interferons and anti-human interleukin (IL)-6 monoclonal anti-bodies (MAbs) have been used to treat patients with this disease. Bone marrow transplantation using autologous marrow purged with MAbs and complement, with anti-myeloma immunotoxins (ITs), or MAb-magnetic bead conjugates has been reported. Adoptive cellular therapy, in vivo with anti-CD3 and IL-2, as well as transplantation of purified autologous CD34+ peripheral blood stem cells, is now being evaluated in clinical trials. Anti-human IL-6 receptor (IL-6R) and anti-CD54 (ICAM-1) MAbs have shown promising results in the therapy of human myeloma cell lines in SCID mice, while an IL-6 antagonist protein, anti-gp130 MAbs, recombinant soluble gp130, anti-B7, anti-HLA-DR, and recombinant soluble CD16 also inhibit the growth of myeloma cell lines in vitro. These experimental therapeutic modalities hold promise for use in humans and may also provide further insights into the pathogenesis of MM.
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PMID:Immunotherapy of multiple myeloma. 754 Apr 68

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

The baculovirus expression system has been used for the production of a variety of proteins, including antibodies. Two single-gene constructs encoding single-chain immunoglobulins have recently been developed. The antibody employed was monoclonal antibody (MAb) CC49 which reacts with the pancarcinoma antigen, tumor associated glycoprotein, TAG-72. One, single-chain construct designated SCA delta CLCH1 (SCIg), consists of the CC49 sFv covalently joined to the human Fc (gamma 1) through the hinge region. The other, SCA delta CLCH1-IL-2 (SCIg-IL-2), has a human IL-2 molecule attached to the carboxyl end of the SCIg. These constructs have been used to test the feasibility of producing biologically active antibodies using the baculovirus expression system. Both constructs have been successfully expressed in insect cells and purified. The baculovirus recombinant single-chain antibodies have been designated, bV-SCA delta CLCH1 (bV-SCIg) and bV-SCA delta CLCH1-IL-2 (bV-SCIg-IL-2) they have been shown to be secreted in the culture supernatant as dimeric molecules of approximately 115 kDa and 140 kDa, respectively. The specificity and antibody dependent cellular cytolytic activity of the baculovirus recombinant single-chain antibodies were shown to be similar to that of the myeloma derived molecules. Glycosylation analysis showed that baculovirus derived proteins were N-glycosylated, but carried few if any high mannose residues. The biological activity of the IL-2 moiety was retained in bV-SCIg-IL-2, as evidenced by its stimulatory effect on the proliferation of the IL-2 dependent cell line HT-2. The observation that a significantly shorter time is required to develop baculovirus recombinant molecules as compared to myeloma derived molecules and that insect cells express single chain MAbs at acceptable levels may have implications for the production of these molecules for clinical use.
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PMID:Baculovirus expression of a functional single-chain immunoglobulin and its IL-2 fusion protein. 759 24

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

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


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