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)

To simplify the screening procedure for murine monoclonal antibodies specific for polymorphic HLA determinants, spleen cells from a mouse immunized with the human cell line BJAB-B95.8.6 were fused with NS1 mouse myeloma cells, and hybridoma supernatants were screened for their reactivity on BJAB-B95.8.6 and two gamma ray-induced HLA-loss mutants of this line. The use of these HLA-loss mutants allowed the rapid identification of two new allospecific MOABs designated TU160 and TU161. Serological as well as biochemical studies revealed TU160 to be specific for HLA-A2, and TU161 for HLA-B13 molecules, respectively. Both MOABs were determined to be antibodies of the IgG class and were able to precipitate their antigens from lysates of radioactively labeled cells.
 ...
PMID:Gamma ray-induced mutants as a tool for the production and characterisation of monoclonal antibodies against HLA-alloantigens. 301 80

Three types of hybridomas were obtained by fusion of murine myeloma cells (NSI-1-Ag4-1) with splenocytes from mice immunized with human lymphoblastoid cells (RPMI-6410t line, acute myeloblastic leukemia). Hybridomas of the first type synthesize monoclonal antibodies Ma-1, which interact with 6410t-cells, but are not bound to the cells of human Burkitt lymphoma-Raji. Raji cells contain HLA-DRw5 and -DRw6 antigens on cell surface but there are no HLA-A2, -B7 and -B12 antigens (specific for 6410t). Thus, Ma-1 are probably derected against some of HLA antigens of loci A or B. Hybridomas of the second type synthesize Ma-2 antibodies which react with 6410t and Raji cells, but are not bound to peripheral blood lymphocytes (PBL). We suppose that Ma-2 antibodies to tumor specific antigens which have common antigen determinants both for Raji and RPMI-6410t cells. The third type of hybridomas synthesizes monoclonal antibodies Ma-3 reacting with all the three types of target cells: 6410t, Raji, and PBL. Ma-3 seems to be directed against human species-specific lymphocyte antigens which remained in 6410t and Raji cells.
 ...
PMID:[Hybridomas synthesizing monoclonal antibodies to surface antigens of human lymphocytes]. 379 64

The epithelial mucin MUC1 is overexpressed on the cell surface of many epithelial malignancies as well as on some B-cell lymphomas and multiple myelomas. Recently, we identified two HLA-A2-restricted T-cell epitopes derived from the MUC1 protein. To further extend the potential application of these peptides, we analyzed the expression of MUC1 on blast cells from patients with acute myelogenous leukemia (AML; n = 43) and several other hematological malignancies including acute lymphoblastic leukemia (n = 24), chronic lymphocytic leukemia (n = 36), hairy cell leukemia (n = 9), follicular lymphoma (n = 7), and multiple myeloma (n = 12). Using reverse transcription-PCR and MUC1-specific monoclonal antibodies, MUC1 expression was found in 67% of AML samples and 92% of myeloma samples. To analyze the presentation of MUC1 peptides by primary AML blasts, we induced MUC1-specific CTLs in vitro using peptide-pulsed dendritic cells from HLA-A2+ healthy donors as antigen-presenting cells. These CTLs efficiently lysed in an antigen-specific and HLA-A2-restricted manner not only target cells pulsed with the antigenic peptide but also tumor cell lines including multiple myeloma cells and primary AML blasts that constitutively expressed both MUC1 and HLA-A2. The specificity of the CTLs was confirmed in a cold target inhibition assay. Our data demonstrate that MUC1-derived peptides are tumor antigens in AML and several other hematological malignancies that could potentially be used for immunotherapeutic approaches.
 ...
PMID:The epithelial tumor antigen MUC1 is expressed in hematological malignancies and is recognized by MUC1-specific cytotoxic T-lymphocytes. 1155 60

Multiple myeloma (MM) is one of the most common hematologic malignancies. Despite extensive therapeutical approaches, cures remain rare exceptions. An important issue for future immunologic treatments is the characterization of appropriate tumor-associated antigens. Recently, a highly glycosylated mucin MUC1 was detected on a majority of multiple myeloma cell lines. We analyzed bone marrow and peripheral blood of 68 patients with HLA-A2-positive myeloma for the presence and functional activity of CD8 T cells specific for the MUC1-derived peptide LLLLTVLTV. Forty-four percent of the patients with MM contained elevated frequencies of MUC1-specific CD8 T cells in freshly isolated samples from peripheral blood (PB) or bone marrow (BM) compared with corresponding samples from healthy donors. BM-residing T cells possessed a higher functional capacity upon specific reactivation than PB-derived T cells with regard to interferon gamma (IFN-gamma) secretion, perforin production, and cytotoxicity.
 ...
PMID:Enrichment of functional CD8 memory T cells specific for MUC1 in bone marrow of patients with multiple myeloma. 1556 90

The purpose of these studies was to develop immunogenic peptides derived from the CD19 and CD20 self-antigens for the induction of antigen-specific CTLs against B-cell malignancies. A total of seven peptides were designed and examined for their HLA-A2.1 affinity and immunogenicity. Of these peptides, we identified two highly immunogenic HLA-A2.1-specific peptides, CD19(150-158) (KLMSPKLYV) and CD20(188-196) (SLFLGILSV), which were capable of inducing peptide-specific CTLs. The CTLs displayed HLA-A2.1-restricted and antigen-specific cytotoxicity against Burkitt's lymphoma, chronic B cell leukemia, and multiple myeloma cell lines. The CD19 or CD20 peptide-specific CTL cytotoxicity was confirmed using HLA-A2.1(+) T2 cells presenting the appropriate peptide. No cytotoxic activity was observed against T2 cells presenting the irrelevant MAGE-3 peptide or T2 cells alone. In addition, the CTLs displayed a significant (P < 0.05) increase in cell proliferation and IFN-gamma secretion (>830 ng/mL) following restimulation with HLA-A2.1(+)/CD19(+)/CD20(+) tumor cells. The CTLs also displayed a distinct phenotype consisting of a high percentage of CD69(+)/CD45RO(+) and a low percentage of CD45RA(+)/CCR7(+) CD4(+) or CD8(+) T cells characteristic of effector memory cell population. Cyclic guanosine 3',5'-monophosphate culture conditions using serum-free AIM-V medium containing human AB serum, recombinant human interleukin 2 (Proleukin) and CD3/CD28 Dynabeads were developed resulting in a 35-fold expansion of CD20 peptide-specific CTLs. The expanded CD20-CTLs retained their cytotoxic activity (28-49%) against the Burkitt's lymphoma cell line. In conclusion, we report here on the identification of novel immunogenic CD19(150-158) (KLMSPKLYV) and CD20(188-196) (SLFLGILSV) peptides that have immunotherapeutic potentials as peptide vaccines or targeted T-cell therapies for treating B-cell malignancies.
 ...
PMID:Identification of CD19 and CD20 peptides for induction of antigen-specific CTLs against B-cell malignancies. 1574 68

We investigated the generation of myeloma-specific CTLs from normal donors HLA mismatched with the myeloma cell line SBN. The T-cell line obtained was cloned and each CTL was assessed against SBN and SBN-EBV (a B-EBV cell line obtained by EBV infection of B cells from SBN patient) simultaneously. Among >270 clones evaluated, 2 CTLs (Vbeta13.1 and Vbeta17) killed SBN but spared SBN-EBV cells. Antibodies against HLA-I, but not HLA-A2, molecules abrogated their recognition of SBN. Moreover, SBN recognition was abrogated by anti-HLA-Cw6 antiserum. Both clones recognized two other HLA-Cw*0602 myeloma cell lines. Neither of them recognized HLA-Cw*0602 B-EBV cell lines, the PBMCs of HLA-Cw*0602-unrelated donors or HLA-Cw*0602 melanoma cell lines. We showed that HLA-Cw6 molecules were more expressed at the cell surface of B-EBV cells as compared with myeloma cells, suggesting that the lack of reactivity against B-EBV cells was not related to a low level of HLA expression. Since CTL clones did not express any KIR or NKG2D, we excluded the fact that NK cell receptors could be involved in myeloma-specific recognition through KIR-HLA-I or NKG2D-MICA,B interactions. Cold target competition and acid elution experiments confirmed that myeloma cell recognition was peptide dependent.
 ...
PMID:Allogeneic T lymphocytes as a source of peptide-dependent T cells specific for myeloma cells. 1602 37

HM1.24 antigen is preferentially overexpressed in multiple myeloma (MM) cells but not in normal cells. To explore the potential of HM1.24 as a target for cellular immunotherapy, we selected 4 HM1.24-derived peptides that possess binding motifs for HLA-A2 or HLA-A24 by using 2 computer-based algorithms. The ability of these peptides to generate cytotoxic T lymphocytes (CTLs) was examined in 20 healthy donors and 6 patients with MM by a reverse immunologic approach. Dendritic cells (DCs) were induced from peripheral-blood mononuclear cells of healthy donors or peripheral-blood stem-cell (PBSC) harvests from patients with MM, and autologous CD8(+) T cells were stimulated with HM1.24 peptide-pulsed DCs. Both interferon-gamma-producing and cytotoxic responses were observed after stimulation with either HM1.24-126 or HM1.24-165 peptides in HLA-A2 or HLA-A24 individuals. The peptide-specific recognition of these CTLs was further confirmed by tetramer assay and cold target inhibition assay. Importantly, HM1.24-specific CTLs were also induced from PBSC harvests from patients with MM and these CTLs were able to kill MM cells in an HLA-restricted manner. These results indicate the existence of functional DCs and HM1.24-specific CTL precursors within PBSC harvests and provide the basis for cellular immunotherapy in combination with autologous PBSC transplantation in MM.
 ...
PMID:Induction of HM1.24 peptide-specific cytotoxic T lymphocytes by using peripheral-blood stem-cell harvests in patients with multiple myeloma. 1603 88

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.
 ...
PMID:Protein transduction of dendritic cells for NY-ESO-1-based immunotherapy of myeloma. 1626 30

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.
 ...
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

We investigated the possibility of immunotherapy for multiple myeloma (MM) using myeloma-specific cytotoxic T lymphocytes (CTLs) that were stimulated in vitro by dendritic cells (DCs) pulsing with purified and optimized myeloma lysates. CD14(+) cells were cultured in the presence of GM-CSF and IL-4. On day 6, the immature DCs were pulsed with the purified myeloma cell lysates, and then maturation of the DCs was induced by the addition of a cytokine cocktail. There were no differences in the phenotypic expressions of mature DCs that were generated by pulsing with CD138(+) cell lysates or total cell lysates. In optimization of the concentration of myeloma lysates, DCs pulsed with 10 microg/mL of myeloma lysate had greater allogeneic T-cell stimulatory capacities than those pulsed with higher concentrations of myeloma lysates. The CTL lines generated by DCs pulsed with myeloma lysates demonstrated potent cytotoxic activities against autologous target cells, but not against HLA-A2(-) cell lines or K562 cell lines. The DCs pulsed with myeloma lysates demonstrated a higher stimulatory capacity for autologous CTL compared with mature nonpulsed DCs. These results suggested that the DCs pulsed with purified and optimized myeloma cell lysates could generate potent myeloma-specific CTLs for approaches in MM.
 ...
PMID:Induction of multiple myeloma-specific cytotoxic T lymphocyte stimulation by dendritic cell pulsing with purified and optimized myeloma cell lysates. 1791 56


1 2 3 4 Next >>