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)

An approach to obtain monoclonal antibodies directed against cell surface proteins induced by interferon has been developed in order to characterize such proteins and determine their role. Hybridomas obtained by fusion of murine myeloma cells and spleen cells of mice immunized with interferon-alpha-treated Daudi cells were screened for the production of antibodies reacting differentially with interferon-alpha-treated and untreated Daudi cells. One such hybridoma, 2D5, produced an antibody reacting with a 28/32 kDa homodimeric protein (p28/32) expressed at the surface of Daudi cells in response to IFN-alpha treatment. IFN-alpha treatment also increased the basal level of p28/32 detected on peripheral blood leukocytes (PBL). 2D5 Antibody was used to probe the expression of p28/32 on different cells and in response to various inducers. It appears that 2D5 reacted in fact with CD69, a marker of leukocyte activation and that, following IFN-alpha treatment, CD69 was not induced on all cultured cell lines tested. Interestingly, IFN-gamma was also able to induce CD69 expression on a restricted number of cell lines but the induction pattern only partially overlapped that of IFN-alpha. As expected, activation of cells with phorbol myristate acetate (PMA) resulted in a notable increase in the level of CD69 on all cell lines considered except for the epithelial and fibroblastic types.
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PMID:CD69 is expressed on Daudi cells in response to interferon-alpha. 161 56

The blood of multiple myeloma patients was examined for non-MHC-restricted cytotoxic lymphocytes. Four colour flow cytometry was used to phenotype the cells within a light scatter gate large enough to include all lymphocytes. NK and T cells were identified using CD16, CD56, and CD3 antibodies, and myeloid cells with CD13 and CD14 antibodies. Three subpopulations of NK cells and 3 subpopulations of CD16+ or CD56+ T cells were enumerated. The CD56+ NK and T cells were also examined with CD69, CD25, and anti-HLA-DR antibodies to assess their activation state. We found no evidence that either the percentage or the absolute number of any subpopulation of the NK cells or CD56+ T cells correlated with disease activity. Neither did we find any significant abnormalities in the numbers of activated CD56+ NK or T cells. We conclude that it is unlikely that circulating non-MHC-restricted cytotoxic lymphocytes are responsible for maintaining disease stability in myeloma patients with indolent disease.
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PMID:Natural killer cells and CD56+ T cells in the blood of multiple myeloma patients: analysis by 4-colour flow cytometry. 881 87

Flow cytometry immunophenotyping of peripheral blood lymphocyte subsets and multivariate data-analytical techniques revealed that among untreated hemato-oncological patients (n = 48) with lymphomas, acute and chronic myeloid and lymphocytic leukemias, monoclonal gammopathy of undetermined significance, and multiple myeloma, 42% had (nonmalignant) lymphocyte profiles clearly distinct from healthy donors. Notably, a similar pattern of increased CD3+ CD57+, CD3+ HLA-DR+, CD3+ CD(16 + 56)+, CD4- CD8+, CD8+ CD57+, CD8+ CD28-, and CD8+ CD62L- subsets was detected. More extensive three-color immunophenotyping on an additional group of 49 untreated patients revealed that both CD4+ and CD8+ T cells displayed significant increases of activation markers: CD69, CD(16 + 56), HLA-DR, CD71, and CD57, and a loss of CD62L and CD28, which is also interpreted as a sign of activation. Consistent with the phenotypical signs of in vivo immune activation, polyclonal cytolytic activity, measured ex vivo in an anti-CD3-redirected assay, was detected within immunomagnetically purified CD4+ T cells of three out of six B-CLL patients investigated, but not within purified CD4+ T cells of five healthy donors. The purified CD8+ T cells of patients (n = 28) and donors (n = 5) on the other hand displayed similar polyclonal cytotoxic activities at the various effector:target ratios investigated. Tumor-directed cytotoxic activity of purified CD4+ (n = 6) and/or CD8+ T cells (n = 15) against freshly isolated autologous tumor cells was not detected in any of the experiments. Collectively, our results demonstrate systemic T cell activation as a common feature in hematological neoplasia, and a markedly enhanced cytolytic activity of the CD4- subset in CLL patients. The reason(s) for this expansion of activated T cells and its pathophysiologic significance, however, remain unclear.
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PMID:Peripheral blood lymphocyte subset shifts in patients with untreated hematological tumors: evidence for systemic activation of the T cell compartment. 959 74

We have analysed the quantitative expression of surface CD69 antigen on human mast cells (MC), from both normal and pathological bone marrow (BM) samples, using flow cytometry. Our major aim was to analyse whether CD69 is constitutively expressed by normal BMMC and to explore the possible differences between CD69 expression by BMMC from normal controls and patients suffering from different pathological conditions. The constitutive expression of surface CD69 was clearly demonstrated in BMMC; however, systemic mast cell disease (SMCD) patients showed significantly higher levels of surface CD69 expression than healthy controls (P < 0.001), chronic lymphocytic leukaemia (P = 0.001), monoclonal gammopathy of unknown significance (P < 0.001), multiple myeloma (P < 0.001) patients, and myelodysplastic syndromes (P = 0.002). Furthermore, almost no overlap between the levels of CD69 expression on BMMC was observed between SMCD cases and the remaining groups of individuals except for the paediatric mastocytosis group (P > 0.05). From the other groups of patients, monoclonal gammopathy of unknown significance (P = 0.04), myelodysplastic syndromes (P = 0.03) and paediatric mastocytosis (P = 0.003) cases showed a significantly higher expression of surface CD69 as compared to normal subjects. In summary, our findings show that the CD69 antigen is overexpressed in SMCD patients.
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PMID:The CD69 early activation molecule is overexpressed in human bone marrow mast cells from adults with indolent systemic mast cell disease. 1046 May 98

Multiple myelomas produce tumor-specific antigen (TSA) in the form of idiotype (Id) on monoclonal Ig. CD4(+) T cells can recognize Id-peptide on MHC class II molecules and protect against challenges with MOPC315 cells, which are, as common for myelomas, class II-negative. The present study explains these previous results by demonstrating that Id can be transferred from myeloma cells to antigen-presenting cells (APC), which present processed Id-peptide on their class II molecules to Id-specific T cell receptor-transgenic (TCR-TG) CD4(+) T cells. Id-primed tumor APC were heterogeneous, the majority being dendritic cells with class II(+), CD11b(+) CD11c(+) CD40(+) CD80(+) CD86(+) markers. The APC were localized beneath CD31(+) endothelial cells of tumor microvessels, and their frequency declined with tumor progression. The APC could stimulate Id-specific naive TCR-TG, short-term polarized TCR-TG, and cloned CD4(+) T cells to proliferate and produce cytokines in vitro. Furthermore, small MOPC315 tumors established in Id-specific TCR-TG mice contained clusters of activated (CD69(+)CD25(+)) and proliferating (BrdUrd(+)) Id-specific transgenic CD4(+) blasts. The activated Id-specific T cells were located adjacent to Id-primed dendritic cells in the tumor. Thus, a TSA can be transferred in vivo from myeloma, and possibly other types of cancer cells to APC for MHC class II presentation to CD4(+) T cells.
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PMID:Dendritic cells purified from myeloma are primed with tumor-specific antigen (idiotype) and activate CD4+ T cells. 1070 28

Bisphosphonates are well-known inhibitors of osteoclastic bone resorption, but recent clinical reports support the possibility of direct or indirect antitumor effects by these compounds. Because bisphosphonates share structural homologies with recently identified gamma delta T-cell ligands, we examined the stimulatory capacity of bisphosphonates to gamma delta T cells and determined whether gamma delta T-cell stimulation by bisphosphonates could be exploited to generate antiplasma cell activity in multiple myeloma (MM). All tested aminobisphosphonates (alendronate, ibandronate, and pamidronate) induced significant expansion of gamma delta T cells (V gamma 9V delta 2++ subset) in peripheral blood mononuclear cell cultures of healthy donors at clinically relevant concentrations (half-maximal activity, 0.9-4 mcmol/L). The proliferative response of gamma delta T cells to aminobisphosphonates was IL-2 dependent, whereas activation of gamma delta T cells (up-regulation of CD25 and CD69) occurred in the absence of exogenous cytokines. Pamidronate-activated gamma delta T cells produced cytokines (ie, interferon [IFN]-gamma) and exhibited specific cytotoxicity against lymphoma (Daudi) and myeloma cell lines (RPMI 8226, U266). Pamidronate-treated bone marrow (BM) cultures of 24 patients with MM showed significantly reduced plasma cell survival compared with untreated cultures, especially in cultures in which activation of BM-gamma delta T cells was evident (14 of 24 patients with MM). gamma delta T-cell depletion from BM cultures completely abrogated the cytoreductive effect on myeloma cells in 2 of 3 tested patients with MM. These results show that aminobisphosphonates stimulating gamma delta T cells have pronounced effects on the immune system, which might contribute to the antitumor effects of these drugs. (Blood. 2000;96:384-392)
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PMID:Stimulation of gammadelta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. 1134 90

To investigate whether superantigen (SAG) from endogenous mouse mammary tumor virus functions as an immunogenic or a tumorigenic factor in tumor development, the BALB/c myeloma cell line FO was transfected with the SAG gene from the 3' Mtv-50 long terminal repeat (LTR) open reading frame (ORF), the product of which was specific for Vbeta6. All five transfectants expressing Mtv-50 LTR ORF mRNA showed stimulatory activity for Vbeta6 T-cell hybridomas in vitro; this activity was inhibited by the addition of anti-Mtv-7 monoclonal antibody (MAb) or anti-major histocompatibility complex class II I-A(d) and I-E(d) MAb. All transfectants with the SAG gene grew more rapidly than did mock transfectants in BALB/c mice after subcutaneous inoculation, whereas all clones, including mock transfectants, grew equally well in athymic nude mice. A significant fraction of Vbeta6 T cells selectively expressed activation markers, including CD44(high), CD62L(low), and CD69(high), and produced large amounts of interleukin 5 (IL-5) and IL-6 in BALB/c mice inoculated with transfectants. These results suggested that the expression of viral SAG enhances the tumorigenicity of a myeloma cell line through the stimulation of SAG-reactive T cells.
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PMID:Expression of mouse mammary tumor virus superantigen accelerates tumorigenicity of myeloma cells. 1095 19

Cytokine flow cytometry (CFC) is a simple and powerful method for measuring antigen-specific T-cell responses by detection of intracellular cytokine staining. We applied this method to the detection of CD4 T-cell responses to tumor vaccines. Patients with multiple myeloma were immunized against their autologous tumor immunoglobulin idiotype, using antigen-pulsed dendritic cell vaccination. Blood samples were drawn before and after vaccination, and CFC and proliferation assays were performed. For CFC, whole blood was incubated overnight with antigen in the presence of costimulatory antibodies to CD28 and CD49d. The blood was then treated with EDTA, erythrocytes were lysed, and leukocytes were fixed, permeabilized, and stained for intracellular cytokines [tumor necrosis factor-alpha (TNF-alpha) or IFN-gamma], CD4, and CD69. Cells were analyzed by flow cytometry and cytokine-producing CD69+ cells enumerated as a percentage of CD4 cells. Of nine patients analyzed, three demonstrated detectable CFC responses to tumor immunoglobulin and/or keyhole limpet hemocyanin (KLH) after vaccination. One of these patients responded only to KLH, whereas the other two responded to both tumor immunoglobulin and KLH. Most responses were detected with both TNF-alpha and IFN-gamma, but one patient's KLH response was detected only with TNF-alpha. There was a positive, but not strong, correlation of cytokine responses with proliferative responses to KLH. Although further follow-up and correlation with clinical outcome is needed, CFC may represent a simple yet detailed assessment of T-cell frequencies and subsets responding to cancer vaccines.
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PMID:Detection of CD4 T-cell responses to a tumor vaccine by cytokine flow cytometry. 1130 Apr 90

The purpose of these studies was to develop immunogenic peptides derived from the CD19 and CD20 self-antigens for the induction of antigen-specific CTLs against B-cell malignancies. A total of seven peptides were designed and examined for their HLA-A2.1 affinity and immunogenicity. Of these peptides, we identified two highly immunogenic HLA-A2.1-specific peptides, CD19(150-158) (KLMSPKLYV) and CD20(188-196) (SLFLGILSV), which were capable of inducing peptide-specific CTLs. The CTLs displayed HLA-A2.1-restricted and antigen-specific cytotoxicity against Burkitt's lymphoma, chronic B cell leukemia, and multiple myeloma cell lines. The CD19 or CD20 peptide-specific CTL cytotoxicity was confirmed using HLA-A2.1(+) T2 cells presenting the appropriate peptide. No cytotoxic activity was observed against T2 cells presenting the irrelevant MAGE-3 peptide or T2 cells alone. In addition, the CTLs displayed a significant (P < 0.05) increase in cell proliferation and IFN-gamma secretion (>830 ng/mL) following restimulation with HLA-A2.1(+)/CD19(+)/CD20(+) tumor cells. The CTLs also displayed a distinct phenotype consisting of a high percentage of CD69(+)/CD45RO(+) and a low percentage of CD45RA(+)/CCR7(+) CD4(+) or CD8(+) T cells characteristic of effector memory cell population. Cyclic guanosine 3',5'-monophosphate culture conditions using serum-free AIM-V medium containing human AB serum, recombinant human interleukin 2 (Proleukin) and CD3/CD28 Dynabeads were developed resulting in a 35-fold expansion of CD20 peptide-specific CTLs. The expanded CD20-CTLs retained their cytotoxic activity (28-49%) against the Burkitt's lymphoma cell line. In conclusion, we report here on the identification of novel immunogenic CD19(150-158) (KLMSPKLYV) and CD20(188-196) (SLFLGILSV) peptides that have immunotherapeutic potentials as peptide vaccines or targeted T-cell therapies for treating B-cell malignancies.
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PMID:Identification of CD19 and CD20 peptides for induction of antigen-specific CTLs against B-cell malignancies. 1574 68

Thalidomide (THAL) is currently used as a novel drug in patients with chemotherapy resistant or relapsed multiple myeloma. THAL antitumor activity seems to be very complex, however the precise mechanisms of its action are still not fully understood. The aim of this study was to assess some of possible mechanisms of THAL action both in in vivo analysis of immune cells phenotype and in in vitro cultures with THAL. The study involved 30 patients with relapsed or chemotherapy refractory multiple myeloma who were qualified to THAL treatment. We assessed immunophenotype of malignant plasma cells and T lymphocytes in both peripheral blood (PB) and bone marrow (BM) samples taken before and after 4 and 8 weeks of THAL treatment. Before therapy cytokine secretion (VEGF, HGF, bFGF, TNF, IL-6 an sIL-6R) and Bcl-2 expression in PB and BM cell cultures with THAL were analyzed. We used flow cytometry technique and ELISA method. The clinical response to therapy was assessed after 4 and 8 weeks of treatment. We also investigated microvessel density (MVD) in bone marrow samples before the THAL treatment and after 6 months of therapy in the group of responding patients. In cell cultures with THAL we detected statistically significant lowering of analyzed cytokines concentration and the decrease in Bcl-2 expression by malignant plasma cells in BM and CD8(+) T lymphocytes in BM and PB. In the group of patients responding to therapy we observed the decrease in the number of myeloma cells and significant increase of CD4(+) and CD8(+) cells in both PB and BM samples. There was statistically significant increase of CD3(+)/CD69(+) cells in the course of therapy, while the percentage of CD3+/HLA-DR(+) cells was significantly lower after 8 weeks of therapy. We also detected lowering of MVD after THAL therapy in responders group. The obtained results demonstrate that THAL efficacy in MM is multidirected and included such mechanisms like down-regulation of proangiogenic cytokines, that could lead to lowering of MVD, induction of apoptosis and influence on malignant cells and T lymphocytes immunophenotype.
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PMID:The influence of thalidomide therapy on cytokine secretion, immunophenotype, BCL-2 expression and microvessel density in patients with resistant or relapsed multiple myeloma. 1580 Jul 17


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