T cell-mediated and non-specific inflammatory mechanisms contribute to the skin pathology of HPV 16 E6E7 transgenic mice.
One of three lines of mice transgenic for the E6 and E7 genes of human papillomavirus type 16 (HPV16) expressed from an alphaA-crystallin promoter also expresses the transgene ectopically in the skin. This line, designated alphaACE6E7#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 alphaACE6E7#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 alphaACE6E7#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 alphaACE6E7#19 mice. Spontaneous skin disease with similar histological appearance, frequency, age of onset and severity in alphaACE6E7#19 mice was observed in scid-/- alphaACE6E7#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.
Centre for Immunology and Cancer Research, Department of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Qld., Australia.
P A
PA
Hilditch-Maguire
D M
DM
Lieppe
D
D
West
P F
PF
Lambert
I H
IH
Frazer
D000367:Age Factors; D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use; D004137:Dinitrochlorobenzene; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D007111:Immunity, Cellular; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007509:Irritants; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic / Q000235:genetics*; D009856:Oncogene Proteins, Viral / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000473:pathology* / Q000821:virology; D012871:Skin Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000276:immunology*
D004137:Dinitrochlorobenzene; C068651:E6 protein, Human papillomavirus type 16; D007166:Immunosuppressive Agents; D007509:Irritants; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D016572:Cyclosporine