Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MHC class I molecules are normally expressed at very low levels in the brain and their up-regulation in response to cytokines and viral infections has been associated with a number of neurological disorders. Here we demonstrate that the down-regulation of surface class I molecules in differentiated primary rat oligodendrocytes was accompanied by reduced steady-state levels of class I heavy-chain mRNA. Transient expression assays were performed in oligodendrocytes and fibroblasts, using a mouse H-2Kb class I promoter chloramphenicol acetyltransferase plasmid termed pH2KCAT (which contained 5'-flanking sequences from -2033 to +5 bp of the H-2Kb gene relative to the transcriptional start site at +1 bp). These assays showed that H-2Kb promoter activity was reduced in oligodendrocytes but not in class I-expressing fibroblasts. H-2Kb promoter activity was up-regulated in oligodendrocytes co-transfected with a plasmid expression vector encoding the transcriptional activator tax of human T-cell leukaemia virus type I, showing that down-regulation of promoter activity was reversible. Deletion mutant analysis of the H-2Kb promoter revealed the presence of negative regulatory elements that were functional in oligodendrocytes at -1.61 to -1.07 kb and -242 to -190 bp. Deletion of sequences in pH2KCAT encompassing the downstream element totally abolished promoter activity in both oligodendrocytes and fibroblasts, whereas a deletion within the upstream negative regulatory element increased promoter activity specifically in oligodendrocytes. The upstream negative regulatory element also down-regulated a linked heterologous herpes simplex virus thymidine kinase promoter in oligodendrocytes, but not in fibroblasts. Gel retardation assays using overlapping DNA probes that spanned the entire -1.61 to -1.07 kb region revealed the presence of a number of DNA-binding activities that were present in oligodendrocyte, but not in fibroblast nuclear extracts.
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PMID:Transcriptional regulation of MHC class I gene expression in rat oligodendrocytes. 946 4

Cyclosporin A-induced autoimmunity (CsA-AI) is a T-cell mediated inflammatory autoimmune disease of the skin resembling human scleroderma and is often referred to as syngeneic-Graft-versus-Host Disease. Induction of CsA-AI is obtained by total body irradiation in combination with syngeneic bone marrow transplantation (BMT) and subsequent administration of CsA for 4 weeks; about 2 weeks after withdrawal of CsA disease develops. In CsA-AI, irradiation is thought to eliminate peripheral autoregulatory T-cells, whereas CsA interferes with selection in the thymus giving rise to putative autoreactive T-cells. MHC class II-self-peptide complexes have been thought to function as autoantigen(s). Moreover, induction of CsA-AI is used in humans to achieve a Graft-versus-Leukemia effect based on this anti-MHC class II reactivity. In this study we therefore have examined whether T-cells of CsA-AI rats respond to syngeneic dendritic cells (DC). Furthermore we determined the in vitro stimulatory capacity of the presumptive antigen presenting cell (APC) in the target organs, i.e. the keratinocytes. In contrast to keratinocytes of control rats the keratinocytes of CsA-AI rats show in situ a strong reactivity with anti-MHC class II specific monoclonal antibody (mAb) and therefore might induce local T-cell activation. Results reveal that T-cells of CsA-AI rats have no increased response to syngeneic DC. This indicates that MHC class II is not the autoantigen and that the autoantigen(s) are not presented by peripheral APC of control animals. With respect to possible APC in the target organ flow cytometry showed a strong induction of MHC class II and upregulation of MHC class I on keratinocytes of CsA-AI rats. However, these cells were unable to give any stimulatory signal to T-cells of control or diseased animals, indicating that the autoantigen(s) are not presented by keratinocytes of CsA-AI rats and that the MHC induction is probably secondary to the inflammatory reaction in the skin. The nature of the autoantigen(s) therefore remains to be determined.
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PMID:Pathogenesis of cyclosporin A-induced autoimmunity: absence of T-cell reactivity towards syngeneic antigen presenting cells. 948 6

To examine possible interference patterns between immunodominant CTL Ags, we analyzed the response to mixtures of five well-characterized H-2Kb-restricted epitopes, each of which had earlier been described as immunodominant within its antigenic system. Clear patterns of dominance were observed between peptides in the mixture, with the CTL response focusing on the Sendai virus nucleoprotein 324-332 and vesicular stomatitis virus nucleoprotein 52-59 epitopes. The dominance of these epitopes correlated with high CTL availability. Subdominance of the OVA(257-264) and the MCF1233 murine leukemia virus envelope 574-581 peptides could not be explained by inferior ability to bind and stabilize MHC class I molecules. Interestingly, immunodominance was broken if the peptide mixture was pulsed on bone marrow-derived dendritic cells, a mode of immunization allowing efficient recognition of a broader set of specificities. Our results show that immunodominance is neither an absolute feature of a given epitope nor does it apply only in relation to other epitopes within the same protein, micro-organism, or cell. Novel "superdominant" hierarchies emerge in the response against multiple "dominant" epitopes. A T cell competition model to explain the data in terms of a balance influenced by CTL frequencies and available APC capacity is discussed.
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PMID:Superdominance among immunodominant H-2Kb-restricted epitopes and reversal by dendritic cell-mediated antigen delivery. 953 Dec 71

CD8+ T-cells recognize antigenic peptides presented by major histocompatibility complex (MHC) class I molecules. These peptides bind to MHC class I molecules in the endoplasmic reticulum (ER) lumen. Antigenic peptides are translocated from the cytosol to the lumen of ER by transporter associated with antigen presentation (TAP) proteins. In this study, it is shown that TAP1 polymorphism influences the peptide substrate specificity in human B-lymphoblastoid and tumor cell lines. TAP1A and 1C alleles specifically enhance translocation of model peptides containing basic C-terminal amino acid residue. However, TAP1B allele does not show specificity for the peptide C-terminus. Human basophilic leukemia (Ku812), and hepatocellular carcinoma (PLC/PRF/5) cells express TAP1 molecules and exhibit TAP-mediated allele-specific peptide uptake after gamma-interferon (gamma-IFN) treatment. Ku812 cells express TAP1A and preferentially take up antigenic peptides with a basic C-terminus, however, PLC/PRF/5 cells with the TAP1B allele take up low but equivalent levels of peptides regardless of basic, acidic, or hydrophobic C-termini. Moreover, TAP2 polymorphisms have no influence on the peptide translocation in normal or tumor cell lines. In addition, Daudi, a beta2-microglobulin (beta2m) deficient human Burkitt lymphoma, cell line also showed TAP-dependent peptide uptake. Taken together, these results suggest that human TAP1 but not TAP2 polymorphisms influence the antigenic peptide transport and that this transport is independent of beta2m in this system.
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PMID:Peptide transport in human lymphoblastoid and tumor cells: effect of transporter associated with antigen presentation (TAP) polymorphism. 956 72

Natural killer (NK) cells possess two types of cytotoxic activity: natural killer cytotoxicity (NKC) and antibody-dependent cell-mediated cytotoxicity (ADCC). The NKC is regulated by the negative signal of the NK receptor, which recognizes major histocompatibility complex (MHC) class I antigens. However, it is not known whether or not the negative signal influences the ADCC. In this study, the relationship of the ADCC and negative signal was investigated. As target cells, adult T-cell leukemia (ATL) cell lines were used. When the target cells were treated with an anti-human T-lymphotropic virus type-1 (anti-HTLV-1) antibody, they were killed by the NK cells by means of the ADCC (ADCC/anti-HTLV-1). The killing levels were parallel with the cell surface HTLV-1 antigenicity. However, when these cells lines were treated with an anti-HLA, the ADCC (ADCC/anti-HLA) showed inverse correlation with the HLA antigenicity. Furthermore, when HLA polymorphic and monomorphic determinants of these target cells were blocked by F(ab')2 fragments of the anti-HLA and W6/32, the ADCC/anti-HLA was enhanced, but the ADCC/anti-HTLV-1 was not enhanced. These results suggest that the ADCC/anti-HLA may have an intimate relationship with the MHC class I antigens. The ADCC/anti-HLA may be suppressed by the negative signal. On the other hand, the ADCC/anti-HTLV-1 may have no relationship with the class I antigens and the negative signal may have no influence against the ADCC/anti-HTLV-1. The biological mechanism of this difference remains to be investigated.
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PMID:Relationship between antibody-dependent cell-mediated cytotoxicity due to anti-HTLV-1 and negative signal of major histocompatibility complex class I antigens on adult T-cell leukemia cell lines. 966 13

C57BL/6 mice characteristically generate vigorous H-2K(b)-restricted cytotoxic T lymphocytes (CTL) directed against an immunodominant CTL epitope (KSPWFTTL) expressed by endogenous AKR/Gross murine leukemia viruses (MuLV). These AKR/Gross MuLV-specific CTL do not efficiently recognize tumor cells induced by Friend/Moloney/Rauscher (FMR) MuLV, which express the highly homologous peptide RSPWFTTL. In this report, we not only confirm the inefficient recognition of FMR tumors by AKR/Gross MuLV-specific CTL, but also demonstrate that RSPWFTTL is poorly immunogenic in C57BL/6 mice. To gain insight into the mechanism(s) contributing to the inefficient recognition of FMR MuLV-induced tumors, we examined the RSPWFTTL dissociation rate from H-2K(b) as well as the ability for RSPWFTTL to diminish CTL effector functions by T-cell antagonism. In contrast to immunogenic peptides, which form stable MHC class I-peptide complexes having slow dissociation rates, poorly immunogenic peptides characteristically have faster dissociation rates. On the basis of a cell-surface MHC class I peptide stabilization assay, the dissociation rate of RSP-WFTTL from H-2K(b) is characterized by a half-life that is nearly identical to the half-life of KSPWFTTL. In addition, we could find no evidence for antagonistic inhibition of AKR/Gross MuLV-specific CTL over a wide concentration range of RSPWFTTL. Analysis of the role of the transporter associated with antigen processing (TAP), by use of recombinant vaccinia and Sindbis viruses expressing a hydrophobic amino-terminal endoplasmic reticulum (ER) targeting sequence coupled to RSPWFTTL, indicated that RSPWFTTL cell-surface presentation can be dramatically enhanced when directly targeted into the ER.
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PMID:A single amino acid variation within an immunodominant AKR/Gross MuLV cytotoxic T-lymphocyte epitope leads to a loss in immunogenicity. 1018 87

We recently established an effective immune T-cell-mediated graft-versus-leukemia (GVL) murine model system in which complete tumor remissions were achievable even in advanced metastasized cancer. We now describe that this T-cell-mediated therapy is dependent on host macrophages expressing the lymphocyte adhesion molecule sialoadhesin (Sn). Depletion of Kupffer cells in tumor-bearing mice during adoptive immunotherapy (ADI) or the treatment of these animals with anti-Sn monoclonal antibodies led to complete or partial inhibition of the immune T-cell-mediated therapeutic effect. Furthermore, Sn+ host macrophages in livers formed clusters during ADI with donor CD8 T cells. To test for a possible antigen presentation function of these macrophages, we used as an in vitro model the antigen beta-galactosidase for which a dominant major histocompatibility complex (MHC) class I Ld-restricted peptide epitope is known to be recognized by specific CD8 cytotoxic T lymphocytes (CTL). We demonstrate that purified Sn+ macrophages can process exogenous beta-galactosidase and stimulate MHC class I peptide-restricted CTL responses. Thus, Sn+ macrophages, which are significantly increased in the liver after ADI, may process tumor-derived proteins via the MHC class I pathway as well as via the MHC class II pathway, as shown previously, and present respective peptide epitopes to CD8 as well as to CD4 immune T cells, respectively. The synergistic interactions observed before between immune CD4 and CD8 T cells during ADI could thus occur in the observed clusters with Sn+ host macrophages.
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PMID:Sialoadhesin-positive host macrophages play an essential role in graft-versus-leukemia reactivity in mice. 1036 Nov 36

Because of the expression of inhibitory receptors (KIR) for major histocompatibility complex (MHC) class I allotypes, a person's natural killer (NK) cells will not recognize and will, therefore, kill cells from individuals lacking his/her KIR epitopes. This study investigated the role of NK cell alloreactivity in human HLA haplotype-mismatched hematopoietic stem cell transplantation and, specifically, the role of the three major NK specificities, ie, those for HLA-C group 1, HLA-C group 2, and HLA-Bw4 alleles. In 20 of 60 donor-recipient pairs, KIR epitope incompatibility and functional analyses of donor NK cell clones predicted donor NK cells could cause graft-versus-host (GVH)/graft-versus-leukemia (GVL) reactions. NK cell clones of donor origin were obtained from transplanted recipients and tested for lysis of recipient's cryopreserved pretransplant lymphocytes. Despite the absence of GVH disease, we detected high frequencies of NK clones which killed recipient's target cells. Lysis followed the rules of NK cell alloreactivity, being blocked only by the MHC class I KIR epitope which was missing in the recipient. The alloreactive NK clones also killed the allogeneic leukemia. Transplants from these KIR epitope incompatible donors had higher engraftment rates. Therefore, a GVL effector and engraftment facilitating mechanism, which is independent of T-cell-mediated GVH reactions, may be operational in HLA mismatched hematopoietic cell transplants.
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PMID:Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. 1038 30

We have previously shown that retroviral vector particles derived from Moloney murine leukemia virus (Mo-MuLV) can efficiently incorporate influenza hemagglutinin (HA) glycoproteins from fowl plague virus (FPV), thus conferring a broad tropism to the vectors. To modify its host range, we have engineered the FPV HA to display four different polypeptides on its N terminus: the epidermal growth factor, an anti-human MHC class I molecules scFv (single-chain antibody), an anti-melanoma antigen scFv, and an IgG Fc-binding polypeptide. All recombinant HA glycoproteins were correctly expressed and processed, and efficiently incorporated into Mo-MuLV retroviral particles, indicating that amino-terminal insertion of large polypeptides did not alter the conformation of HA chimeras. Virions carrying the different chimeras bound specifically to cells expressing the targeted cell surface molecules of each ligand. In addition, all virion types were infectious but exhibited various degrees of specificity regarding the use of the targeted cell surface molecule versus the wild-type FPV HA receptor for cell entry and infection. For some ligands tested, infectivity was significantly increased on cells that express the targeted receptor, compared with cells that express only the wild-type HA receptor. Furthermore, some polypeptides could abolish infectivity via the wild-type FPV HA receptor. Our data therefore indicate that it is possible to engineer the HA envelope glycoprotein by fusing ligands to its amino-terminal end without affecting its fusion activity.
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PMID:Retroviral display of functional binding domains fused to the amino terminus of influenza hemagglutinin. 1039 78

Activation of NK cells by target cells leads to cytotoxicity as well as production of various cytokines including IFN-gamma. MHC class I molecules on target cells regulate NK cytotoxicity. However, little is known about the regulation of IFN-gamma production by NK cells. We examined the production of IFN-gamma in individual murine NK cells stimulated with tumor cell lines by flow cytometric analysis of intracellular IFN-gamma. Among several tumor lines tested, the rat basophilic leukemia line RBL-1 induced particularly high level of IFN-gamma production in IL-2-activated NK cells, whereas other lines, including the prototypic NK target YAC-1, induced very low or no IFN-gamma production. Transfection of murine classical MHC class I molecules into RBL-1 cells substantially inhibited IFN-gamma production. This inhibition of IFN-gamma production by MHC class I was independent of Ly-49 or CD94/NKG2A expression on NK cells. These results indicate that some target cells directly stimulate IL-2-activated NK cells and induce IFN-gamma production, but the requirements for the induction of IFN-gamma production seem different from those for NK cytotoxicity. Furthermore, similar to NK cytotoxicity, induction of IFN-gamma production is inhibited by MHC class I on stimulating cells. However, the MHC class I-specific receptors inhibiting IFN-gamma production are different from those for NK cytotoxicity.
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PMID:IFN-gamma production and cytotoxicity of IL-2-activated murine NK cells are differentially regulated by MHC class I molecules. 1058 40


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