A novel HLA (HLA-A* 0201) transgenic rabbit model for preclinical evaluation of human CD8+ T cell epitope-based vaccines against ocular herpes

AA Chentoufi, G Dasgupta, ND Christensen… - The Journal of …, 2010 - journals.aai.org
AA Chentoufi, G Dasgupta, ND Christensen, J Hu, ZS Choudhury, A Azeem, JV Jester…
The Journal of Immunology, 2010journals.aai.org
We introduced a novel humanized HLA-A* 0201 transgenic (HLA Tg) rabbit model to assess
the protective efficacy of a human CD8+ T cell epitope-based vaccine against primary ocular
herpes infection and disease. Each of the three immunodominant human CD8+ T cell
peptide epitopes from HSV-1 glycoprotein D (gD 53–61, gD 70–78, and gD 278–286) were
joined with a promiscuous human CD4+ T cell peptide epitope (gD 49–82) to construct three
separate pairs of CD4–CD8 peptides. Each CD4–CD8 peptide pair was then covalently …
Abstract
We introduced a novel humanized HLA-A* 0201 transgenic (HLA Tg) rabbit model to assess the protective efficacy of a human CD8+ T cell epitope-based vaccine against primary ocular herpes infection and disease. Each of the three immunodominant human CD8+ T cell peptide epitopes from HSV-1 glycoprotein D (gD 53–61, gD 70–78, and gD 278–286) were joined with a promiscuous human CD4+ T cell peptide epitope (gD 49–82) to construct three separate pairs of CD4–CD8 peptides. Each CD4–CD8 peptide pair was then covalently linked to an N ε-palmitoyl–lysine residue via a functional base lysine amino group to construct CD4–CD8 lipopeptides. HLA Tg rabbits were immunized sc with a mixture of the three CD4–CD8 HSV-1 gD lipopeptides. The HSV-gD–specific T cell responses induced by the mixture of CD4–CD8 lipopeptide vaccine and the protective efficacy against acute virus replication and ocular disease were determined. Immunization induced HSV-gD 49–82–specific CD4+ T cells in draining lymph node (DLN); induced HLA-restricted HSV-gD 53–61, gD 70–78, and gD 278–286–specific CD8+ T cells in DLN, conjunctiva, and trigeminal ganglia and reduced HSV-1 replication in tears and corneal eye disease after ocular HSV-1 challenge. In addition, the HSV-1 epitope-specific CD8+ T cells induced in DLNs, conjunctiva, and the trigeminal ganglia were inversely proportional with corneal disease. The humanized HLA Tg rabbits appeared to be a useful preclinical animal model for investigating the immunogenicity and protective efficacy of human CD8+ T cell epitope-based prophylactic vaccines against ocular herpes. The relevance of HLA Tg rabbits for future investigation of human CD4–CD8 epitope-based therapeutic vaccines against recurrent HSV-1 is discussed.
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