Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three predominantly CD8+ CTL lines, TIL 501, TIL 620, and TIL 660, were generated from three HLA-A2+ melanoma patients by culturing tumor-infiltrating lymphocytes in 1000 U/ml IL-2. These tumor-infiltrating lymphocytes lysed 12 of 18 HLA-A2+ autologous and allogeneic melanomas, but none of 20 HLA-A2-negative melanomas. They also did not lyse the MHC class I negative lymphoma-leukemia cell lines, Daudi, K562, or HLA-A2+ non-melanoma cell lines including PHA or Con A-induced lymphoblast, fibroblast, EBV-transformed B cell, Burkitt's B cell lymphoma, and colon cancer cell lines. Autologous and allogeneic melanoma lysis was inhibited by anti-CD3, by anti-MHC class I, and by anti-HLA-A2 mAb, indicating recognition of shared tumor Ag among melanoma cell lines in a TCR-dependent, HLA-A2-restricted manner. Six HLA-A2-negative melanoma cell lines obtained from five HLA-A2-negative patients were co-transfected with the HLA-A2.1 gene and pSV2neo. All 17 cloned transfectants expressing cell surface HLA-A2 molecules, but none of 12 transfectants lacking HLA-A2 expression, were lysed by these three HLA-A2-restricted, melanoma-specific CTL. Lysis of the HLA-A2+ transfectants was inhibited by anti-CD3, by anti-MHC class I, and by anti-HLA-A2 mAb, indicating recognition of shared tumor Ag on transfectants in a TCR-dependent, HLA-A2-restricted manner. These results identify the HLA-A2.1 molecule as an Ag-presenting molecule for melanoma Ag. They also suggest that common melanoma Ag are expressed among melanoma patients regardless of HLA type. These findings have implications for the development of melanoma vaccines that would induce antitumor T cell responses.
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PMID:Shared human melanoma antigens. Recognition by tumor-infiltrating lymphocytes in HLA-A2.1-transfected melanomas. 172 79

We have targeted protein antigens to antigen-presenting cells in vitro by using antibody heteroaggregates containing an antibody against a protein antigen covalently crosslinked to an antibody against a target structure on the surface of the antigen-presenting cells. Antigen presentation was assessed by measurement of lymphokine released by antigen-specific T cell hybridomas. Depending on the experimental conditions, the crosslinked antibodies decreased the amount of antigen required to give a response by the hybridomas by factors of 10(2) to 10(3). Enhanced presentation occurred when antigen was targeted to MHC class I and class II molecules, surface immunoglobulin, or Fc gamma receptors on the surface of the murine B cell lymphoma-hybridoma, TA3. An enhancement of antigen presentation also occurred when antigen was targeted to surface IgD, or class I and class II MHC molecules on murine splenic B cells, and when antigen was targeted to class I and class II molecules on irradiated adherent spleen cells. No response was seen when antigen was targeted to Fc gamma R on B cells or adherent spleen cells. The ability of each crosslinked antibody to enhance presentation paralleled the total amount of each that bound to the surface of the antigen-presenting cells. Antigen presentation, mediated by crosslinked antibody, was antigen-specific and I-A restricted. The presentation of one antigen by using crosslinked antibody did not result in enhanced presentation of a second, bystander antigen. These results suggest that a novel means of stimulating immune responses may be possible in vivo, by targeting antigen to surface structures on antigen-presenting cells.
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PMID:Targeted antigen presentation using crosslinked antibody heteroaggregates. 295 30

Vaccination of mice with tumor-derived idiotypic IgM from the B cell lymphoma, BCL1, induces an anti-idiotypic immune response which suppresses tumor development. One of the mechanisms by which tumor cells can escape attack is by failing to express significant levels of idiotypic immunoglobulin at the cell surface, and a stable variant of this phenotype has been isolated. The variant, termed SNAG 1, continues to synthesize idiotypic IgM, which can be detected in the cytoplasm, but it neither secretes nor expresses IgM on the cell surface (less than 10% of the levels of the original BCL tumor), even though the H and L chains show no gross structural changes. The SNAG 1 cells resemble the parent BCL cells in morphology, in expression of MHC class I and II Ag and in bearing FcR. A significant difference between the BCL lymphoma cells and the variant cells is that the latter fail to respond to LPS by either DNA synthesis or secretion of IgM, suggesting that surface Ig might be required for such a response. The variant has a slower rate of division than the parent tumor both in vitro and in vivo, and a rather different organ distribution. Study of such variants might allow analysis of the mechanisms involved in surface Ig expression and its possible role in tumor cell growth and migration.
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PMID:Idiotype vaccination leads to the emergence of a stable surface Ig-negative variant of the mouse lymphoma BCL1, with different growth characteristics. 316 50

The major histocompatibility (MHC) class I antigens are coordinately expressed in most cells. However, some tumors or virus-infected cells lack expression of one MHC class I antigen, while expression of the other MHC class I antigens is unaffected. We previously described the selective expression of MHC class I antigens on a B-cell lymphoma from SJL/J mice called RCS5. This tumor expresses H-2Ks, but has lost cell surface expression of H-2Ds. To understand the mechanism responsible for the selective loss of H-2Ds on the cell surface, we analysed H-2Ds mRNA and protein in the RCS5 tumor. Here we report that H-2Ds mRNA was expressed in RCS5, but H-2Ds protein was not detected in cell lysates. To determine whether the H-2Ds mRNA from RCS5 was able to direct the synthesis of H-2Ds protein, we performed cDNA cloning, in vitro translation and gene transfer experiments using a cell line related to RCS5 (cRCS-X). Our results indicated that the inhibition of H-2Ds expression in cRCS-X occurred after transcription of a non-defective H-2Ds mRNA. Furthermore, H-2Ds antigen expression was restored in cRCS-X using a retroviral vector to express the recombinant H-2Ds cDNA. These results indicate that the inhibition of H-2Ds expression could be overcome either by out competing an inhibitor that functions in trans or by removing cis-acting regulatory sequences from the endogenous H-2Ds mRNA.
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PMID:Selective loss of H-2Ds antigen on a murine B lymphoma due to a post-transcriptional block in expression. 854 50

We have generated cytotoxic T-lymphocytes (CTLs) from the peripheral blood (PB) of eight B-cell non-Hodgkin's lymphoma (NHL) patients by in vitro coculture with autologous fresh tumor cells. Their functional activity was assessed in 51Cr release assay and was found to be MHC class I restricted. Our results indicate the presence of T-cells cytotoxic for autologous tumor cells in the PB of these patients but these were relatively small numbers in small lymphocytic lymphomas (SLLs). Treatment of fresh tumor cells with rIFN-gamma and rTNF-alpha alone, or in combination significantly increased their susceptibility in 4/5 cases of SLLs, and a case of diffuse large cell lymphoma and Burkitt lymphoma (BL), while, B-cell lymphoma, rich in T-cells, did not show any appreciable increase. Fresh tumor cells were also analysed for MHC class I and ICAM-1 antigens by flow cytometry, in 5/8 cases before and after cytokine treatment. Significant upregulation of MHC class I antigens but with no detectable change in ICAM-1 observed in a case of SLL and BL, correlated with enhanced susceptibility. These findings suggest the possible role of MHC class I antigens in the cytotoxic susceptibility of autologous tumor cells in B-cell NHL.
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PMID:Auto-tumor reactive cytotoxic T-cell responses in B-cell non-Hodgkin's lymphoma. 937 6

Multiple myeloma idiotypic protein is clone-specific and therefore represents an ideal tumour antigen for immune targeting. In this study we determined whether a synthetic peptide corresponding to the autologous idiotypic VH CDR3 sequence could elicit peptide-specific immune responses in a patient with IgA myeloma. Not unlike B-cell lymphoma, the immune repertoire of the patient contained T cells capable of mounting proliferative and cytotoxic responses to antigen-presenting cells loaded with the CDR3 peptide. Furthermore, the T cells were also able to secrete interferon-gamma upon peptide rechallenge. Antigen recognition by peptide-primed T cells was MHC dependent and could be blocked by antibodies to both monomorphic MHC class I and class II molecules. These results therefore indicate the presence of T-cell epitopes on the VH CDR3 sequence. In addition, CDR3 peptide-primed T cells were also able to mount similar immune responses when rechallenged with the intact IgA idiotypic protein, suggesting that functional T-cell epitopes had been derived from the CDR3 sequence of the idiotypic protein. Our results therefore provide a new perspective to the immunogenicity of the idiotypic protein in myeloma.
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PMID:Immunogenicity and cross-reactivity with idiotypic IgA of VH CDR3 peptide in multiple myeloma. 950 27

Five cases of primary mediastinal B-cell lymphoma (PMBL) each have been studied with 375 microsatellite markers from all 22 autosomes. Of the 151 genomic alterations among the 1,875 assays, only five were allelic losses. The remainder of the microsatellite alterations consisted of 114 allelic imbalances and 32 instabilities. Microsatellite alterations were found in all cases on chromosomal arms 6p and 9p. These allelic imbalances most likely are indicative of genetic amplification, a finding agreeing well with those of studies using either comparative genomic hybridization or arbitrarily primed polymerase chain reaction, in which amplification of chromosome arm 9p in PMBL has been found. The allelic imbalances on chromosome arm 6p always included marker D6S276 located at 6p21.3-p22.3, where the MHC class I genes reside. These allelic imbalances may be reflective of alterations in the expression of the MHC gene products, characteristic of PMBL. Allelic anomalies close to the MYB gene locus on 6q were detected in two cases and prompted the analysis of MYB rearrangements in a series of 30 lymphomas. One rearrangement was detected in one of 18 cases of PMBL and in none of 10 diffuse, large B-cell lymphomas and two T-cell lymphomas. Our genome-wide microsatellite analysis provides independent confirmation that PMBL is characterized by infrequent chromosomal losses and by frequent genetic alterations involving chromosomal arm 9p. For the first time, chromosomal arm 6p has been identified as a highly frequent target of genetic alterations in this tumor type. Finally, MYB may also be involved occasionally in PMBL pathogenesis.
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PMID:Alteration of chromosome arm 6p is characteristic of primary mediastinal B-cell lymphoma, as identified by genome-wide allelotyping. 1131 7

The idiotypic determinants associated with the variable regions of antibody molecules are known to function as tumor-associated antigens (TAAs). However, there is no clear-cut evidence documenting their efficacy in inducing TAA-specific cytotoxic T-lymphocytes (CTLs). In most previous studies, idiopeptides were implicated in elicitation of TAA-specific CD4+ T-cells. Using a murine B-cell lymphoma, 2C3, we earlier demonstrated induction of splenic CD4+ and CD8+ T-lymphocytes directed to idiotypic Ig of the tumor. In the present study, we provide more direct evidence of the existence of Id-specific CTLs in the spleens of 2C3 bearing BALB/c mice using an scFv-transfectoma, P815A4, as a target. While both P815A4 and 2C3 cells were equally susceptible to cytolysis by the effector cells, lysis was evident only during early tumor progression. Moribund animals at the late stage of tumor growth failed to demonstrate any significant cytotoxic immune response against either tumor. Antibodies to MHC class I alleles Kd, Dd, Ld, beta2m and CD8 molecules all inhibited cytotoxicity. The CTL population from early tumor-bearers recognized 2C3 tumor in the context of all major H-2d alleles; however, in case of P815A4 cells, it was restricted to Kd and Dd alleles only. Based on these antibody inhibition studies, it appears that the idiopeptides generated in both tumors are in some way different, yet they were recognized equally by CTLs not only from the tumor-bearers but also by CTLs from 2C3-hyperimmune mice. It appears that scFv-containing transfectomas expressing antibody variable region epitopes would be useful for both elucidating CTL-defined idiopeptides and monitoring TAA-specific CTL response in tumor-bearing animals.
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PMID:A stable single-chain variable fragment expressing transfectoma demonstrates induction of idiotype-specific cytotoxic T-cells during early growth stages of a murine B-lymphoma. 1172 38

NKG2D, together with NKp46 and NKp30, represents a major triggering receptor involved in the induction of cytotoxicity by both resting and activated human natural killer cells. In this study, we analyzed the expression and the functional relevance of MHC class I-related chain A (MICA) and UL16 binding protein (ULBP), the major cellular ligands for human NKG2D, in human tumor cell lines of different histological origin. We show that MICA and ULBP are frequently coexpressed by carcinoma cell lines, whereas MICA is expressed more frequently than ULBP by melanoma cell lines. Interestingly, the MICA(-) ULBP(+) phenotype was detected in most T cell leukemia cell lines, whereas the MICA(-) ULBP(-) phenotype characterized all acute myeloid leukemia and most B-cell lymphoma cell lines analyzed. These results, together with functional experiments, based on monoclonal antibody-mediated blocking of either NKG2D or its ligands, showed that killing of certain MICA(-) cell tumors is at least in part NKG2D dependent. Indeed, leukemic T cells as well as certain B-cell lymphomas were killed in a NKG2D-dependent fashion upon recognition of ULBP molecules. Moreover, ULBP could induce NKG2D-mediated NK cell triggering also in tumors coexpressing MICA. Our data suggest that the involvement of NKG2D in natural killer cell-mediated cytotoxicity strictly correlates with the expression and the surface density of MICA and ULBP on target cell tumors of different histotypes.
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PMID:Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. 1241 45

This retrospective analysis of preclinical and clinical radiolabeled immunoglobulin studies focuses on three well-known observations: (1) IV tumor reactive IgG provides higher response rates in patients with hematological malignancies than in patients with solid tumors. (2) Patients with CD20 positive B cell lymphoma require a high IV IgG protein dose for effective tumor targeting. (3) Most patients experience high uptake of IV administered radiolabeled IgG in normal liver. This review supports the following new hypotheses: (1) The blood-tumor barrier in most solid tumors is higher than in most hematological malignancies. (2) The blood-tumor barrier in CD20 positive B cell lymphomas is lowered by the IV administration of high doses [> 100 mg] of anti-CD20 IgG, presumably due to IgG induced intra-tumoral production of vaso-active biological response modifiers. (3) The blood-tumor barrier is low in Hodgkin's disease, presumably due to the continuous and innate production of biological response modifiers in tissues containing Hodgkin's disease. (4) The uptake of tumor reactive IgG in the normal liver is controlled by the Fc portion of the IgG. The radioimmunoconjugate is not catabolized in the liver. This appears to indicate that the F(c) portion of the IgG binds to the MHC class I like, F(c)gammaRn receptors in liver endothelium and hepatocytes and not to F(c)gamma RI, RII or RIII receptors The new hypotheses require verification and can be instrumental in the design of new more effective clinical RIT studies.
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PMID:A review of the intravenous administration of radiolabeled immunoglobulin G to cancer patients. High or low protein dose? 1266 7


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