T cell-mediated and non-specific inflammatory mechanisms contribute to theskin pathology of HPV 16 E6E7 transgenic mice

One of three lines of mice transgenic for the E6 and E7 genes of human papi llomavirus type 16 (HPV16) expressed from an alpha A-crystallin promoter al so expresses the transgene ectopically in the skin. This line, designated a lpha ACE6E7#19, develops skin disease from 3 months of age, characterised b y epidermal hyperplasia and eventual skin loss. Administration of complete Freund's adjuvant (CFA) to alpha ACE6E7#19 mice, but not to nontransgenic l ittermate controls, induced local epidermal hyperplasia which was histologi cally similar to the spontaneously arising skin pathology. Local applicatio n of 2,4-dinitrochlorobenzene (DNCB) to DNCB-sensitised aACE6E7#19 mice, bu t not DNCB-sensitised controls, also induced hyperplasia. Treatment with cy closporin 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 h yperplastic skin disease in alpha ACE6E7#19 mice. Spontaneous skin disease with similar histological appearance, frequency, age of onset and severity in alpha ACE6E7#19 mice was observed in scid-/- aACE6E7#19 mice, despite im mune paresis. Antigen-specific immune responses and T-cell cytokines a re t herefore not necessary for the induction of skin disease. We propose that e pidermal hyperplasia associated with HPV16 E6 and E7 expression in skin is accelerated by local secretion of pro-inflammatory cytokines, whose product ion can be enhanced by activated CD4+ T cells.