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 vaccines, based on dendritic cells pulsed with idiotype or tumor lysate, have been met with limited success, probably in part due to insufficient cross-priming of myeloma antigens. A powerful method to introduce myeloma-associated antigens into the cytosol of dendritic cells is protein transduction, a process by which proteins fused with a protein transduction domain (PTD) freely traverse membrane barriers. NY-ESO-1, an immunogenic antigen by itself highly expressed in 60% of high-risk myeloma patients, was purified to near homogeneity both alone and as a recombinant fusion protein with a PTD, derived from HIV-Tat. Efficient entry of PTD-NY-ESO-1 into dendritic cells, confirmed by microscopy, Western blotting, and intracellular flow cytometry, was achieved without affecting dendritic cell phenotype. Experiments with amiloride, which inhibits endocytosis, and N-acetyl-l-leucinyl-l-norleucinal, a proteasome inhibitor, confirmed that PTD-NY-ESO-1 entered dendritic cells by protein transduction and was degraded by the proteasome. Tetramer analysis indicated superior generation of HLA-A2.1, CD8+ T lymphocytes specific for NY-ESO-1(157-165) with PTD-NY-ESO-1 compared with NY-ESO-1 control protein (44% versus 2%, respectively). NY-ESO-1-specific T lymphocytes generated with PTD-NY-ESO-1 secreted IFN-gamma indicative of a Tc1-type cytokine response. Thus, PTD-NY-ESO-1 accesses the cytoplasm by protein transduction, is processed by the proteasome, and NY-ESO-1 peptides presented by HLA class I elicit NY-ESO-1-specific T lymphocytes.
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PMID:Protein transduction of dendritic cells for NY-ESO-1-based immunotherapy of myeloma. 1626 30

The aim of the present study was to explore hTERT as a target for IFN-induced sensitization to apoptosis in multiple myeloma (MM). IFN-alpha and IFN-gamma downregulated telomerase activity in the IL-6-dependent MM cell line U-266-1970. In MM cells undergoing IFN-induced sensitization to Fas-mediated apoptosis, the repression of telomerase was increased as compared to IFN-alpha treatment alone. Similar to the sensitization effect of IFN, the use of a dominant negative IkappaBalpha vector inhibiting hTERT activity via transcriptional targeting resulted in augmentation of Fas-mediated apoptosis. The mechanism underlying the reduction of telomerase activity by IFN was shown to be transcriptional repression of the hTERT gene. The present study does not support a direct effect of IFN on NF-kappaB binding to the hTERT promoter as underlying the transcriptional repression. We conclude that one potential mechanism whereby IFNs induce apoptosis sensitization is by repressing hTERT transcription and telomerase activity, thereby constituting attractive targets for MM therapy.
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PMID:Interferon-induced sensitization to apoptosis is associated with repressed transcriptional activity of the hTERT promoter in multiple myeloma. 1646 Jun 86

The present study demonstrates that immunization with a low dose of unmodified live myeloma tumor cells (FO) elicited tumor-specific immunity. BALB/c mice were vaccinated with 10(4) live dendritic cells (DC)-FO fusion cells or 10(3) live FO cells. 80% of vaccinated mice survived from the later challenge with 1 x 10(6) FO cells, whereas all control mice developed tumors. Additionally, vaccination with live FO cells gave no protection against the growth of Lewis lung carcinoma cells in C57BL/6 mice. Cellular immunity was found to be primarily responsible for anti-tumor responses. In an adoptive immune model, the development of myeloma was greatly reduced by transfusion of lymphocytes but not sera from mice immunized with FO. T cells from immunized mice also induced lysis of FO cells in the cytotoxic T lymphocyte (CTL) assay. After co-culture with FO, IFN-gamma released from immunized T helper cells increased >10-fold, while IL-4 remained unchanged in comparison with control T cells. These findings provided the first evidence that immunization with a low dose of unmodified live FO cells was safe to mice and capable of eliciting specific protective immunity against tumor growth.
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PMID:Native anti-tumor responses elicited by immunization with a low dose of unmodified live tumor cells. 1646 79

To assess GM-CSF immune accessory effects in tumor-bearing mice, an animal tumor model was established by inoculating SP2/0 myeloma cells s.c. into the flank of Balb/c mice and 14 days later, injecting either 400 mug recombinant pcDNA3.1/mGM-CSF or a blank plasmid s.c. or i.m. into the tumor four times. The tumor weight, the activities of CTL and NK, the serum levels of IFN-gamma, IL-2 and lymphocytes infiltrating in tumor tissue were analysed 8 weeks later with MTT, ELISA and pathological section methods. The results showed that the tumor lump was reduced in mice injected s.c. (0.880 +/- 0.405 g) or i.m. (0.378 +/- 0.411 g) with pcDNA3.1/mGM-CSF compared with control mice injected s.c. (1.548 +/- 0.221g, P < 0.01)or i.m. (1.554 +/- 0.249g, P < 0.001) with a blank vector. Lymphocyte infiltration in tumor tissues was very apparent in mice injected i.m. with pcDNA3.1/mGM-CSF. In contrast, there was no lymphocyte infiltration in tumor tissues of control mice. In addition, the serum concentrations of IFN-gamma, IL-2 and the activities of CTL and NK cells were significantly increased in mice injected with pcDNA3.1/mGM-CSF compared with a control mice (P < 0.01). In conclusion, direct gene immunization of recombinant pcDNA3.1/mGM-CSF is a feasible strategy for tumor therapy.
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PMID:Investigation of GM-CSF immune accessory effects in tumor-bearing mice by direct gene immunization. 1669 79

Multiple myeloma (MM) is one of the most common hematological malignancies. Despite a variety of therapeutical approaches including high-dose cytostatic treatment with subsequent autologous or allogeneic stem cell transplantation, as well as vaccination, cures remain rare exceptions. An important issue for future immunological treatments is the identification and characterization of appropriate tumor-associated antigens. However, the number of tumor-associated antigens in MM is limited. PBK/TOPK and activated serin kinase 2 (PAK2) are novel serin kinases that have recently been identified. PBK/TOPK is overexpressed in Burkitt lymphoma, acute lymphoblastic leukemia, and MM; PAK2 is expressed in malignant lymphatic cells. The cyclin kinase inhibitor 1A (CDKN1A) is overexpressed in MM compared to normal plasma cells. We hereby identified and characterized for the first time HLA-class-I-restricted immunogenic peptides in the amino acid sequences of PAK2 and CDKN1A. Using two independent prediction algorithms, we identified two peptides in PAK2 and three peptides in CDK1NA with high binding to HLA-A2. Using an IFN-gamma ELISPOT assay, we could demonstrate the presence and functional activity of CD8-peptide-specific T cells with all tested peptides. To show HLA-A2-restricted antigen recognition, the specific inhibition of T cell recognition was demonstrated with an anti-HLA-A2-blocking antibody. By analysis of peripheral blood of 34 healthy donors for the presence and functional activity of CD8 T cells specific for these peptides, we could demonstrate that peptide T-cell precursors specifically recognizing at least one of the tested peptides are present in 50-60% of the tested donors and that these T-cell precursors can be expanded in vitro. We conclude that PAK2- and CDKN1A-derived peptides can elicit a strong and consistent CD8 T-cell response in an in vitro model. Further investigations will examine the presence and functionality of such T cells in the tumor-bearing host.
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PMID:Identification and characterization of HLA-class-I-restricted T-cell epitopes in the putative tumor-associated antigens P21-activated serin kinase 2 (PAK2) and cyclin-dependent kinase inhibitor 1A (CDKN1A). 1671 96

MHC class II transactivator (CIITA), a co-activator that controls MHC class II (MHC II) transcription, functions as the master regulator of MHC II expression. Persistent activity of the CIITA type III promoter (pIII), one of the four potential promoters of this gene, is responsible for constitutive expression of MHC II by B lymphocytes. In addition, IFN-gamma induces expression of CIITA in these cells through the type IV promoter (pIV). Positive regulatory domain 1-binding factor 1 (PRDI-BF1), called B lymphocyte-induced maturation protein 1 (Blimp-1) in mice, represses the expression of CIITA pIII in plasma and multiple myeloma cells. To investigate regulation of CIITA pIV expression by PRDI-BF1 in the B lymphocyte lineage, protein/DNA-binding studies, and functional promoter analyses were performed. PRDI-BF1 bound to the IFN regulatory factor-element (IRF-E) site in CIITA pIV. Ectopic expression of either PRDI-BF1 or Blimp-1 repressed this promoter in B lymphocytes. In vitro binding and functional analyses of CIITA pIV demonstrated that the IRF-E is the target of this repression. In vivo genomic footprint analysis demonstrated protein binding at the IRF-E site of CIITA pIV in U266 myeloma cells, which express PRDI-BF1. PRDI-BF1beta, a truncated form of PRDI-BF1 that is co-expressed in myeloma cells, also bound to the IRF-E site and repressed CIITA pIV. These findings demonstrate for the first time that, in addition to silencing expression of CIITA pIII in B lymphocytes, PRDI-BF1 is capable of binding and suppressing CIITA pIV.
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PMID:Positive regulatory domain I-binding factor 1 mediates repression of the MHC class II transactivator (CIITA) type IV promoter. 1676 45

NK cells and alphabeta- and gammadelta-CTL play important roles in cellular immunity against tumors. We previously demonstrated that NPC patients have a quantitative and qualitative deficit in gammadelta-CTL and EBV-specific alphabeta-CTL when compared to normal subjects and NPC long-term survivors. In this study we report further observations of a complementary activation of peripheral NK cells in NPC patients. The NK cells in these patients, compared to those of healthy subjects and NPC survivors, were preferentially activated in response to the stimulation of myeloma cell line XG-7 and expanded in the presence of exogenous IL-2. The production of IFN-gamma was lowest in the patient group, whereas IL-12, IL-15 and TNF-alpha were produced in higher levels in patients than in the donors and survivors. The cytolytic effect of the NK cells against NPC cells in the patient group was also higher than that of the donors and survivors. Furthermore, the patients at later stages of NPC had lower gammadelta-CTL activity but higher NK cytotoxicity towards NPC targets, with higher production of IL-12, IL-15 and TNF-alpha but lower production of IFN-gamma than in patients at earlier stages. This might be part of a triggered compensatory re-activation of the innate immunity, believed to be mediated through various cytokines and chemokines when adaptive T cell immunity is breached. Together, these data suggest complementary roles of innate and adaptive immune response in tumor immunity where NK cells, gammadelta- and alphabeta-CTL compensate for the deficits of one another at different stages of tumor invasion.
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PMID:Complementary activation of peripheral natural killer cell immunity in nasopharyngeal carcinoma. 1680 22

MHC class II is expressed in restricted lineages and is modulated in response to pathogens and inflammatory stimuli. This expression is controlled by MHC CIITA, which is transcribed from multiple promoters. Although factors required for induction of CIITA are well characterized, less is known about the mechanisms leading to repression of this gene. During plasma cell differentiation, B lymphocyte-induced maturation protein-1 (PRDM1/Blimp-1) represses promoter (p)III of CIITA, responsible for constitutive expression in B cells. pIV is inducible by IFN-gamma in epithelia, macrophages and B cells. An IFN regulatory factor-element (IRF-E) in CIITA-pIV, which is bound by IRF-1 and IRF-2, is necessary for this response. This site matches the PRDM1/Blimp-1 consensus binding site, and PRDM1/Blimp-1 is expressed in cell lineages in which this promoter is operative. We, therefore, investigated whether PRDM1 regulates CIITA-pIV and found that PRDM1 bound to CIITA-pIV in vivo and the IRF-E in vitro. PRDM1 repressed IFN-gamma-mediated induction of a CIITA-pIV luciferase reporter in a fashion dependent on an intact consensus sequence and competes with IRF-1/IRF-2 for binding to the IRF-E and promoter activation. In human myeloma cell lines that express IRFs, PRDM1 occupancy of CIITA-pIV was associated with resistance to IFN-gamma stimulation, while short interfering RNA knockdown of PRDM1 led to up-regulation of CIITA. Our data indicate that PRDM1 is a repressor of CIITA-pIV, identifying a target of particular relevance to macrophages and epithelia. These findings support a model in which PRDM1/Blimp-1 can modulate the cellular response to IFN-gamma by competing with IRF-1/IRF-2 dependent activation of target promoters.
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PMID:Repression of IFN-gamma induction of class II transactivator: a role for PRDM1/Blimp-1 in regulation of cytokine signaling. 1698 96

This study was purposed to investigate the effects of thalidomide on proliferation of peripheral blood mononuclear cells (PBMNCs), levels of lymphocyte subsets, secretion of cytokines and its killing activity, and to elucidate the immunoregulation mechanisms in treatment of multiple myeloma with thalidomide. The method of MTT was used to detect the effects of thalidomide on the proliferations and the cytotoxic activity of PBMNC; the flow cytometer was used to analyze the lymphocyte subsets; the ELISA was used to measure the concentrations of cytokines in culture supernatants. The results showed that thalidomide enhanced the proliferations of the CD8+ T, NK cells in PHA-stimulated PBMNC from healthy volunteers, increased the secretion of IL-6 significantly, and decreased the secretion of IFN-gamma, and the secretions of IL-2 and IL-10 were not affected. Compared with control group, at the same ratio of effectors to targets the thalidomide (5 microg/ml) could enhance the cytotoxic activity of PBMNC (P < 0.01), the cytotoxic activity was maximal when the ratio of effectors to targets was 40:1. It is concluded that thalidomide preferentially enhances the proliferations of CD8+ T, NK cells in PHA-stimulated PBMNC from healthy volunteers, and enhances the cytotoxic activity of PBMNC by increasing the secretion of IL-6 significantly, in short, thalidomide can exert anti-myeloma effects by increasing cellular immune function.
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PMID:[Positive immunoregulation of thalidomide on human peripheral blood mononuclear cell cultures]. 1720 88

Anti-idiotypic T cells were analyzed in myeloma patients (n=18) vaccinated with idiotypic protein together with the adjuvant cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or interleukin-12 (IL-12). In the group given IL-12/GM-CSF, 78% developed idiotype specific T cells as compared to 22% in the group given only IL-12 (proliferation/ELISPOT assays) (p<0.05). The percentage of immune-responding patients increased when quantitative real time polymerase chain reaction assays for cytokines were included. A predominance of a Th1 (IFN-gamma/TNF-alpha) immune response was noted in the IL-12 group while a Th2 (IL-5) response prevailed in the IL-12/GM-CSF group (p=0.053). Application of multiple read-out systems improved the characterization of the immune response.
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PMID:Idiotype protein vaccination in combination with adjuvant cytokines in patients with multiple myeloma--evaluation of T-cell responses by different read-out systems. 1722 43


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