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)

Because there is controversy regarding whether subsets of peripheral blood lymphocytes (PBLs) are part of the malignant clone in patients with multiple myeloma, we studied this question by immunoglobulin and T cell receptor gene analysis. Southern blot analysis with antibody probes demonstrated clonal immunoglobulin gene rearrangements in PBLs of seven of nine patients that were identical to those seen in their marrow plasma cells. Circulating plasma cells were not detected in any of these patients. In contrast, no patient demonstrated clonally rearranged T cell receptor genes. In one sequentially studied patient, PBLs obtained at diagnosis when he had stage I (Durie-Salmon) contained only germline DNA, while analysis of PBLs at relapse (stage III) revealed a clonally rearranged band. These data confirm the notion that circulating lymphocytes in patients with myeloma are part of the malignant clone and, furthermore, these malignant cells are of B cell rather than T cell lineage.
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PMID:Evidence for peripheral blood B lymphocyte but not T lymphocyte involvement in multiple myeloma. 311 35

Reduced lymphocyte responses were detected in the peripheral blood (PB) of patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) in the autologous mixed lymphocyte reaction (AMLR) using irradiated non-T cells as stimulator cells and T cells as responder cells. The AMLR responses of synovial tissue (ST) and of synovial fluid (SF) lymphocytes were normal. Dendritic cells both from the peripheral blood (PB), ST and SF were very potent stimulators in the AMLR and in vivo activated, HLA-DR positive T cells both from ST and SF were able to stimulate autologous PB T-cells in both RA and JRA patients. A rabbit antiserum produced against a fragment comprising the variable heavy (VH) chain region of an IgG3 human myeloma protein (Kup) reacted with peripheral blood T cells and inhibited the AMLR responses. Thus, VH antigens are integral parts of the T cell receptor for autologous HLA-DR (Ia) antigens.
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PMID:Autologous mixed lymphocyte reactions in rheumatoid arthritis. Characterization of stimulator cells and the recognition unit for autoantigens on the responder cells. 624 37

BALB/c mice with established subcutaneous IgA plasmacytomas (MOPC-315, MOPC-167, McPC-603, or TEPC-15) develop large numbers of circulating theta-bearing lymphocytes that have surface membrane receptors for IgA. The extraordinary expansion of T alpha cells in mice with IgA plasmacytomas accounts for the large number of lymphocytes with surface membrane myeloma protein that are found in these mice. The IgA myeloma protein that was originally bound to the T cell receptor in vivo was competitively displaced in vitro by other purified IgA myeloma proteins but not by their F(ab)' fragments. After overnight incubation in vitro, or brief exposure to pronase, IgA was released from the T cell surface, rendering available a surface membrane receptor for IgA. In vitro binding of purified IgA to the T alpha cell receptor was not inhibited by purified IgG1 or IgM myeloma proteins. T alpha cells were not increased in mice with three variant plasmacytomas that did not secrete large amounts of IgA. These observations: i) establish the generality of T alpha cell expansion in mice with IgA plasmacytomas, ii) establish an association between elevated serum IgA levels and T alpha cell expansion, and iii) identify a source of large numbers of T alpha cells that can be specifically purified for structural and functional studies.
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PMID:Lymphocyte surface membrane immunoglobulin in myeloma. II. T cells with IgA-Fc receptors are markedly increased in mice with IgA plasmacytomas. 696 97

A total of 96 peripheral blood stem cell harvests (PBSCH) were collected following standard chemotherapy from 27 patients with leukemia, lymphoma, and myeloma. Tumor molecular markers were analyzed in diagnostic samples by Southern blot [immunoglobulin heavy chain (IgHJ), T cell receptor (TcR) delta chain, TcR beta chain] and polymerase chain reaction (PCR) amplification [IgH, TcR delta, t(14;18) translocation] and found in 11 of 22 and 13 of 27 patients, respectively. At a sensitivity of 2 to 5%, Southern blot analysis failed to detect tumor in PBSCH. Using PCR with sensitivities of 10(-4) (IgH, TcR delta) to 10(-6) [t(14;18)] tumor was present in 34 PBSCH collected from five patients with acute lymphoblastic leukemia and two with lymphoma. In these patients, PBSCH collected after successive courses of chemotherapy remained consistently positive. However, no tumor was detected in 28 PBSCH from five patients with lymphoma and one with myeloma. Of eight patients who had bone marrow examined (six concurrently) within 3 weeks of PBSCH, one had tumor in the PBSCH but not in the bone marrow, and three had tumor in the bone marrow but not in the PBSCH, indicating a possible advantage in using PBSC for autologous transplantation in these patients. Although PBSC are an alternative source of stem cells to bone marrow and are considered to have a lower incidence of tumor contamination, the majority of PBSC in this study were positive by PCR analysis. PCR analysis was unable to determine if a positive result represents clonogenic cells capable of initiating relapse following transplant.
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PMID:Molecular detection of tumor contamination in peripheral blood stem cell harvests. 791 73

The T cell receptor alpha and beta chains are covalently linked via a disulfide bond in their extracellular constant regions. To use these domains as specific hetero-cross-linkers of two different polypeptides, we created genetic constructs encoding a chimeric antibody Fab fragment in which mouse immunoglobulin constant regions from a phosphorylcholine-specific antibody were substituted for human alpha beta-T cell receptor (TCR) extracellular constant regions (for solubilization, the transmembrane- and cytoplasmic-regions of the receptor were deleted). These constructs, i.e., chimeric heavy (VHC beta C kappa) and light (VLC alpha) chains, were cotransfected into murine SP2/0 myeloma cells for expression. Cells transfected with the genes expressed mRNAs for chimeric heavy and light chains. Without CD3 molecules, the two chimeric chains specifically associated via a disulfide bond to form a chimeric Fab fragment in the cells. These data indicate that the TCR C alpha- and C beta-regions might be used as potent specific hetero-cross-linkers for protein engineering.
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PMID:T cell receptor-extracellular constant regions as hetero-cross-linkers for immunoglobulin variable regions. 837 Jun 65

Based on the presence of T cell receptor-beta (TcR-beta) gene rearrangements in L428 and HDLM-1 cells, the expression of CD2 in HDLM-1 cells, and the presence of immunoglobulin heavy-chain (IgH) gene rearrangement in KM-H2 cells, some researchers have concluded that these long-term cell lines derived from patients with Hodgkin's disease are lymphoid in nature. The information obtained from these cell lines has also been used in arguments for a lymphoid origin of H-RS cells in tissue despite the frequent absence of lymphoid markers and Ig/TcR gene rearrangements in these cells. We questioned whether one can use the limited expression of lymphoid markers or the limited gene rearrangement to conclude that H-RS cells have a lymphoid origin, because these markers may be aberrant in tumor cells. In this study, we examined the expression of two T-cell-specific transcription factors (TCF-1 and GATA-3) and one B-cell-specific transcription factor (BSAP) in cultured H-RS cells by using a gel mobility shift assay. The sensitivity and specificity of this assay for determination of cell lineage have been established in a large number of cultured human and murine cell lines. All three types of H-RS cell lines were consistently negative for BSAP, TCF-1, and GATA-3. The absence of GATA-3 was confirmed in H-RS cells in tissues by an in situ hybridization technique. Virtually all B-cell lines, with the exception of some myeloma cell lines, are positive for BSAP, which is the transcription factor for promoters for several B-cell markers, including VpreB1, lambda 5, CD19, and CD20. All T-cell lines tested were positive for TCF-1 and GATA-3, which are the transcription factors for promoters for several T-cell-restricted markers, including CD2, CD3, TcR, and lck. The absence of BSAP, TCF-1, and GATA-3 clearly indicates an underlying difference between H-RS cells and lymphoid cells.
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PMID:Absence of T-cell- and B-cell-specific transcription factors TCF-1, GATA-3, and BSAP in Hodgkin's Reed-Sternberg cells. 878 Jan 59

Myeloma cells have been used to produce milligram quantities of soluble alpha beta T cell receptor (TCR) molecules as single-chain polypeptides in which the TCR variable (V) domains are connected by a peptide linker (TCR scFv). Unlike most TCR scFv produced in bacteria, the purified TCR scFv were stable and showed no tendency to aggregate when kept at concentrations up to 10 mg/ml. Circular dichroism analyses of the TCR scFv indicated that they contained a high proportion of beta-pleated sheet structures. Since the V alpha subunits present in the TCR scFv contained their own signal sequences, they provided the opportunity to determine by N-terminal amino acid sequencing the position of the signal cleavage of three distinct mouse V alpha. Two of the experimentally determined signal cleavage sites differed from those previously predicted on the basis of biochemical and statistical criteria. The expression approach outlined in this report has been applicable to three distinct alpha beta TCR and should contribute to the large scale production of soluble TCR amenable to structural studies.
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PMID:Characterization of T cell receptor single-chain Fv fragments secreted by myeloma cells. 889 54

Clonal T cell populations with idiotype specificity are present in the peripheral blood of a proportion of patients with multiple myeloma. We have identified the presence of both T cell subpopulations with a specificity for autologous immunoglobin fragments and T cell receptor beta gene rearrangements in peripheral blood samples of patients with myeloma. T cell receptor beta gene rearrangements were detected in 38 of 119 patient samples (32%) and were more common in progressive disease (70%), than at diagnosis (25%) or in stable disease (23%). The 38 patients who had T cell receptor beta gene rearrangements detected at any time had a better overall survival (median not yet achieved) than the patients who never had rearrangements detected (median 45 months, n = 49; chi2 = 6.2, P < 0.01). All 12 patients with T cell receptor beta gene rearrangements at diagnosis are still alive whereas the median survival for 28 patients with a germline configuration at diagnosis was 40 months (chi2 = 5.8, P > 0.01). The presence of T cell receptor beta gene rearrangements even conferred a survival advantage during progressive disease (median survival 44 months vs 19 months; chi2 = 8.7, P < 0.003). Two colour flow cytometry with biotinylated autologous immunoglobulin fragments demonstrated idiotype-reactive T cells in the peripheral blood of five out of 15 patients all of whom had T cell gene rearrangements. The remaining 10 patients had neither idiotype-reactive T cells nor a detectable T cell receptor beta gene rearrangement in concurrent samples. Thus in patients with myeloma there was a good correlation between the presence of T cell receptor beta gene rearrangements and idiotype-reactive T cells. Patients with a rearranged T cell receptor beta gene had a significantly better prognosis.
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PMID:The prognostic significance of T cell receptor beta gene rearrangements and idiotype-reactive T cells in multiple myeloma. 926 86

The T cell receptor (TCR) variable (V) gene repertoire was analyzed in patients with monoclonal gammopathy of undetermined significance (MGUS) (n = 17), multiple myeloma (MM) stage I (n = 16), MM stages II/III (n = 31) and age-matched controls (n = 27) by immunofluorescence and flow cytometry using a panel of mouse monoclonal antibodies (mAb) (n = 10) against TCR V alpha and V beta gene products. T cell expansion was defined as a value > or = thrice the normal median value for each respective TCR V mAb. Fifty-three percent of all patients displayed CD8+ expansion(s) as compared to 30% of age-matched controls (p < 0.001). Within the CD4 subset, 18% of the patients displayed T cell expansion(s) in comparison to 11% of the controls (not significant). Interestingly, the CD8+ expansion(s) were more frequently noted in patients with a low tumor burden (MGUS/MMI) (73%) as compared to those with advanced disease (MM II/III) (32% and control donors (30%) (p < 0.01). Likewise, multiple CD8+ expansions (two or more) were more common in MGUS/MM I patients than in MM II/III and controls (p < 0.01). The T cell expansions were stable over time in patients with a stable disease. A high degree of clonality of the expansions was detected by TCR CDR3 fragment length analysis, determination of J beta gene usage and nucleotide sequencing. The frequent finding of oligoclonal CD8+ T cell expansions in patients with a low tumor mass, but not in patients with advanced disease justifies further work in order to identify the relevance of expanded CD8+ T cells. In one patient with T cell reactivity against the autologous myeloma idiotype, two expansions within the CD8 population (V beta 3 and V beta 5.2 respectively) displayed no reactivity against the idiotype. Instead, idiotype recognition was confined to a CD8 non-expanded V beta 22+ T cell population, with a highly restricted TCR usage (CDR3 fragment length analysis).
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PMID:T cell repertoire in patients with multiple myeloma and monoclonal gammopathy of undetermined significance: clonal CD8+ T cell expansions are found preferentially in patients with a low tumor burden. 934 66

With the exception of childhood common acute lymphoblastic leukaemia (cALL), treatment of other hematopoietic B cell lineage tumours such as non-Hodgkin's lymphoma (B-NHL), adult ALL and multiple myeloma (MM) is unsatisfactory. Similarly, the therapeutic outcome of acute and chronic myeloid leukaemia (AML, CML) is frequently dismal. At the same time, leukaemia/lymphoma cells represent ideal targets for immunotherapy. The present review summarizes our preclinical experience with a novel type of cytotoxic T cell based immunotherapy for B-lineage and myeloid tumours. Staphylococcal enterotoxin-derived superantigens (SAgs) are among the most potent T cell activators known, linking the T cell receptor to HLA-DR on natural target cells. SAgs were genetically engineered to reduce DR binding and were then fused to Fab parts of tumour-directed monoclonal antibodies (mAbs). Using these "targeted" SAgs, highly efficient lysis of B-lineage (B-NHL, B-CLL, ALL, MM) and myeloid (AML, CML) tumour cells by T-cells was achieved in vitro and in an animal model. We are entering an interesting era of innovative cancer therapy based on novel man-made biotherapeutic agents.
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PMID:Targeted superantigens for immunotherapy of haematopoietic tumours. 970 86


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