Delayed-type hypersensitivity response to human papillomavirus type 16 E6 protein in a mouse model

Abstract

A mouse model incorporating the epitheliotropic nature of human papillomavirus (HPV) infections has been used to study an immune response to HPV type 16 (HPV-16) E6 protein in vivo. Using a transplantation technique, a novel immortal keratinocyte cell line expressing the E6 protein has been grafted onto syngeneic mice to re-form a differentiated epithelium overlying a granulation tissue bed. By this approach the presentation of viral antigens to the immune system can be modelled in a way analogous to the natural infection. Here we report a delayed-type hypersensitivity (DTH) reaction in grafted mice challenged intradermally with a recombinant vaccinia virus expressing the HPV-16 E6 protein. The specificity of the response was confirmed by the absence ofa DTH reaction to challenge with virus expressing either HPV-16 E7 or LI protein.More than 65 different types of human papillomavirus (HPV) have been described, classified on the basis of nucleotide homology. At least 20 genotypes are associated with lesions of the genital tract. Benign genital warts (condylomata acuminata of low malignant potential) are most frequently associated with types 6 and 11, whereas types 16 and 18 are found predominantly in anogenital dysplasias and carcinomas.Our understanding of the immunobiology of papillomaviruses, although limited, is central to any strategy for prophylactic or therapeutic intervention. The evidence from immunosuppressed patients (Alloub et al.,

Intracutaneous DNA Vaccination with the E8 Gene of Cottontail Rabbit Papillomavirus Induces Protective Immunity against Virus Challenge in Rabbits

“…In this study, we introduced DTH skin tests as an additional method to assess host immunity after E8 vaccination. DTH skin tests have been used to examine T-cell-mediated immunity to HPV antigens in human and mouse models (3,20,21). Höpfl and coworkers also used skin tests to assess viral immunity to CRPV virions in rabbits with CRPV infections (22).…”

Human Papillomavirus (HPV) Infection in Southern Africa: Prevalence, Immunity, and Vaccine Prospects

“…Although the available evidence supports the association of Th1 responses with HPV lesion regression, the viral antigens against which the response is directed are presently poorly defined. In a murine model that mimics a natural HPV infection by expressing HPV proteins in keratinocytes, CMI responses were directed against E6 and E7 (31,32). During cotton tail rabbit papillomavirus (CRPV) infections in rabbits, a T cell proliferative response to E2 has been shown to be the best predictor of wart regression (33).…”

Codon optimized expression of HPV 16 E6 renders target cells susceptible to E6-specific CTL recognition

“…In fact, successful induction of E7-specific CTL has been described in mice upon immunization with synthetic peptides [7], recombinant protein [8], CVLPs [9], transfected dendritic cells [10], recombinant vaccinia viruses [11] and recombinant plasmids expressing E7 [12] or a non-tumorigenic variant thereof [13,14]. Actually, most studies have focused on the induction of E7-specific T cell responses, whereas E6 was only included in a few studies [11,[15][16][17][18][19][20][21]. However, recent evidence suggests that in particular the E6-specific T cell responses are critical in controlling HPV-related neoplasia [22][23][24][25].…”