Limitations of HLA‐transgenic mice in presentation of HLA‐restricted cytotoxic T‐cell epitopes from endogenously processed human papillomavirus type 16 E7 protein

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Abstract
Summary: We investigated the use of mice transgenic for human leucocyte antigen (HLA) A*0201 antigen‐binding domains to test vaccines composed of defined HLA A*0201‐restricted cytotoxic T‐lymphocyte (CTL) epitopes of human papillomavirus (HPV) type 16 E7 oncoprotein. HPV is detected in >90% of cervical carcinomas. HPV16 E7 oncoprotein transforms cells of the uterine cervix and functions as a tumour‐associated antigen to which immunotherapeutic strategies may be directed. We report that although the HLA A*0201 E7 epitope peptides function both to prime for E7 CTL responses, and to sensitize target cells for E7‐directed CTL killing in situations where antigen processing is not required, the epitopes are not processed out of either endogenously expressed or immunization‐introduced E7, by the mouse antigen‐processing and presentation machinery. Thus (1) CTL induced by HLA A*0201 peptide immunization killed E7 peptide‐pulsed target cells, but did not kill target cells expressing whole E7; (2) immunization with whole E7 protein did not elicit CTL directed to HLA A*0201‐restricted E7 CTL epitopes; (3) HLA A*0201‐restricted CTL epitopes expressed in the context of a DNA polytope vaccine did not activate E7‐specific T cells either in ‘conventional’ HLA A*0201 transgenic (A2.1Kb) mice, or in HHD transgenic mice in which expression of endogenous H‐2 class 1 is precluded; and (4) HLA A*0201 E7 peptide epitope immunization was incapable of preventing the growth of an HLA A*0201‐ and E7‐expressing tumour. There are generic implications for the universal applicability of HLA‐class 1 transgenic mice for studies of human CTL epitope presentation in murine models of human infectious disease where recognition of endogenously processed antigen is necessary. There are also specific implications for the use of HLA A2 transgenic mice for the development of E7‐based therapeutic vaccines for cervical cancer.

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