T Cell-Mediated and Non-Specific Inflammatory Mechanisms Contribute to the Skin Pathology of HPV 16 E6E7 Transgenic Mice

Abstract

One of three lines of mice transgenic for the E6 and E7 genes of human papillomavirus type 16 (HPV16) expressed from an αA-crystallin promoter also expresses the transgene ectopically in the skin. This line, designated αACE6E7#19, develops skin disease from 3 months of age, characterised by epidermal hyperplasia and eventual skin loss. Administration of complete Freund’s adjuvant (CFA) to αACE6E7#19 mice, but not to non-transgenic littermate controls, induced local epidermal hyperplasia which was histologically similar to the spontaneously arising skin pathology. Local application of 2,4-dinitrochlorobenzene (DNCB) to DNCB-sensitised αACE6E7#19 mice, but not DNCB-sensitised controls, also induced hyperplasia. Treatment with cyclosporin A (CsA) or systemic depletion of CD4+ cells significantly reduced the incidence of skin disease. These data suggest that local inflammation, and cytokines produced by T helper cells, contribute to the induction of hyperplastic skin disease in αACE6E7#19 mice. Spontaneous skin disease with similar histological appearance, frequency, age of onset and severity in αACE6E7#19 mice was observed in scid–/– αACE6E7#19 mice, despite immune paresis. Antigen-specific immune responses and T-cell cytokines are therefore not necessary for the induction of skin disease. We propose that epidermal hyperplasia associated with HPV16 E6 and E7 expression in skin is accelerated by local secretion of pro-inflammatory cytokines, whose production can be enhanced by activated CD4+ T cells.

Model systems of human papillomavirus‐associated disease

“…As a result, various animal PVs have been used, with their appropriate animal hosts, to study aspects of basic PV biology, with more complex animal models being used to study the role of HPV gene products on neoplastic progression, immune regulation and virus entry. The latter include the various transgenic models for HPV16 and for the β‐PVs , along with HPV tumour challenge models that may help in the development of immune therapeutics. Animal models have also been used to investigate the role of antibodies in blocking infection by HPV pseudoviruses carrying marker genes, and have had a wider use in establishing the utility of prophylactic vaccines in disease prevention.…”

“…A combination of organotypic raft culture for the study of the high‐risk HPV types, coupled with protein function analysis and clinical observations of human tissue, has similarly led to our current understanding of α‐HPV‐associated disease . In addition to these approaches, a number of studies led to the generation of transgenic mice that express viral gene products constitutively under exogenous promoter control . For the high‐risk α‐HPV types, this work has been driven largely by Lambert and colleagues , who have examined the consequences of HPV16 E6 / E7 expression under the control of the basal cell keratin 14 (K14) promoter in a range of different tissues.…”