The Experts below are selected from a list of 279 Experts worldwide ranked by ideXlab platform
Riccardo Gavioli - One of the best experts on this subject based on the ideXlab platform.
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Proteasome inhibitors reconstitute the presentation of cytotoxic T-cell epitopes in Epstein-Barr virus-associated tumors.
International journal of cancer, 2002Co-Authors: Riccardo Gavioli, Simona Vertuani, Maria G. MasucciAbstract:EBV-infected cells and EBV-associated tumors may evade CTL recognition by defective antigen processing, resulting in poor presentation of CTL epitopes. Since the proteasome is the major source of MHC class I–presented peptides, we analyzed the effect of proteasome inhibitors on the expression of surface HLA class I and the generation of EBV-derived CTL epitopes presented by the HLA-A2 and HLA-A11 alleles. Treatment with covalent and reversible inhibitors of the proteasome partially reduced the total and allele-specific expression of surface HLA class I in EBV-carrying LCLs. HLA-A2 expression was also decreased by treatment with leupeptin and bestatin, while HLA-A11 expression was affected by treatment with phenanthroline. Despite their general inhibitory effect on HLA class I expression, all proteasome inhibitors tested enhanced the presentation of 2 subdominant HLA-A2 epitopes from EBV LMP1 and LMP2, while the presentation of the immunodominant HLA-A11-restricted epitope from EBNA4 was inhibited by MG132 and lactacystin and increased by ZL3VS. Treatment with ZL3VS restored the presentation of endogenously expressed EBNA4 in 1 HLA-A11-positive BL cell line. These findings suggest that specific inhibitors of the proteasome may be used to increase the antigenicity of virus-infected and malignant cells that are per se inefficient at generating particular CTL target epitopes. © 2002 Wiley-Liss, Inc.
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The lifespan of major histocompatibility complex class I/peptide complexes determines the efficiency of cytotoxic T-lymphocyte responses.
Immunology, 1999Co-Authors: Fabiola Micheletti, Martina Bazzaro, Alessandro Canella, Mauro Marastoni, Serena Traniello, Riccardo GavioliAbstract:Major histocompatibility complex (MHC)/peptide association and stability are determined by specific amino acid interactions between peptide antigens and the MHC groove, and are regarded as a critical feature in ensuring efficient monitoring by T cells. In this investigation we examined the relationship between MHC/peptide stability and the immunostimulatory capacity of MHC/peptide complexes. For this purpose we compared synthetic peptide analogues derived from the immunodominant HLA-A11-presented IVTDFSVIK (IVT) epitope, for their capacity to reactivate IVT-specific memory cytotoxic T-lymphocyte (CTL) responses. The analogues differentiated from the wild-type epitope by single amino acid substitution at position 2. All peptides showed similar affinity for HLA-A11 molecules and were recognized by IVT-specific CTL clones, but induced HLA-A11 complexes at the cell surface with different lifespan. This model offered the possibility of comparing the capacity of an immunogenic epitope to stimulate a unique population of T-cell precursors depending on the lifespan of its presentation at the cell surface. We demonstrated that stable HLA-A11/peptide complexes efficiently stimulate IVT-specific CTL responses, while HLA-A11/peptide complexes with short lifespan do not. The precise identification of the role of amino acid residues in the formation of stable MHC/peptide complexes may be relevant for the design of wild-type-derived epitopes with high immunogenicity. These analogues may have important applications in the immunotherapy of infectious diseases and immunogenic tumours.
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HIGH STRUCTURAL SIDE CHAIN SPECIFICITY REQUIRED AT THE SECOND POSITION OF IMMUNOGENIC PEPTIDES TO OBTAIN STABLE MHC/PEPTIDE COMPLEXES
FEBS letters, 1998Co-Authors: Riccardo Gavioli, Maria G. Masucci, Serena Traniello, Remo Guerrini, Roberto Tomatis, Mauro MarastoniAbstract:Peptides binding to HLA-A11 contain a hydrophobic or a small polar amino acid at position 2 and a lysine at the carboxy terminus. Synthetic peptides carrying natural and unnatural amino acids in position 2 were used to determine the requirements for formation of stable HLA-A11/peptide complexes. By kinetic analysis we demonstrate that a stereospecific interaction between the side chain residue in position 2 and a subsite of pocket B is required to obtain stable HLA/peptide complexes. This specific interaction is mediated by a methyl group or by an ethyl group bound to the asymmetric Cbeta atom with the correct configuration. Experiments performed with different peptide sequences suggest that the presence of adequate anchor residues may be sufficient to produce stable HLA/peptide complexes.
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HLA-A11-mediated protection from NK cell-mediated lysis: Role of HLA-A11-presented peptides
Human immunology, 1996Co-Authors: Riccardo Gavioli, Qian-jin Zhang, Maria G. MasucciAbstract:Abstract The capacity of MHC class I to protect target cells from NK is well established, but the mechanism by which these molecules influence NK recognition and the physical properties associated with this function remain poorly defined. We have examined this issue using as a model the HLA-A11 allele. HLA-A11 expression correlated with reduced susceptibility to NK and interferon-activated cytotoxicity in transfected sublines of the A11-defective Burkitt's lymphoma WW2-BL and the HLA class I A,B-null C1R cell line. Protection was also achieved by transfection of HLA-A11 in the peptide processing mutant T2 cells line (T2/A11), despite a very low expression of the transfected product at the cell surface. Induction of surface HLA-A11 by culture of T2/A11 cells at 26 °C or in the presence of β 2 m did not affect lysis, whereas NK sensitivity was restored by culture in the presence of HLA-A11-binding synthetic peptides derived from viral or cellular proteins. Acid treatment rendered T2/A11 and C1R/A11 cells sensitive to lysis, but protection was restored after preincubation with peptide preparations derived from surface stripping of T2/A11 cells Similar peptide preparations from T2 cells had no el fect The results suggest that NK protection is mediated by HLA-All molecules carrying a particular set of peptides that are translocated to the site of MHC class I assembly in the ER in a TAP-independent fashion.
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Effect of Anchor Residue Modifications on the Stability of HLA-A11/Peptide Complexes
Biochemical and biophysical research communications, 1995Co-Authors: Riccardo Gavioli, Maria G. Masucci, Qj Zhang, Mauro Marastoni, Remo Guerrini, Eva Reali, Roberto Tomatis, Serena TranielloAbstract:Abstract MHC class I antigens bind peptides derived from endogenous proteins and present them to cytotoxic T lymphocytes. This binding is selective and shows high allele specificity. Peptides binding to HLA-A11 contain a hydrophobic or a small polar amino acid at position 2 and a lysine at the carboxy terminus. Peptide analogues, derived from previously identified high affinity peptides and carrying amino acid substitutions in position 2, were used to determine the requirements for formation of stable HLA-A11/peptide complexes. By kinetic analysis we were able to discriminate among apparent and true binders. Only analogues carrying in position 2 the amino acids valine, threonine and isoleucine formed stable complexes with HLA-A11 with a half life ≥ 72 hours.
M G Masucci - One of the best experts on this subject based on the ideXlab platform.
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T cell responses and virus evolution: loss of HLA A11-restricted CTL epitopes in Epstein-Barr virus isolates from highly A11-positive populations by selective mutation of anchor residues.
The Journal of experimental medicine, 1994Co-Authors: P O De Campos-lima, J. Brooks, Victor Levitsky, A B Rickinson, S P Lee, M G MasucciAbstract:Epstein-Barr virus (EBV) is a B lymphotropic herpesvirus of humans that elicits strong HLA class I-restricted cytotoxic T lymphocyte (CTL) responses. An influence of such responses on virus evolution was first suggested by our finding that EBV isolates from the highly HLA A11-positive Papua New Guinea (PNG) population carried a lys-thr mutation at residue 424 of the nuclear antigen EBV-encoded nuclear antigen (EBNA4) that destroyed the immunodominant target epitope for A11-restricted CTL recognition. Here we turn to a much larger population, Southern Chinese, where the A11 allele is again present in over 50% of the individuals. Each of 23 EBV isolates analyzed from this population were also mutated in the EBNA4 416-424 epitope, the mutations selectively involving one of the two anchor residues in positions 2 (417 val-leu) or 9 (424 lys-asp, -arg or -thr) that are critical for A11-peptide interaction. The majority of the Chinese isolates and all 10 PNG isolates also carried mutations affecting positions 1 and 2 of the next most immunodominant A11-restricted epitope, EBNA4 residues 399-408. These changes clearly affected antigenicity since A11-positive lymphoblastoid cell lines (LCLs) carrying these mutant EBV strains were not recognized by A11-restricted CTLs raised against the prototype B95.8 virus. Furthermore, Chinese donors naturally infected with these mutant viruses did not mount detectable A11-restricted CTL responses on in vitro stimulation with autologous LCL cells carrying either the B95.8 or their endogenous EBV strain. In two different highly A11-positive populations, therefore, immune pressure appears to have selected for resident EBV strains lacking immunodominant A11-restricted CTL epitopes.
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HLA-A11 epitope loss isolates of Epstein-Barr virus from a highly A11+ population.
Science (New York N.Y.), 1993Co-Authors: P O De Campos-lima, Riccardo Gavioli, Alan B. Rickinson, Martin Rowe, Qj Zhang, L E Wallace, Riccardo Dolcetti, M G MasucciAbstract:Cytotoxic T lymphocytes (CTLs) control viral infections by recognizing viral peptides presented by major histocompatibility complex (MHC) class I molecules. Human leukocyte antigen (HLA)-A11-restricted CTLs that recognize peptide residues 416 to 424 of the Epstein-Barr virus (EBV) nuclear antigen-4 frequently dominate EBV-induced responses in A11+ Caucasian donors. This epitope is conserved in type A EBV strains from Caucasians and central African populations, where A11 is relatively infrequent. However, strains from highly A11+ populations in New Guinea carry a lysine-to-threonine mutation at residue 424 that abrogates CTL recognition and binding of the peptide to nascent A11 molecules. The results suggest that evolution of a widespread and genetically stable virus such as EBV is influenced by pressure from MHC-restricted CTL responses.
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Multiple HLA A11-restricted cytotoxic T-lymphocyte epitopes of different immunogenicities in the Epstein-Barr virus-encoded nuclear antigen 4
Journal of virology, 1993Co-Authors: Riccardo Gavioli, R J Murray, P O De Campos-lima, Michael G. Kurilla, L E Wallace, Riccardo Dolcetti, A B Rickinson, M G MasucciAbstract:Epstein-Barr virus (EBV), a ubiquitous herpesvirus, induces potent HLA class I-restricted cytotoxic T-lymphocyte (CTL) responses. Analyses of target antigen choice have shown that the very strong CTL responses which are often observed through the HLA A11 allele map are due almost entirely to a single transformation-associated EBV protein, the nuclear antigen EBNA4. Here, we sought to determine the number and relative immunogenicities of HLA A11-restricted epitopes within this 938-amino-acid protein. An initial screening with a series of recombinant vaccinia virus vectors encoding progressively truncated forms of EBNA4 was followed by peptide sensitization experiments using overlapping 14- or 15-mers from the entire sequence. These two approaches allowed the identification of five epitope regions located between residues 101 and 115, 416 and 429, 396 and 410, 481 and 495, and 551 and 564 of the EBNA4 molecule. CTL preparations from all seven HLA A11-positive donors tested had demonstrable reactivities against the 416-to-429 peptide, whereas reactivities against the other epitopes either tended to be lost on serial passage or, for some of the donors, were never detected. The immunodominance of the 416-to-429 epitope was further supported by peptide dilution assays using polyclonal effectors and by CTL cloning experiments. Analysis of the 416-to-429 region identified the nanomer 416-424 (IVTDFSVIK) as the cognate peptide. This peptide was able to sensitize targets to lysis by A11-restricted CTL clones at concentrations as low as 5 x 10(-14) M.
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Recognition of the Epstein-Barr virus-encoded nuclear antigens EBNA-4 and EBNA-6 by HLA-A11-restricted cytotoxic T lymphocytes: implications for down-regulation of HLA-A11 in Burkitt lymphoma.
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Riccardo Gavioli, G. Klein, P O De Campos-lima, Michael G. Kurilla, Elliott Kieff, M G MasucciAbstract:Evasion from cytotoxic T-lymphocyte (CTL) surveillance may be an important step in the pathogenesis of Epstein-Barr virus (EBV)-carrying Burkitt lymphoma (BL) as suggested by the consistent down-regulation of all transformation-associated viral antigens, except EBV nuclear antigen 1 (EBNA-1), and of certain HLA class I alleles in BL biopsies and cell lines that maintain the tumor cell phenotype in vitro. The most common HLA class I defect recorded in BL lines is a selective down-regulation of HLA-A11. To gain some insight into the role of HLA-A11 down-regulation in pathogenesis of BL, we have investigated the target specificity of HLA-A11-restricted CTLs derived by stimulation of lymphocytes from three EBV-seropositive individuals with autologous EBV-transformed lymphoblastoid cell lines. Recombinant vaccinia viruses carrying the coding sequences for EBNA-1, -2A, -2B, -5, -3, -4, and -6 (also known as EBNA-1, -2A, -2B, -LP, -3a, -3b, and -3c, respectively) and EBV latent membrane protein 1 were used to induce high levels of expression of the relevant EBV antigen in fibroblasts derived from HLA class I-matched individuals. EBNA-4-expressing fibroblasts were the predominant target of HLA-A11-restricted CTLs in all three donors. A less pronounced and less regular EBNA-6-specific cytotoxic component was found in two of the donors.
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Immune escape by Epstein-Barr virus (EBV) carrying Burkitt's lymphoma: in vitro reconstitution of sensitivity to EBV-specific cytotoxic T cells.
International immunology, 1992Co-Authors: M G Masucci, H Ploegh, R J Murray, Qj Zhang, R. Gavioli, P. O. De Campus–lime, J. Brooks, H. Griffin, Alan B. RickinsonAbstract:Epstein-Barr virus (EBV) positive Burkitt's lymphoma (BL) cells are markedly less sensitive to EBV-specific cytotoxic T cell (CTL) recognition than EBV-transformed lymphoblastoid cell lines of normal B cell origin. Three features of the BL cell phenotype might contribute to this reduced susceptibility: (i) low expression of cell adhesion molecules, (ii) low expression of HLA class I and selective down-regulation of particular alleles, and (iii) down-regulation of all transformation-associated EBV antigens except EBV-encoded nuclear antigen (EBNA)-1. This study assesses the individual importance of each of these features for immune escape. For this purpose the WW1-BL cell line was used which expresses all the known transformation-associated EBV antigens (EBNA-1 to -6 and latent membrane protein-1 and -2) but which is negative for HLA A11 and for the adhesion molecule leukocyte function associated antigen-3 (LFA-3). Using recombinant vectors, these deficiencies have been sequentially corrected and the cells have been tested for sensitivity to EBV (B95.8 strain)-induced CTL preparations recognizing epitope(s) of EBNA-4 in the context of HLA A11. Expression of HLA A11 alone or in combination with LFA-3 did not sensitize WW1-BL cells to these effectors. Lysis was only achieved when HLA A11 was co-expressed with the B95.8 virus-encoded EBNA-4 protein, and in these circumstances sensitization did not require LFA-3. These results indicate that reconstitution of the relevant HLA-EBV epitope target complex on the cell membrane is sufficient to render BL cells sensitive to virus-specific cytolysis. The requirement for EBNA-4 reconstitution to achieve lysis of the WW1-BL/A11 transfectant suggested that the resident WW1 virus-encoded EBNA-4 protein did not contain the relevant target epitope for HLA A11-restricted recognition. This was confirmed by transferring the WW1 virus isolate into another A11-positive B cell background.
Maria G. Masucci - One of the best experts on this subject based on the ideXlab platform.
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Proteasome inhibitors reconstitute the presentation of cytotoxic T-cell epitopes in Epstein-Barr virus-associated tumors.
International journal of cancer, 2002Co-Authors: Riccardo Gavioli, Simona Vertuani, Maria G. MasucciAbstract:EBV-infected cells and EBV-associated tumors may evade CTL recognition by defective antigen processing, resulting in poor presentation of CTL epitopes. Since the proteasome is the major source of MHC class I–presented peptides, we analyzed the effect of proteasome inhibitors on the expression of surface HLA class I and the generation of EBV-derived CTL epitopes presented by the HLA-A2 and HLA-A11 alleles. Treatment with covalent and reversible inhibitors of the proteasome partially reduced the total and allele-specific expression of surface HLA class I in EBV-carrying LCLs. HLA-A2 expression was also decreased by treatment with leupeptin and bestatin, while HLA-A11 expression was affected by treatment with phenanthroline. Despite their general inhibitory effect on HLA class I expression, all proteasome inhibitors tested enhanced the presentation of 2 subdominant HLA-A2 epitopes from EBV LMP1 and LMP2, while the presentation of the immunodominant HLA-A11-restricted epitope from EBNA4 was inhibited by MG132 and lactacystin and increased by ZL3VS. Treatment with ZL3VS restored the presentation of endogenously expressed EBNA4 in 1 HLA-A11-positive BL cell line. These findings suggest that specific inhibitors of the proteasome may be used to increase the antigenicity of virus-infected and malignant cells that are per se inefficient at generating particular CTL target epitopes. © 2002 Wiley-Liss, Inc.
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HIGH STRUCTURAL SIDE CHAIN SPECIFICITY REQUIRED AT THE SECOND POSITION OF IMMUNOGENIC PEPTIDES TO OBTAIN STABLE MHC/PEPTIDE COMPLEXES
FEBS letters, 1998Co-Authors: Riccardo Gavioli, Maria G. Masucci, Serena Traniello, Remo Guerrini, Roberto Tomatis, Mauro MarastoniAbstract:Peptides binding to HLA-A11 contain a hydrophobic or a small polar amino acid at position 2 and a lysine at the carboxy terminus. Synthetic peptides carrying natural and unnatural amino acids in position 2 were used to determine the requirements for formation of stable HLA-A11/peptide complexes. By kinetic analysis we demonstrate that a stereospecific interaction between the side chain residue in position 2 and a subsite of pocket B is required to obtain stable HLA/peptide complexes. This specific interaction is mediated by a methyl group or by an ethyl group bound to the asymmetric Cbeta atom with the correct configuration. Experiments performed with different peptide sequences suggest that the presence of adequate anchor residues may be sufficient to produce stable HLA/peptide complexes.
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Natural variants of the immunodominant HLA A11-restricted CTL epitope of the EBV nuclear antigen-4 are nonimmunogenic due to intracellular dissociation from MHC class I:peptide complexes.
Journal of immunology (Baltimore Md. : 1950), 1997Co-Authors: Victor Levitsky, Qian-jin Zhang, Michael G. Kurilla, Jelena Levitskaya, Maria G. MasucciAbstract:EBV isolates from human populations with a high frequency of HLA A11 evade recognition by CTLs specific for an immunodominant A11-restricted epitope derived from the EBV nuclear antigen 4 (EBNA-4). We have previously described four nonimmunogenic variants of this epitope carrying single amino acid substitutions in the anchor residues of the peptide. We have now investigated the antigenicity, A11 binding capacity, endoplasmic reticulum translocation, endogenous processing, and presentation of these variants. The nonimmunogenic peptides were either unable to bind to HLA A11 or formed complexes of significantly lower stability compared with the immunogenic epitope. The latter peptides were produced in relatively large amounts by endogenous processing of EBNA-4 and associated with A11 molecules almost as efficiently as the immunogenic epitope, but the complexes failed to accumulate at the cell surface. The defect was not reversed by incubation of lymphoblastoid cell lines carrying the variant EBV strains at 26 degrees C. CTL lysis of HLA A11 positive targets was achieved by expressing one of the nonimmunogenic peptides through a vaccinia recombinant. However, the amount of peptide required for CTL sensitization exceeded, by at least 30-fold, that required for recognition of the immunogenic epitope. Collectively, these results suggest that complexes containing the nonimmunogenic peptides are formed but are then destroyed intracellularly. Thus, a specialized sorting mechanism seems to contribute in shaping the repertoire of peptides presented to T lymphocytes.
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HLA-A11-mediated protection from NK cell-mediated lysis: Role of HLA-A11-presented peptides
Human immunology, 1996Co-Authors: Riccardo Gavioli, Qian-jin Zhang, Maria G. MasucciAbstract:Abstract The capacity of MHC class I to protect target cells from NK is well established, but the mechanism by which these molecules influence NK recognition and the physical properties associated with this function remain poorly defined. We have examined this issue using as a model the HLA-A11 allele. HLA-A11 expression correlated with reduced susceptibility to NK and interferon-activated cytotoxicity in transfected sublines of the A11-defective Burkitt's lymphoma WW2-BL and the HLA class I A,B-null C1R cell line. Protection was also achieved by transfection of HLA-A11 in the peptide processing mutant T2 cells line (T2/A11), despite a very low expression of the transfected product at the cell surface. Induction of surface HLA-A11 by culture of T2/A11 cells at 26 °C or in the presence of β 2 m did not affect lysis, whereas NK sensitivity was restored by culture in the presence of HLA-A11-binding synthetic peptides derived from viral or cellular proteins. Acid treatment rendered T2/A11 and C1R/A11 cells sensitive to lysis, but protection was restored after preincubation with peptide preparations derived from surface stripping of T2/A11 cells Similar peptide preparations from T2 cells had no el fect The results suggest that NK protection is mediated by HLA-All molecules carrying a particular set of peptides that are translocated to the site of MHC class I assembly in the ER in a TAP-independent fashion.
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Effect of Anchor Residue Modifications on the Stability of HLA-A11/Peptide Complexes
Biochemical and biophysical research communications, 1995Co-Authors: Riccardo Gavioli, Maria G. Masucci, Qj Zhang, Mauro Marastoni, Remo Guerrini, Eva Reali, Roberto Tomatis, Serena TranielloAbstract:Abstract MHC class I antigens bind peptides derived from endogenous proteins and present them to cytotoxic T lymphocytes. This binding is selective and shows high allele specificity. Peptides binding to HLA-A11 contain a hydrophobic or a small polar amino acid at position 2 and a lysine at the carboxy terminus. Peptide analogues, derived from previously identified high affinity peptides and carrying amino acid substitutions in position 2, were used to determine the requirements for formation of stable HLA-A11/peptide complexes. By kinetic analysis we were able to discriminate among apparent and true binders. Only analogues carrying in position 2 the amino acids valine, threonine and isoleucine formed stable complexes with HLA-A11 with a half life ≥ 72 hours.
Alan B. Rickinson - One of the best experts on this subject based on the ideXlab platform.
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Latent Gene Sequencing Reveals Familial Relationships among Chinese Epstein-Barr Virus Strains and Evidence for Positive Selection of A11 Epitope Changes
Journal of virology, 2003Co-Authors: R. S. Midgley, Andrew I. Bell, Duncan J. Mcgeoch, Alan B. RickinsonAbstract:Epstein-Barr virus (EBV) strains from the highly HLA-A11-positive Chinese population are predominantly type 1 and show a variety of sequence changes (relative to the contemporary Caucasian prototype strain B95.8) in the nuclear antigen EBNA3B sequences encoding two immunodominant HLA-A11 epitopes, here called IVT and AVF. This has been interpreted by some as evidence of immune selection and by others as random genetic drift. To study epitope variation in a broader genomic context, we sequenced the whole of EBNA3B and parts of the EBNA2, 3A, and 3C genes from each of 31 Chinese EBV isolates. At each locus, type 1 viruses showed
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HLA-A11-Restricted Epitope Polymorphism among Epstein-Barr Virus Strains in the Highly HLA-A11-Positive Chinese Population: Incidence and Immunogenicity of Variant Epitope Sequences
Journal of virology, 2003Co-Authors: R. S. Midgley, Andrew I. Bell, Q. Y. Yao, D. Croom-carter, Andrew D. Hislop, Bruce M. Whitney, Anthony Tc Chan, Philip J. Johnson, Alan B. RickinsonAbstract:An individual's CD8(+)-cytotoxic-T-lymphocyte (CTL) response to Epstein-Barr virus (EBV) latent cycle antigens focuses on a small number of immunodominant epitopes often presented by just one of the available HLA class I alleles; for example, HLA-A11-positive Caucasians frequently respond to two immunodominant HLA A11 epitopes, IVTDFSVIK (IVT) and AVFDRKSDAK (AVF), within the nuclear antigen EBNA3B. Here, we reexamine the spectrum of EBV strains present in the highly HLA-A11-positive Chinese population for sequence changes in these epitopes relative to the Caucasian type 1 prototype strain B95.8. The IVT epitope was altered in 61 of 64 Chinese type 1 viruses, with four different sequence variants being observed, and the AVF epitope was altered in 46 cases with six different sequence variants; by contrast, all 10 Chinese type 2 viruses retained the prototype 2 epitope sequences. All but one of the type 1 epitope variants were poorly recognized by IVT- or AVF-specific CTLs in pulse-chase assays of peptide-mediated target cell lysis. More importantly, we screened HLA-A11-positive Chinese donors carrying viruses with known epitope mutations for evidence of epitope-specific CTL memory by enzyme-linked immunospot assays: none of the type 1 variants tested, nor the type 2 prototype, appeared to be immunogenic in vivo. The data remain consistent with the possibility that, during virus-host coevolution, pressure from the host CTL-mediated immune response has given A11 epitope-loss viruses a selective advantage.
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HLA-A11 epitope loss isolates of Epstein-Barr virus from a highly A11+ population.
Science (New York N.Y.), 1993Co-Authors: P O De Campos-lima, Riccardo Gavioli, Alan B. Rickinson, Martin Rowe, Qj Zhang, L E Wallace, Riccardo Dolcetti, M G MasucciAbstract:Cytotoxic T lymphocytes (CTLs) control viral infections by recognizing viral peptides presented by major histocompatibility complex (MHC) class I molecules. Human leukocyte antigen (HLA)-A11-restricted CTLs that recognize peptide residues 416 to 424 of the Epstein-Barr virus (EBV) nuclear antigen-4 frequently dominate EBV-induced responses in A11+ Caucasian donors. This epitope is conserved in type A EBV strains from Caucasians and central African populations, where A11 is relatively infrequent. However, strains from highly A11+ populations in New Guinea carry a lysine-to-threonine mutation at residue 424 that abrogates CTL recognition and binding of the peptide to nascent A11 molecules. The results suggest that evolution of a widespread and genetically stable virus such as EBV is influenced by pressure from MHC-restricted CTL responses.
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Immune escape by Epstein-Barr virus (EBV) carrying Burkitt's lymphoma: in vitro reconstitution of sensitivity to EBV-specific cytotoxic T cells.
International immunology, 1992Co-Authors: M G Masucci, H Ploegh, R J Murray, Qj Zhang, R. Gavioli, P. O. De Campus–lime, J. Brooks, H. Griffin, Alan B. RickinsonAbstract:Epstein-Barr virus (EBV) positive Burkitt's lymphoma (BL) cells are markedly less sensitive to EBV-specific cytotoxic T cell (CTL) recognition than EBV-transformed lymphoblastoid cell lines of normal B cell origin. Three features of the BL cell phenotype might contribute to this reduced susceptibility: (i) low expression of cell adhesion molecules, (ii) low expression of HLA class I and selective down-regulation of particular alleles, and (iii) down-regulation of all transformation-associated EBV antigens except EBV-encoded nuclear antigen (EBNA)-1. This study assesses the individual importance of each of these features for immune escape. For this purpose the WW1-BL cell line was used which expresses all the known transformation-associated EBV antigens (EBNA-1 to -6 and latent membrane protein-1 and -2) but which is negative for HLA A11 and for the adhesion molecule leukocyte function associated antigen-3 (LFA-3). Using recombinant vectors, these deficiencies have been sequentially corrected and the cells have been tested for sensitivity to EBV (B95.8 strain)-induced CTL preparations recognizing epitope(s) of EBNA-4 in the context of HLA A11. Expression of HLA A11 alone or in combination with LFA-3 did not sensitize WW1-BL cells to these effectors. Lysis was only achieved when HLA A11 was co-expressed with the B95.8 virus-encoded EBNA-4 protein, and in these circumstances sensitization did not require LFA-3. These results indicate that reconstitution of the relevant HLA-EBV epitope target complex on the cell membrane is sufficient to render BL cells sensitive to virus-specific cytolysis. The requirement for EBNA-4 reconstitution to achieve lysis of the WW1-BL/A11 transfectant suggested that the resident WW1 virus-encoded EBNA-4 protein did not contain the relevant target epitope for HLA A11-restricted recognition. This was confirmed by transferring the WW1 virus isolate into another A11-positive B cell background.
Kyogo Itoh - One of the best experts on this subject based on the ideXlab platform.
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A new epitope peptide derived from hepatitis C virus 1b possessing the capacity to induce cytotoxic T-lymphocytes in HCV1b-infected patients with HLA-A11, -A31, and -A33
Cancer Immunology Immunotherapy, 2007Co-Authors: Satoko Matsueda, Michio Sata, Shigeru Yutani, Akira Yamada, Yukari Takao, Mayumi Tamura, Nobukazu Komatsu, Tatsuya Ide, Kyogo ItohAbstract:Background Hepatitis C virus (HCV) frequently causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma after long-term persistent infection. Among various genotypes of HCV, HCV1b is resistant to standard interferon therapy, and thus the development of new treatment modality is needed. Results To provide a scientific basis for specific immunotherapy for HCV1b, we investigated HCV1b-derived epitope peptides recognized by human leukocyte antigen (HLA)-A11, -A31, or -A33-restricted cytotoxic T-lymphocytes (CTLs), and report here three novel vaccine candidate peptides selected by both antibody screening and CTL-inducing capacity from among 46 peptides of conserved regions of HCV1b sequences with binding motifs to HLA-A11, -A31, and -A33. Significant levels of IgG reactive to each of the three peptides were detected in the plasma of more than 50% of the HCV1b^+ patients. One peptide at positions 30–39 of the core protein induced peptide-specific CTLs from peripheral blood mononuclear cells (PBMCs) of HLA-A11^+, -A31^+, and -A33^+ patients. The other two peptides at positions 35–43 of the core protein and at positions 918–926 of the non-structural protein 2 also induced peptide-specific CTLs from the PBMCs of HLA-A11^+ and -A33^+ patients. Conclusion Therefore, the peptide at positions 30–39 of the core protein could be an appropriate target molecule of specific immunotherapy for all HLA-A11^+, -A31^+, and -A33^+ patients with HCV1b-related diseases.
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A new epitope peptide derived from hepatitis C virus 1b possessing the capacity to induce cytotoxic T-lymphocytes in HCV1b-infected patients with HLA-A11, -A31, and -A33
Cancer immunology immunotherapy : CII, 2007Co-Authors: Satoko Matsueda, Michio Sata, Shigeru Yutani, Akira Yamada, Yukari Takao, Mayumi Tamura, Nobukazu Komatsu, Tatsuya Ide, Kyogo ItohAbstract:Hepatitis C virus (HCV) frequently causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma after long-term persistent infection. Among various genotypes of HCV, HCV1b is resistant to standard interferon therapy, and thus the development of new treatment modality is needed. To provide a scientific basis for specific immunotherapy for HCV1b, we investigated HCV1b-derived epitope peptides recognized by human leukocyte antigen (HLA)-A11, -A31, or -A33-restricted cytotoxic T-lymphocytes (CTLs), and report here three novel vaccine candidate peptides selected by both antibody screening and CTL-inducing capacity from among 46 peptides of conserved regions of HCV1b sequences with binding motifs to HLA-A11, -A31, and -A33. Significant levels of IgG reactive to each of the three peptides were detected in the plasma of more than 50% of the HCV1b(+) patients. One peptide at positions 30-39 of the core protein induced peptide-specific CTLs from peripheral blood mononuclear cells (PBMCs) of HLA-A11(+), -A31(+), and -A33(+) patients. The other two peptides at positions 35-43 of the core protein and at positions 918-926 of the non-structural protein 2 also induced peptide-specific CTLs from the PBMCs of HLA-A11(+) and -A33(+) patients. Therefore, the peptide at positions 30-39 of the core protein could be an appropriate target molecule of specific immunotherapy for all HLA-A11(+), -A31(+), and -A33(+) patients with HCV1b-related diseases.
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New peptide vaccine candidates for epithelial cancer patients with HLA-A3 supertype alleles
Journal of immunotherapy (Hagerstown Md. : 1997), 2007Co-Authors: Satoko Matsueda, Hiroko Takedatsu, Shigeki Shichijo, Kyogo Itoh, Masanori Noguchi, Tetsuro Sasada, Koichi Azuma, Yuki Ishihara, Yoshihiro Komohara, Mamoru HaradaAbstract:We previously identified 2 cancer-associated antigens, immediate early response gene X-1 (IEX) and small GTPase (Ran), and their 5 epitopes using human leukocyte antigen (HLA)-A33-restricted and tumor-infiltrating T cells from a colon cancer patient. In this study, we examined whether or not these peptides can induce cytotoxic T lymphocytes (CTLs) in HLA-A11+ or HLA-A31+ epithelial cancer patients because the HLA-A11, HLA-A31, and HLA-A33 alleles share binding motifs as an HLA-A3 supertype family, which is widely distributed in many ethnic populations. Among them, the 2 peptides, IEX 47-56 and IEX 61-69, induced peptide-specific CTLs from peripheral blood mononuclear cells of cancer patients with the HLA-A11 and HLA-A31 alleles more efficiently than the other 3 peptides. Antibody blocking and cold inhibition experiments revealed that the cytotoxicity of peptide-induced CTLs against cancer cells was attributable to peptide-specific and CD8+ T cells. Together with our previous findings, these results indicate that the 2 IEX peptides could be appropriate vaccine candidates for HLA-A11, HLA-A31, and HLA-A33 positive epithelial cancer patients. This information could expand the chance of a peptide-based cancer vaccine for epithelial cancer patients of many ethnic populations.
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Identification of peptide vaccine candidates for prostate cancer patients with HLA-A3 supertype alleles.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2005Co-Authors: Satoko Matsueda, Hiroko Takedatsu, Kyogo Itoh, Akihisa Yao, Masahiro Tanaka, Masanori Noguchi, Mamoru HaradaAbstract:The peptide vaccine candidates identified to date have been focused on the HLA-A2 and HLA-A24 alleles. The HLA-A11, HLA-A31, and HLA-A33 alleles share binding motifs and belong to an HLA-A3 supertype family. In this study, we attempted to identify CTL-directed peptide candidates, derived from prostate-related antigens and shared by HLA-A11+, HLA-A31+, and HLA-A33+ prostate cancer patients. Based on the binding motif to the HLA-A3 supertype alleles, 42 peptides were prepared from prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), and prostatic acid phosphatase (PAP). These peptides were first screened for their ability to be recognized by immunoglobulin G (IgG) of prostate cancer patients and subsequently for the potential to induce peptide-specific and prostate cancer-reactive CTLs from peripheral blood mononuclear cells (PBMC) of cancer patients with the HLA-A11, HLA-A31, and HLA-A33 alleles. Five peptide candidates, including the PSA(16-24), PAP(155-163), PAP(248-257), PSMA(207-215), and PSMA(431-440) peptides, were frequently recognized by IgGs of prostate cancer patients. These peptides efficiently induced peptide-specific and prostate cancer-reactive CTLs from PBMCs of cancer patients with the HLA-A11, HLA-A31, and HLA-A33 alleles. Antibody blocking and cold inhibition experiments revealed that the HLA-A3 supertype-restricted cytotoxicity against prostate cancer cells could be ascribed to peptide-specific and CD8+ T cells. We identified prostate-related antigen-derived new peptide candidates for HLA-A11-, HLA-A31-, and HLA-A33-positive prostate cancer patients. This information could facilitate the development of a peptide-based anticancer vaccine for patients with alleles other than HLA-A2 and HLA-A24.
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Identification of Peptide Vaccine Candidates for Prostate Cancer Patients with HLA-A3 Supertype Alleles
Clinical Cancer Research, 2005Co-Authors: Satoko Matsueda, Hiroko Takedatsu, Kyogo Itoh, Akihisa Yao, Masahiro Tanaka, Masanori Noguchi, Mamoru HaradaAbstract:Purpose: The peptide vaccine candidates identified to date have been focused on the HLA-A2 and HLA-A24 alleles. The HLA-A11, HLA-A31 , and HLA-A33 alleles share binding motifs and belong to an HLA-A3 supertype family. In this study, we attempted to identify CTL-directed peptide candidates, derived from prostate-related antigens and shared by HLA-A11 + , HLA-A31 + , and HLA-A33 + prostate cancer patients. Experimental Design: Based on the binding motif to the HLA-A3 supertype alleles, 42 peptides were prepared from prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), and prostatic acid phosphatase (PAP). These peptides were first screened for their ability to be recognized by immunoglobulin G (IgG) of prostate cancer patients and subsequently for the potential to induce peptide-specific and prostate cancer–reactive CTLs from peripheral blood mononuclear cells (PBMC) of cancer patients with the HLA-A11, HLA-A31 , and HLA-A33 alleles. Results: Five peptide candidates, including the PSA 16-24 , PAP 155-163 , PAP 248-257 , PSMA 207-215 , and PSMA 431-440 peptides, were frequently recognized by IgGs of prostate cancer patients. These peptides efficiently induced peptide-specific and prostate cancer–reactive CTLs from PBMCs of cancer patients with the HLA-A11, HLA-A31 , and HLA-A33 alleles. Antibody blocking and cold inhibition experiments revealed that the HLA-A3 supertype–restricted cytotoxicity against prostate cancer cells could be ascribed to peptide-specific and CD8 + T cells. Conclusions: We identified prostate-related antigen-derived new peptide candidates for HLA-A11-, HLA-A31-, and HLA-A33-positive prostate cancer patients. This information could facilitate the development of a peptide-based anticancer vaccine for patients with alleles other than HLA-A2 and HLA-A24 .