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)

Presentation of tumour antigen by malignant cells not expressing costimulatory molecules is considered to be a major cause of the failure of the host's immune response against tumours. This study has determined the expression of the B7 family of costimulatory molecules on malignant plasma cells and the expression of the counter receptor molecules, CD28 and CD152 (CTLA-4), on T cells of patients with multiple myeloma. CD28 expression was present on most CD4 cells but was lower on CD8 cells especially from those patients who also showed evidence of expanded T cell clones (median 40%. z=2.4; p<0.02). CD152 expression was increased in 50% (9/18) of patients with myeloma. CD80 (B7-1) expression was present on the plasma cells of only 1 of 27 samples but CD86 (B7-2) expression within the normal range was present on the plasma cells of 14 of 27 samples. Primitive plasma cells (CD38++ CD45++) had a higher expression of CD86 (median 78%) than mature plasma cells (CD38++ CD45-) (median 19%, z=3.7; p<0.01). Thus patients with expanded T cell clones have a downregulated T cell CD28 expression and lack B7-1 expression on their malignant plasma cells. These results are consistent with the concept that engagement of the T cell receptor by tumour antigen on B7-1 deficient malignant plasma cells would result in T cell anergy rather than productive immunity.
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PMID:The expression of T cell related costimulatory molecules in multiple myeloma. 986 2

Previous investigations have demonstrated that an expanding circulating T cell population is able to modulate the malignant clone in multiple myeloma. More recently, an expansion of T cell subsets exhibiting a restricted T cell repertoire has been detected in some MM patients. To further elucidate if a selected T cell expansion occurs in MM, we studied the T cell receptor (TCR) variable (V) region expression from a cohort of previously diagnosed and treated MM patients (N=37). The latter was done by assessing the reactivity of a panel of monoclonal antibodies specific for different V region families (alpha or beta) in combination with anti-CD4 or anti-CD8, for purified blood T cells from MM patients. TCR V region usage in MM patients was compared to blood T cells from age matched (N=13) control individuals. The multivariate analysis of variance did not uncover a difference for distribution of TCR V region usage between the normal controls and the MM cohort. However, there were individual MM patients who had expanded T cells with specific TCR V region expression when compared to the control group. Several MM patients had multiple, expanded CD4 and/or CD8 subsets based on TCR V region expression. The majority of MM patients had expanded T cell subsets that constituted less than 10% of the total blood T cell pool. However, a few MM patients (N=3) had larger percentages (range 34-84%) of these expanded T cell subsets within their blood T (CD3+) cells. The stage of disease and treatment status (currently on or off therapy) did not associate with the pattern of restricted T cell repertoire. Finally, a smaller cohort of newly diagnosed, untreated MM patients (N=13) also demonstrated an expanded T cell repertoire. However, these patients had more CD4 than CD8 cell subsets involved in the altered V region expression in several Vbeta families. Thus, these results add to the evidence that this malignant B cell disorder whether newly diagnosed or of longer duration, may be accompanied by an altered T cell repertoire characterized in part by expanded T cell clones.
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PMID:Altered T cell repertoire usage in CD4 and CD8 subsets of multiple myeloma patients, a Study of the Eastern Cooperative Oncology Group (E9487). 1019 29

The association of leukemia and multiple myeloma is well described usually as a complication of chemotherapy but also in the absence of chemotherapy or at diagnosis. Such leukemias are typically acute myeloid leukemia (AML), particularly myelomonocytic subtype, and cases of acute promyelocytic leuke (APL) are rarely reported. Controversy exists as to whether myeloma and AML originate from a single haematopoietic progenitor or arise from different cell lineages. We report a case of a 58 year old female who developed APL 10 months following diagnosis of nonsecretory light chain (kappa) myeloma which had been treated with local spinal irradiation and low dose oral melphalan and prednisone. Clonality had originally been demonstrated by light chain restriction (kappa) of her bone marrow plasma cells whilst immunoglobulin heavy chain and T cell receptor genes were germ line. At development of APL cytogenetics revealed t(15;17) and PML-RAR fusion gene was detected by RT-PCR. The patient was treated with all-trans retinoic acid (ATRA) and received 2 cycles of consolidation chemotherapy with Idarubicin. Following this therapy the t(15;17) and PML-RAR were both undetectable whilst the clonal population of kappa staining plasma cells persisted. This particular patient represents a rare case of APL complicating multiple myeloma with persistence of the myeloma clone but disappearance of PML-RAR alpha RNA following therapy. This case study appears to support the argument that the APL and myeloma originated from distinct cell lineages.
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PMID:Acute promyelocytic leukaemia complicating multiple myeloma: evidence of different cell lineages. 1060 2

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

Recent reports of clinical responses following donor lymphocyte infusions (DLI) in patients with relapsed multiple myeloma (MM) after allogeneic BMT have demonstrated the ability of allogeneic cells to mediate a graft-versus-myeloma (GVM) effect, but the mechanisms involved have not been determined. To identify changes in the T cell compartment associated with DLI, we performed a molecular analysis of the T cell receptor (TCR) repertoire in four patients with relapsed MM who received infusions of CD4+ lymphocytes from HLA-identical sibling donors. Three of the four patients demonstrated a clinical anti-myeloma response following DLI but also developed graft-versus-host disease (GVHD). The TCR repertoire was examined after PCR amplification of 24 Vbeta gene subfamilies. This method determines the relative utilization of each Vbeta gene subfamily and also allows the identification of clonal and oligoclonal T cell populations through analysis of CDR3 regions for each TCR Vbeta gene subfamily. Serial blood samples were obtained over at least a 1 year period before and after DLI and results compared to 10 normal donors. Serial analysis of CDR3 size profiles demonstrated the appearance of clonal T cell populations after DLI in each of the three responding patients. The appearance of some clones was noted within the first 3 months after DLI and coincided with decreasing levels of monoclonal paraprotein indicating an ongoing GVM response. Other T cell clones appeared at later time points and coincided with the development of GVHD. These findings demonstrate that T cell clones with different patterns of onset can be identified in the peripheral blood of MM patients following DLI. Further functional characterization of these distinct clonal expansions will be required to determine whether these T cell clones are mediators of either anti-myeloma or anti-host activity.
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PMID:Changes in T cell receptor repertoire associated with graft-versus-tumor effect and graft-versus-host disease in patients with relapsed multiple myeloma after donor lymphocyte infusion. 1073 96

Multiple myeloma (MM) is an incurable plasma cell/plasmablast malignancy with a great need for innovative treatment strategies. Since experimental immunotherapy with targeted superantigens (SAg) proved to be effective in other haematopoietic tumours, we investigated whether this would also hold true for MM. We used the bacterial SAg Staphylococcus enterotoxin A (SEA), a potent activator of T cell cytotoxicity by means of its binding to particular T cell receptor Vbeta sequences on effector cells and MHC class II molecules on target cells. To eliminate potentially unspecific binding via MHC class II, SEA was point mutated (SEAm). In a second step SEAm was genetically fused to protein A (PA), resulting in a fusion protein (PA-SEAm). This fusion protein was used together with four different plasma-cell-specific/associated mAbs to direct T cells towards 10 MM target cell lines. Three of these mAbs were directed against syndecan-1/CD138, known to be highly expressed on MM and plasma cells, but absent on other haematopoietic cells. All MM cell lines proved to be sensitive to SAg-activated T cell killing (15-50% lysis), as measured in a 51Cr-release assay. This effect was clearly mediated via the plasma-cell-reactive antibodies, as control antibodies only conferred a low background lysis. MM therapy based on targeted SAgs could in theory be hampered by dysfunctional T cells in MM patients. However, we show that T cells from MM patients and healthy controls responded equally well to activation by SAg.
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PMID:Multiple myeloma cells are killed by syndecan-1-directed superantigen-activated T cells. 1167 98

We present a case of multiple myeloma who died of liver failure 7.5 months after initial diagnosis. Postmortem liver biopsy revealed diffuse CD3-expressing plasma cell infiltration and eosinophilic amorphous material deposition which was considered as light chain deposits. T cell receptor-gamma rearrangement was not detected in liver biopsy sections using the polymerase chain reaction despite CD3 positivity. To our knowledge, this is the first report of CD3-expressing plasma cell infiltration in tissue sections. The discordance between the phenotype and the genotype suggests a partial activation of genes encoding the T cell antigens by the transforming event. We also concluded that CD3 positivity was associated with short survival, which is consistent with previous data.
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PMID:Hepatic failure due to CD3+ plasma cell infiltration of the liver in multiple myeloma. 1181 71

Myeloma cells secrete monoclonal immunoglobulin (Ig), called myeloma protein. The variable (V) regions of myeloma proteins are unique to each plasma cell tumor, and therefore contain highly tumor-specific antigenic determinants called idiotopes (Id). In ongoing clinical trials, myeloma patients are vaccinated against the Id of their own myeloma protein. T cells with specificity for Id are thought to be of importance in eradication of multiple myeloma. We have developed a mouse model to study the molecular and cellular mechanisms for how Id-specific T cell protect against myeloma. A T cell receptor (TCR) transgenic mouse model has been established. CD4+ T cells in these mice recognize a particular Id-peptide presented on a MHC class II molecule. The Id-peptide represents an 11-mere of the variable region L chain of a particular mouse myeloma, MOPC315. TCR-transgenic mice are protected against a challenge with MOPC315 cells. Id-specific CD4+ cells protect in the absence of anti-Id antibodies. Dendritic cells in s.c. tumors take up myeloma protein and present Id-peptide on class II molecules to CD4+ cells which become activated and then kill bystander myeloma cells by an unknown mechanism. When TCR-transgenic mice are injected with large amounts of MOPC315 myeloma cells, resistance is overcome and some 30% of mice develop tumors. In these mice, Id-specific T cells become deleted as the myeloma protein serum concentration exceeds 50 microg/ml. In conclusion, in an experimental model, Id-specific CD4+ T cells protect against myeloma. However, once a tumor is established, Id-specific T cells become incapacitated. Based on these results, it is suggested that Id-vaccination in humans should be reserved for eradication of minimal residual disease, eg after high dose chemotherapy and stem cell transplantation.
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PMID:A mouse model for immunotherapy of myeloma. 1239 39

Production of monoclonal antibodies (mAb) using genetic immunisation is a potential alternative when purified antigen is difficult to obtain, or when induction of an antibody response to a limited part of an antigen is wanted. DNA immunisation using only the constant parts of trout immunoglobulin light chains coding regions was attempted here, because mAbs against the variable (V) part of immunoglobulins do not recognise the whole repertoire of the isotype. After positive results with the light chains and establishing of a proper screening system (ELISA), generation of monoclonal antibodies against trout T cell receptor was also performed. The DNA constructs were used both for immunisation of mice and for protein expression in EBNA 293 cells. Mice were immunised with the constructs 3-5 times by intramuscular injection, with or without adjuvants during 1-3 months. Spleens of positive mice were fused with myeloma Sp2/0 cells and clones were screened by ELISA using double-screening (recombinant protein/trout cells).MAbs 46E5 (anti-IgL2C), 4F2 (anti-TCRalpha), 18B3 (anti-TCRalphaC) and 4E5 (anti-TCRalphaC) show specific binding to its antigen in Western blot, mAb 18B3 and 7H7(anti-TCRalpha) shows specific staining of trout splenocytes in flow cytometry and mAb 7H7 induces proliferation of trout peripheral blood leucocytes (PBL) in vitro.
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PMID:The generation of monoclonal antibodies by genetic immunisation: antibodies against trout TCRalpha and IgL isotypes. 1268 Dec 76

The effectors of mucosal and natural immunity (i.e. natural killer, NK, cells and NKT lymphocytes) are known to play an important role in host defence against tumors. Gammadelta T lymphocytes are the most represented cell populations in mucosal associated lymphoid tissue and share several characteristics of T and NK cells. Two main subsets of gammadelta T cells are known: one, expressing the Vdelta2 T cell receptor (TCR), is found in the peripheral blood, while T cells expressing Vdelta1 TCR are resident in epithelial tissues. The former subset is capable of killing myeloma and Burkitt lymphoma cells, while the latter has been implied in the defence against epithelial cancers. Furthermore, there is increasing evidence that alphabeta and gammadelta T lymphocytes make distinct contributions to anticancer surveillance. Indeed, unlike alphabeta T cells, gammadelta T lymphocytes are involved in the recognition of antigens that do not undergo the conventional major histocompatibility complex (MHC)-driven antigen presentation. Down-regulation of expression of MHC alleles as well as tumor-specific antigens is observed frequently during tumor progression, resulting in an impairment of MHC-restricted, alphabeta-T-cell-mediated tumor-specific immunity. Given the unique set of antigens recognized and the lack of requirement for classical antigen-presenting molecules, gammadelta T lymphocytes might, therefore, represent a useful and potent system in anti-cancer surveillance, as proposed for the immune response against pathogens. Evidence that gammadelta and alphabeta cells make distinct contribution to anti-cancer surveillance have been recently provided in mice. Here, we discuss the potential role played by resident Vdelta1+ and circulating Vdelta2+ T lymphocytes in the defense against solid tumors and hematological malignancies.
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PMID:Role of gammadelta T lymphocytes in tumor defense. 1535 83


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