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Identification of an HLA‐A*0201 cytotoxic T lymphocyte epitope specific to the endothelial antigen Tie‐2
Author(s) -
Ramage Judith M.,
Metheringham Rachael,
Conn Andrew,
Spendlove Ian,
Moss Robert S.,
Patton Daniel T.,
Murray J. Clifford,
Rees Robert C.,
Durrant Lindy G.
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20120
Subject(s) - epitope , biology , cytotoxic t cell , antigen , immunology , major histocompatibility complex , human leukocyte antigen , angiogenesis , endothelium , microbiology and biotechnology , cancer research , in vitro , genetics
Tie‐2 stabilises pericyte–endothelial interactions during angiogenesis and is highly expressed on endothelium during several diseases, including arthritis, age‐related macular degeneration and cancer. A vaccine that targets endothelium overexpressing Tie‐2 may result in vessel damage and stimulate an inflammatory cascade resulting in disease regression. We have identified a region unique to Tie‐2 (amino acids 1–196) that is homologous in humans and mice. Using computer algorithms, several HLA‐A*0201 epitopes that are identical in mice and humans were predicted within this region; however, binding assays showed that the majority of these epitopes were of low affinity. Modification of the anchor residues of 4 epitopes enhanced HLA binding. These epitopes were incorporated by site‐directed mutagenesis into a Tie‐2 DNA construct. Immunisation of HLA*0201 transgenic mice with one of the modified Tie‐2 constructs stimulated CTLs that recognised both wild‐type and modified peptide‐pulsed target cells. In contrast, no CTLs were generated in mice immunised with wild‐type Tie‐2 construct, demonstrating that the modified epitope was necessary in the generation of CTLs. Moreover, CTLs from mice immunised with the modified construct killed HLA‐A*0201 endothelial cells overexpressing Tie‐2. Our study demonstrates that it is possible to break tolerance to the endothelial antigen Tie‐2, suggesting that it may be feasible to design a vaccine to activate CTLs to kill endothelial cells overexpressing Tie‐2. © 2004 Wiley‐Liss, Inc.