TY - JOUR
T1 - Selective amino acid substitutions of a subdominant Epstein-Barr virus LMP2-derived epitope increase HLA/peptide complex stability and immunogenicity
T2 - Implications for immunotherapy of Epstein-Barr virus-associated malignancies
AU - Micheletti, Fabiola
AU - Guerrini, Remo
AU - Formentin, Annarita
AU - Canella, Alessandro
AU - Marastoni, Mauro
AU - Bazzaro, Martina
AU - Tomatis, Roberto
AU - Traniello, Serena
AU - Gavioli, Riccardo
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1999
Y1 - 1999
N2 - The latent membrane protein 2 is an immunogenic antigen expressed in Epstein-Barr virus (EBV)-associated tumors and consequently it may represent a target for specific cytotoxic T lymphocyte (CTL)-based immunotherapies. However, the efficacy of such a therapy is limited by the poor immunogenicity of the protein that induces weak CTL responses directed to the CLGGLLTMV (CLG) epitope only in the minority of EBV-seropositive donors. We have now demonstrated that selective peptide stimulation of peripheral blood lymphocytes induced CLG-specific CTL in all donors, suggesting that this epitope can be a suitable target for specific immunotherapies. We found that the CLG peptide has a low affinity for HLA-A(*)0201 and does not produce stable complexes, both factors that are likely to determine the strength of CTL responses to this epitope. Therefore, we synthesized and tested CLG analogues carrying single or combined amino acid substitutions to increase HLA/peptide stability. Among the analogues tested we identified two peptides which, compared to the natural epitope, showed higher affinity for HLA-A(*)0201 molecules, and produced stable complexes. These peptides demonstrated a potent, specific stimulatory capacity and could be used for selective CTL-based therapies.
AB - The latent membrane protein 2 is an immunogenic antigen expressed in Epstein-Barr virus (EBV)-associated tumors and consequently it may represent a target for specific cytotoxic T lymphocyte (CTL)-based immunotherapies. However, the efficacy of such a therapy is limited by the poor immunogenicity of the protein that induces weak CTL responses directed to the CLGGLLTMV (CLG) epitope only in the minority of EBV-seropositive donors. We have now demonstrated that selective peptide stimulation of peripheral blood lymphocytes induced CLG-specific CTL in all donors, suggesting that this epitope can be a suitable target for specific immunotherapies. We found that the CLG peptide has a low affinity for HLA-A(*)0201 and does not produce stable complexes, both factors that are likely to determine the strength of CTL responses to this epitope. Therefore, we synthesized and tested CLG analogues carrying single or combined amino acid substitutions to increase HLA/peptide stability. Among the analogues tested we identified two peptides which, compared to the natural epitope, showed higher affinity for HLA-A(*)0201 molecules, and produced stable complexes. These peptides demonstrated a potent, specific stimulatory capacity and could be used for selective CTL-based therapies.
KW - Cytotoxic T lymphocyte
KW - Epitope
KW - Epstein-Barr virus
KW - HLA class I
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U2 - 10.1002/(SICI)1521-4141(199908)29:08<2579::AID-IMMU2579>3.0.CO;2-E
DO - 10.1002/(SICI)1521-4141(199908)29:08<2579::AID-IMMU2579>3.0.CO;2-E
M3 - Article
C2 - 10458773
AN - SCOPUS:0032788204
SN - 0014-2980
VL - 29
SP - 2579
EP - 2589
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 8
ER -