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)

Polymorphic epithelial mucin (MUC1) was detected in myeloma cells and in sera of multiple myeloma patients. HLA-unrestricted CTL that recognize tumor-associated epitopes on MUC1 has been shown to be induced from breast and pancreas cancer patients. To investigate whether such CTL can also be induced from multiple myeloma patients, an allogeneic mixed leukocyte tumor cell culture was performed. PBMCs of a multiple myeloma patient were stimulated by different allogeneic breast carcinoma and myeloma cell lines. The cultured PBMCs were proliferated and a CTL line TN was established. TN exclusively expressed TCR-alpha/beta, CD3, and CD8. TN lysed breast carcinoma and myeloma cell lines but did not lyse K562, which is sensitive to NK cells. The cytotoxicity of TN was inhibited by anti-CD3 Abs but not by anti-HLA Abs. Thus, the TCR-alpha/beta was considered to be involved in the recognition of the target cells but HLA was not. Furthermore, TN lysed transformed mouse fibroblast cells transfected with MUC1 cDNA, suggesting that this CTL line recognizes MUC1 directly. Thus, it is concluded that precursors of HLA-unrestricted and anti-MUC1 reactive CTL could exist in the peripheral blood of multiple myeloma patients and that myeloma cells can express epitopes on MUC1, which can be recognized by the CTL.
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PMID:Expression of MUC1 on myeloma cells and induction of HLA-unrestricted CTL against MUC1 from a multiple myeloma patient. 805 15

A number of investigators have demonstrated that there exists a relationship between Ag receptors of Ts cells (TCR) and their soluble suppressor factors. With a view to elucidating this relationship, the primary structures of receptors of Ts cells, induced in mice by tolerogenic conjugates of Ag and monomethoxypolyethylene glycol, were characterized in this study. The cDNA encoding the alpha and beta chains of TCR of cloned Ts cells specific for (i) OVA and (ii) human monoclonal (myeloma) IgG (HIgG) were produced by polymerase chain reaction. From the analysis of the V alpha genes of TCR of Ts cells it was deduced that these receptors utilized a new member of the V alpha 15 gene family, which was productively joined to the J alpha genes that differed for each of the Ts cells of the two distinct specificities. Similarly, sequence analysis of the beta chain cDNA of the two Ts cell clones revealed that both clones utilized the V beta 8.2 gene, and that their J beta gene differed from each other. It is inferred that the Ts cells generated in response to the different tolerogenic Ag(mPEG)n conjugates belonged to a subset of T cells utilizing similar TCR alpha beta chains and differed only in their J alpha/J beta regions. Most importantly, pretreatment of mice with a mixture of pentadecapeptides comprising the TCR alpha chain of the OVA-Ts cells, down-regulated the immune response specific to OVA, but not to HIgG. Moreover, injection of mice with a pentadecapeptide corresponding to the CDR3 region of the TCR alpha chain of either OVA-Ts or HIgG-Ts suppressed specifically the Ab response to OVA or HIgG, respectively. On the basis of all these results, it is concluded that the CDR3 of the TCR-alpha chain of Ts cells plays a pivotal role in the Ts network underlying the specific down-regulation of the immune responses induced by tolerogenic Ag(mPEG)n conjugates.
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PMID:Analysis of T-cell receptor alpha beta chains of CD8+ suppressor T cells induced by tolerogenic conjugates of antigen and monomethoxypolyethylene glycol. Involvement of TCR alpha-CDR3 domain in immunosuppression. 904

MUC1 is a highly immunogenic epithelial mucin and serves as a tumor-associated antigen in breast, pancreatic and ovarian carcinomas. We previously reported the expression of MUC1 on myeloma cells and the establishment of an HLA-unrestricted cytotoxic T lymphocyte (CTL) line TN that recognized MUC1 from peripheral blood mononuclear cells in a multiple myeloma patient. In this study, we attempted to induce such CTL from six other multiple myeloma patients consecutively in order to show that the induction of the CTL line TN had not resulted from some idiosyncrasy of the first patient. Bone marrow mononuclear cells were used to induce CTL, because they contain myeloma cells that might stimulate the autologous lymphocytes. Bulk CTL lines were induced from two out of six patients. The CTL line TS was CD8+ cell dominant and KY was CD4+ cell dominant. Both CTL lines lysed MUC1+ myeloma and breast carcinoma cell lines. The cytotoxicity of the CTL lines was inhibited by anti-CD3, anti-alpha beta TCR and anti-MUC1 mAb. It was also inhibited by a MUC1 transfectant, but not by a mock transfectant in cold target inhibition assays. MUC1 was transfected into a human colonic carcinoma cell line. The reactivity of anti-MUC1 core protein mAb and the cytotoxicity of the CTL against the transfectant was enhanced by the treatment of the cells with an O-glycosylation inhibitor. Thus it is generally accepted that the HLA-unrestricted CTL which directly recognize the underglycosylated from of MUC1 using their TCR could be induced from a certain proportion (approximately 30%) of untreated multiple myeloma patients.
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PMID:Cytotoxic T lymphocytes derived from bone marrow mononuclear cells of multiple myeloma patients recognize an underglycosylated form of MUC1 mucin. 918 25

It is controversial whether altered levels of TCR/CD3-associated signalling molecules play a role in the T-cell dysfunction of cancer patients. In multiple myeloma (MM), peripheral blood T (PBT) lymphocytes are functionally impaired by prolonged exposure to tumour cells, and so we investigated the organization of the TCR/CD3-associated signal transduction machinery. The aim of this study was two-fold: first, to investigate the levels of CD3zeta, p56(lck), p59(fyn), ZAP-70, protein kinase C-alpha (PKC-alpha) and phospholipase C-gamma (PLC-gamma) in MM PBT cells; second, to determine whether levels of expression were correlated with clinical or prognostic factors. Forty-four MM patients were studied and 25 age-matched normal donors served as controls. On average, PKC-alpha was the only significantly decreased (P<0.001) signalling molecule, whereas levels of CD3zeta, p56(lck), p59(fyn), PLC-gamma and ZAP-70 were not statistically different. However, there was wide variation between individual patients, and levels for each single protein also varied. A 75% or greater decrease in protein expression was observed, ranging from 8% (p59(fyn)) to 68% (PCK-alpha) of MM patients. When patients were grouped according to the cut-off values of prognostic factors such as the serum levels of C reactive protein (CRP), beta2-microglobulin (beta2M), neopterin (NPT) and the labelling index (LI%) of bone marrow (BM) plasma cells, the only difference observed was the lower PKC-alpha expression in patients with high serum NPT values. None of the T-cell signalling molecule levels was affected by the duration of tumour exposure, calculated on the number of years and/or months that had elapsed since diagnosis, or by disease status. In conclusion, there was a significant decrease of PCK-alpha in MM T cells; however, neither this decrease nor the heterogenous levels of the other T-cell signalling molecules were clearly correlated with prognosis, duration of tumour exposure, and disease status.
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PMID:Distribution of T-cell signalling molecules in human myeloma. 921 82

Concomitant chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) is a rare disease. Studies on the clonal origin of both lymphocyte and plasma cell in this disease has been few. So far it has not been reported in China. The paper reports a case of 92-year old patient with concomitant CLL and MM and the research results on the origin of lymphocyte and plasma cell by analyzing the morphologic characteristics, monoclonal antibodies, immunoglobulin Ig or TCR gene rearrangement (GR), Ig single-strand conformation polymorphsm (SSCP) fingerprint mapping and heteroduplex formation. The Ig H GR segments same in size, single strand conformation and sequence characteristics have been obtained from both peripheral blood and bone marrow DNA, even though the cells of CLL and MM had different characteristics in morphology and different secretion of IgM lambda and IgA lambda. The results suggested that the malignant cells of both CLL and MM in this patient had common origin from the B-cell.
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PMID:[Analysis of clonal origin of concomitant chronic lymphocytic leukemia and multiple myeloma in a patient with advanced age]. 938 18

IgG myeloma proteins (MPs) produced by monoclonal plasma cells derived from B2 lymphocytes have been reported to bind to various autoantigens but the binding generally has been of low affinity. Moreover, T cells from some multiple myeloma patients can respond specifically to idiotypes of their own paraproteins. We analyzed the capacity of more than 20 human IgG MP to bind, a recombinant single-chain molecule containing complete V beta 8.1 and V alpha 1 structures, sets of synthetic peptide epitopes corresponding to a complete TCR beta chain, and a set of CDR1 epitopes corresponding to 24 human V beta gene products, and intact monoclonal T cells. Two of 20 MPs bound strongly to the recombinant TCR. Five of the same set, including these, bound to a synthetic epitope corresponding to the CDR1 segment. On a mass basis, the binding was approximately 1000-fold greater than that of pooled polyclonal IgG. The binding activity was confined to the Fab fragment and was specifically inhibitable by appropriate peptide determinants. Spectrotypic analysis using a set of CDR1 epitopes indicated that individual proteins showed characteristic binding patterns ranging from highly specific to relatively promiscuous. Highly reactive MPs also bound to TCR on intact cells in immunocytofluorescence by flow cytometry. These results are consistent with the relatively frequent occurrence of autoantibodies to TCR determinants and indicate that MPs can be derived from this autoantibody subset.
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PMID:Binding of human IgG myeloma proteins to autologous T-cell receptor determinants. 941 36

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

Different MHC class I-specific killer inhibitory receptors (KIRs) are expressed in vivo by a minor fraction of activated memory CD8+ cells. It has been postulated that KIRs may 'fine-tune' specific responses by altering their threshold of activation by the TCR-CD3 complex. We have previously shown that, in multiple myeloma (MM) patients, a large fraction of peripheral blood CD8+ cells display the phenotype of chronically activated memory T cells (CD38+, HLA-DR+, CD25-, CD45R0+, CD28-). We investigated the expression of KIRs on MM T cells and determined their possible influence on cytolytic responses elicited via the CD3-TCR complex. The expression of CD94, a molecule that is part of a heterodimeric KIR recognizing the non-classical MHC surface HLA-E molecule, was almost threefold higher in MM T cells than in age-matched normal control subjects (P < 0.0001). CD94 expression was preferentially confined to CD8+ cells but not restricted to activated (HLA-DR+) and/or memory (CD45R0+) T cells. Unlike normal T cells, in which CD94 is assembled with glycoproteins of the NKG2 family to form functional receptors with activating or inhibitory properties, most CD94+ MM T cells were devoid of both the NKG2-A and NKG2-C glycoproteins detected in the inhibitory or activating form respectively. CD94 blockade did not significantly affect either T-cell proliferation or cytotoxic T-lymphocyte generation induced by the myeloma-derived cell lines NCI and RPMI 8226. Similarly, the cytolytic activity induced by direct anti-CD3-mediated targeting of MM T cells to FCR+ P815 target cells was unaffected by the addition of anti-CD94 and/or anti-NKG2-A/C monoclonal antibodies (mAbs). These data indicate that the large majority of MM CD8+ cells do not express a functional CD94 receptor. Thus, their ability to 'fine-tune' an appropriate immune response against tumour cells can be impaired.
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PMID:Increased expression of non-functional killer inhibitory receptor CD94 in CD8+ cells of myeloma patients. 1084 81

Expanded T-cell clones in the peripheral blood of patients with multiple myeloma and smoldering myeloma are usually CD8 positive and persist over long periods, suggesting that they are the result of chronic antigenic stimulation. The presence of enlarged T-cell clones can be demonstrated as bands other than the germ-line bands on Southern blots probed for the T-cell receptor beta gene (Vbeta), or defined by anti-TCRVbeta monoclonal antibody staining. However, the most sensitive way to demonstrate clonality within a population of T-cells is by analysis of the length of complementarity-determining region 3 of the rearranged TCR gene, followed by sequencing. Furthermore, my colleagues and I have previously shown that the CD57+ T-cells expressing the "expanded" TCRVbeta are monoclonal or biclonal, whereas the CD57- cells are usually polyclonal.
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PMID:Clonality detection of expanded T-cell populations in patients with multiple myeloma. 1596 9

Growing evidence indicates that multiple myeloma (MM) and other malignancies are susceptible to CTL-based immune interventions. We studied whether transcription factors inherently involved in the terminal differentiation of mature B lymphocytes into malignant and nonmalignant plasma cells provide MM-associated CTL epitopes. HLA-A*0201 (A2.1) transgenic mice were used to identify A2.1-presented peptide Ag derived from the plasma cell-associated transcriptional regulators, positive regulatory domain I-binding factor 1 (PRDI-BF1) and X box-binding protein 1 (XBP-1). A2.1-restricted CTL specific for PRDI-BF1 and XBP-1 epitopes efficiently killed a variety of MM targets. PRDI-BF1- and XBP-1-reactive CTL were able to recognize primary MM cells from A2.1(+) patients. Consistent with the expression pattern of both transcription factors beyond malignant and nonmalignant plasma cells, PRDI-BF1- and XBP-1-specific CTL activity was not entirely limited to MM targets, but was also associated with lysis of certain other malignancies and, in defined instances, with low-to-intermediate level recognition of a few types of normal cells. Our results also indicate that the A2.1-restricted, PRDI-BF1- and XBP-1-specific human CD8(+) T cell repertoire is affected by partial self tolerance and may thus require the transfer of high-affinity TCR to break tolerance. We conclude that transcription factors governing terminal cellular differentiation may provide MM- and tumor-associated CTL epitopes.
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PMID:Targeting positive regulatory domain I-binding factor 1 and X box-binding protein 1 transcription factors by multiple myeloma-reactive CTL. 1600 35

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