Detection of CD8+ T cell responses to human papillomavirus type 16 antigens in women using imiquimod as a treatment for high-grade vulval intraepithelial neoplasia.
OBJECTIVE
To investigate CD8+ T cell reactivity to human papillomavirus (HPV) 16 antigens in patients with high-grade vulval intraepithelial neoplasia (VIN) before, during and after treatment with 5% imiquimod cream.


METHODS
CD8-enriched responder cell populations were obtained from 10 patients with high-grade VIN using imiquimod cream as a treatment. Overlapping synthetic peptides covering the entire primary sequences of the HPV16 E6, E7 and E4 proteins were used to screen for CD8+ T cell responses using an ELISPOT assay of interferon (IFN)-gamma release.


RESULTS
Reactivity to the proteins was detected in all patients on at least one occasion. With the exception of one patient, CD8+ T cell reactivity generally increased at some stage during treatment. The magnitude and specificities of responses changed over the treatment period. This was particularly noticeable in response to peptides derived from the E4 protein. CD8+ T cell reactivity to HPV16 E7 appeared to be dominant amongst women with high-grade VIN. The magnitude and specificity of response had no correlation with clinical response to imiquimod.


CONCLUSIONS
HPV16 specific CD8+ T cell activity was detected in patients with high-grade VIN. Imiquimod use appeared to increase the magnitude of the response and broaden the specificity of response in some patients. Despite the presence of these CD8+ T cells, the disease state persisted; therefore, a role for HPV-specific cytotoxic T cells (CTLs) in VIN resolution remains unproven.
Todd
Richard W
RW
Department of Gynaecologic Oncology, Birmingham Women's NHS Trust, Birmingham B15 2TG, UK. rick@todd38.freeserve.co.uk
Steele
Jane C
JC
Etherington
Ian
I
Luesley
David M
DM
D000328:Adult; D000595:Amino Acid Sequence; D000634:Aminoquinolines / Q000627:therapeutic use*; D000914:Antibodies, Viral / Q000097:blood; D000918:Antibody Specificity; D000957:Antigens, Viral, Tumor / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D006801:Humans; D000077271:Imiquimod; D007371:Interferon-gamma / Q000378:metabolism; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000276:immunology; D027383:Papillomaviridae / Q000235:genetics / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D014846:Vulvar Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology
D000634:Aminoquinolines; D000914:Antibodies, Viral; D000957:Antigens, Viral, Tumor; D000970:Antineoplastic Agents; D004279:DNA, Viral; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C069119:oncogene protein E4, Human papillomavirus type 16; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma; D000077271:Imiquimod