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Annals of Surgical Oncology, Vol 5, Issue 1 93-99, Copyright © 1998 by Society of Surgical Oncology

ARTICLES

An HLA-restricted, p53 specific immune response from HLA transgenic p53 knockout mice

T. M. McCarty, Z. Yu, X. Liu, D. J. Diamond and J. D. Ellenhorn
Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA.

BACKGROUND: p53 is over-expressed in most human malignancies and is therefore an attractive target for immunotherapy. Unfortunately, a human cytotoxic T cell response to p53 is difficult to generate. p53 knockout transgenic mice may provide a model to circumvent immunologic tolerance to p53 and develop high-affinity p53-specific cytotoxic T lymphocytes (CTL). METHODS: p53 knockout, HLA A2.1 transgenic mice were generated and immunized with the immunodominant wild-type p53 nonamer peptide epitope p53149-157. Two weeks later splenocytes were harvested and stimulated in vitro with acid-treated, p53 peptide-pulsed syngeneic blast cells. Cultures were restimulated weekly with acid-treated, p53 peptide-pulsed Jurkat cells transfected with the HLA A2.1 gene. Peptide-specific cytotoxic activity was measured by chromium release assay, and the resulting CD8+ effectors were cloned via limiting dilution. RESULTS: P53 peptide-specific CTL were generated against p53149-157. Clones generated from the p53149-157 cell line demonstrated high affinity and specificity for p53149-157 when presented by HLA A2.1+ antigen-presenting cells. The p53149-157 CTL killed only cells overexpressing p53 cells that were HLA A2.1+ and did not kill cells with normal levels of p53 expression or those that were HLA A2.1-. CONCLUSION: HLA transgenic mice not previously exposed to the p53 protein provide a useful model for generating high-affinity p53-specific CTL.


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