Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myeloma plasma cells constitute 10% to 90% of the total bone marrow cell count in patients with multiple myeloma (MM). These cells express a variety of cell surface markers, such as HLA-ABC and HLA-DR, and surface antigens that are necessary for professional antigen-presenting cells, including adhesion and costimulatory molecules. In this study, we examined the expression of major histocompatability complex (MHC) and costimulatory molecules on CD38(bright,++) plasma cells in bone marrow aspirates from eight MM patients. Small percentages of plasma cells expressed weak but detectable levels of HLA-DR, HLA-DQ, CD40, CD80, and CD86, which could be upregulated by interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha. CD38++ plasma cell and CD38(dim,+) cells were sorted from freshly isolated bone marrow mononuclear cells and tested for their capacity to act as antigen-presenting cells. Indeed, both CD38++ plasma cells and CD38+ cells were able to stimulate allogeneic T cells and present the soluble antigens purified protein derivative and tetanus toxoid to autologous T cells. Recognition of the antigens led to T-cell proliferation and secretion of IFN-gamma and was MHC class-I and -II restricted. Antigen processing and presentation by CD38++ and CD38+ cells were abolished by treatment of the cells with chloroquine. Hence, our study provides for the first time evidence that myeloma plasma cells may act as antigen-presenting cells. Further studies are warranted to examine in detail the molecules required for inducing T-cell stimulation.
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PMID:Myeloma bone marrow plasma cells: evidence for their capacity as antigen-presenting cells. 929 30

Rheumatoid factors (RF) recognize conformational determinants located within the Fc portion of IgG. By analyzing a panel of monoclonal rheumatoid arthritis (RA)-derived RFs, we previously demonstrated that the somatically generated light chain complementarity-determining region 3 (CDR3) contributes to RF specificity. We have now generated a panel of heavy chain mutants of the B'20 Ab, a high affinity RA-derived IgM RF. B'20 also binds avidly to protein A and weakly to ssDNA and tetanus toxoid. B9601, a RF negative Ab that is highly homologous to B'20 but does not bind any of the Ags tested, and RC1, a low affinity polyreactive RF, were used to generate heavy chain mutants with framework (FR) and CDR switches. The mutated heavy chains were cotransfected into a myeloma cell line with the germline counterpart of the B'20 light chain, and the expressed Ig tested for antigenic specificity. We show that both RF specificity and polyreactivity of B'20 is dependent on its unique heavy chain CDR3 region. Replacement with a B9601 CDR3 shortened to the same length as the B'20 CDR3, and with only 5 amino acid differences, did not restore Fc binding. Conversely, absence of protein A binding of B9601 is due to the presence of a serine residue at position 82a in the B9601 heavy chain FR3 region. Together, our data suggest that Ig gene recombination events can generate B cells with autoantibody specificities in the preimmune repertoire. Abnormal release, activation, expansion, or mutation of such cells might all contribute to the generation of a high titer RF response in patients with RA.
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PMID:Rheumatoid factor specificity of a VH3-encoded antibody is dependent on the heavy chain CDR3 region and is independent of protein A binding. 972 22

The aim of this study was to investigate long-term immunity to tetanus toxoid among patients with hematological disease who had been treated with conventional doses of chemotherapy. Altogether 206 patients with different hematological malignancies were included in the study. There were marked differences between the rates of seronegativity against tetanus, varying from 20% to 70% in different groups of study patients. We found that 21 of 80 (36%) patients with AML, 45 of 80 (56%) with ALL, 12 of 22 (54%) with lymphoma, 4 of 13 (31%) with myeloma and 2 of 11 (18%) with CML were not immune to tetanus. In a multivariate logistic regression model increasing age (P = 0.0001), lymphoid malignancy (P = 0.0005) and advanced disease stage (P = 0.0001) were independent risk factors for loss of tetanus immunity in patients with hematological malignancies.
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PMID:Tetanus immunity in patients with hematological malignancies. 977 65

Vaccination with idiotypic protein protects against B-cell lymphoma, mainly through anti-idiotypic antibody. For use in patients, DNA vaccines containing single-chain Fv derived from tumor provide a convenient alternative vaccine delivery system. However, single-chain Fv sequence alone induces low anti-idiotypic response and poor protection against lymphoma. Fusion of the gene encoding fragment C of tetanus toxin to single-chain Fv substantially promotes the anti-idiotypic response and induces strong protection against B-cell lymphoma. The same fusion design also induces protective immunity against a surface Ig-negative myeloma. These findings indicate that fusion to a pathogen sequence allows a tumor antigen to engage diverse immune mechanisms that suppress growth. This fusion design has the added advantage of overcoming potential tolerance to tumor that may exist in patients.
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PMID:DNA vaccines with single-chain Fv fused to fragment C of tetanus toxin induce protective immunity against lymphoma and myeloma. 980 42

A variety of approaches to antitumor therapy are currently being explored that use both antigen-encoding DNA and noncoding nucleotides as a component of gene vaccination. Among the specific strategies reviewed are a construct that fuses a single-chain variable fragment (scFv) that incorporates both the variable-region genes necessary to encode the idiotypic determinants with fragment C (FrC) of tetanus toxin; a novel vector system using herpes simplex virus 1 (HSV-1) for in vivo gene delivery; the possibility of eliciting hyperacute xenograft response to treat human cancer; and the use of gene gun-mediated granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA-based tumor cell vaccines. The protection provided by DNA vaccination against viral diseases such as influenza suggested a role for such vaccines against cancer. However, unlike vaccines against infectious diseases, cancer vaccines are therapeutic, rather than prophylactic. With multiple myeloma, for example, it is possible that the optimal timing of administration of such a vaccine is during a remission that has been induced by traditional therapies, to eliminate residual disease. DNA cancer vaccines are designed to activate immune responses to tumor antigens to which the immune system has already been exposed. To do so, the vaccines must first overcome immune tolerance that may have already developed to the tumor. There is increasing evidence that tumor antigens, unlike viral or bacterial antigens, do not consistently activate an immune response. One major factor in determining whether a reaction occurs appears to be whether antigen presentation is accompanied by danger signals. With viral or bacterial infection, the accompanying tissue destruction and inflammation produce costimulatory signals that promote T-cell activation. However, inflammatory and tissue-destructive processes are absent during initial tumor transformation. The typical outcome may be immunologic tolerance.
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PMID:DNA vaccination against multiple myeloma. 998 89

To generate mature and fully functional CD83(+) dendritic cells derived from circulating CD14(+) cells highly purified from the leukapheresis products of multiple myeloma patients.CD14(+) monocytes were selected by high-gradient magnetic separation and differentiated to immature dendritic cells with granulocyte-macrophage colony-stimulating factor and interleukin-4 for 6-7 days and then induced to terminal maturation by the addition of tumor necrosis factor-alpha or stimulation with CD40 ligand. Dendritic cells were characterized by immunophenotyping, evaluation of soluble antigens uptake, cytokine secretion, capacity of stimulating allogeneic T cells, and ability of presenting nominal antigens, including tumor idiotype, to autologous T lymphocytes. Phenotypic analysis showed that 90% +/- 6% of cells recovered after granulocyte-macrophage colony-stimulating factor and interleukin-4 stimulation expressed all surface markers typical of immature dendritic cells and demonstrated a high capacity of uptaking soluble antigens as shown by the FITC-dextran assay. Subsequent exposure to maturation stimuli induced the downregulation of CD1a and upregulation of CD83, HLA-DR, costimulatory molecules and induced the secretion of large amounts of interleukin-12. Mature CD83(+) cells showed a diminished ability of antigen uptake whereas they proved to be potent stimulators of allogeneic T cells in a mixed lymphocyte reaction. Monocyte-derived dendritic cells, pulsed before the addition of maturation stimuli, were capable of presenting soluble proteins such as keyhole limpet hemocyanin and tetanus toxoid to autologous T cells for primary and secondary immune response, respectively. Conversely, pulsing of mature (CD83(+)) dendritic cells was less efficient for the induction of T-cell proliferation. More importantly, CD14(+) cells-derived dendritic cells stimulated autologous T-cell proliferation in response to a tumor antigen such as the patient-specific idiotype. Moreover, idiotype-pulsed dendritic cells induced the secretion of interleukin-2 and gamma-interferon by purified CD4(+) cells. T-cell activation was better achieved when Fab immunoglobulin fragments were used as compared with the whole protein. When dendritic cells derived from CD14(+) cells from healthy volunteers were analyzed, we did not find any difference with samples from myeloma patients as for cell yield, phenotypic profile, and functional characteristics. These studies demonstrate that mobilized purified CD14(+) cells represent the optimal source for the production of a homogeneous cell population of mature CD83(+) dendritic cells suitable for clinical trials in multiple myeloma.
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PMID:Efficient presentation of tumor idiotype to autologous T cells by CD83(+) dendritic cells derived from highly purified circulating CD14(+) monocytes in multiple myeloma patients. 1098 94

DNA delivery of tumor antigens can activate specific immune attack on cancer cells. However, antigens may be weak, and immune capacity can be compromised. Fusion of genes encoding activating sequences to the tumor antigen sequence facilitates promotion and manipulation of effector pathways. Idiotypic determinants of B-cell tumors, encoded by the variable region genes, are clone-specific tumor antigens. When assembled as single-chain Fv (scFv) alone in a DNA vaccine, immunogenicity is low. Previously, we found that fusion of a sequence from tetanus toxin (fragment C; FrC) promoted anti-idiotypic protection against lymphoma and myeloma. We have now investigated an alternative fusion gene derived from a plant virus, potato virus X coat protein, a primary antigen in humans. When fused to scFv, the self-aggregating protein generates protection against lymphoma and myeloma. In contrast to scFv-FrC, protection against lymphoma is mediated by CD4+ T cells, as is protection against myeloma. Plant viral proteins offer new opportunities to activate immunity against linked T-cell epitopes to attack cancer.
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PMID:Plant viral genes in DNA idiotypic vaccines activate linked CD4+ T-cell mediated immunity against B-cell malignancies. 1147 70

Specific precipitates and purified human antibodies were reduced and alkylated and subjected to starch gel electrophoresis in 8 M urea to dissociate and separate the L and H polypeptide chains. Dissociated antibodies to dextran, levan, teichoic acid, blood group A substance, and tetanus toxoid showed sharp bands corresponding to L polypeptide chains. The patterns differed for antibodies of different specificities. Some differences were also seen among antibodies of the same specificity from different individuals. Purified antidextran antibodies showed particularly simple patterns resembling those of purified human gamma myeloma proteins. In some cases only one L chain band was present.
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PMID:STUDIES ON HUMAN ANTIBODIES. I. STARCH GEL ELECTROPHORESIS OF THE DISSOCIATED POLYPEPTIDE CHAINS. 1412 15

Human antibodies against dextran, teichoic acid, blood group A substance, levan, tetanus toxoid, and nuclei were isolated and analyzed for their content of Gm(a), Gm(b), and Inv(a) gamma-globulin genetic factors. The majority of these antibodies contained all the genetic factors determined in the donor's whole gamma-globulin, but in many antibodies at very different concentrations. In a few instances specific factors could not be detected despite their presence in the individual's whole gamma-globulin. Different antibodies isolated from the serum of the same individual showed different relative concentrations of genetic factors. The distribution of genetic factors seen in certain isolated human antibodies appeared to approach the selective occurrence of these factors in myeloma proteins.
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PMID:STUDIES ON HUMAN ANTIBODIES. II. DISTRIBUTION OF GENETIC FACTORS. 1412 16

Tumor-specific markers are important in identifying and tracking malignant cells. In this regard, functionally rearranged immunoglobulin variable (V) region genes in B-cell tumors fulfill and extend these criteria. V genes provide signature motifs in tumor cells and can delineate critical features of the clonal history of the cell of origin. They also define a tumor-specific antigen, which can be targeted for immunotherapy. Our focus has been on using novel DNA fusion vaccines to induce antitumor immunity. Here, we describe in detail the methods for identifying tumor-derived V genes at the nucleotide level in the malignant plasma cells of multiple myeloma. We further present the methodology for assembly of tumor V genes as single-chain variable region fragments (scFv), fused in frame with an immunopotentiating nontoxic bacterial sequence, Fragment C (FrC) of tetanus toxin. These scFv.FrC DNA vaccines provide protection in myeloma models and are currently in clinical trials. The vaccines are patient specific and can be rapidly assembled for clinical use.
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PMID:Identification and assembly of V genes as idiotype-specific DNA fusion vaccines in multiple myeloma. 1596 98


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