title: Detection of human papillomavirus (HPV) 16-specific CD4+ T-cell immunity in patients with persistent HPV16-induced vulvar intraepithelial neoplasia in relation to clinical impact of imiquimod treatment.
abstract: OBJECTIVE
  Topical application of the immune response modifier imiquimod is an alternative approach for the treatment of human papillomavirus (HPV)-positive vulvar intraepithelial neoplasia (VIN) and aims at the immunologic eradication of HPV-infected cells. We have charted HPV16-specific immunity in 29 patients with high-grade VIN and examined its role in the clinical effect of imiquimod treatment.
  
  
  METHODS
  The magnitude and cytokine polarization of the HPV16 E2-, E6-, and E7-specific CD4+ T-cell response was charted in 20 of 29 patients by proliferation and cytokine bead array. The relation between HPV16-specific type 1 T-cell immunity and imiquimod treatment was examined in a group of 17 of 29 patients.
  
  
  RESULTS
  HPV16-specific proliferative responses were found in 11 of the 20 patients. In eight of these patients, T-cell reactivity was associated with IFNgamma production. Fifteen of the women treated with imiquimod were HPV16+, of whom eight displayed HPV16 E2- and E6-specific T-cell immunity before treatment. Imiquimod neither enhanced nor induced such immunity in any of the subjects. Objective clinical responses (complete remission or >75% regression) were observed in 11 of the 15 patients. Of these 11 responders, eight patients displayed HPV16-specific type 1 CD4+ T-cell immunity, whereas three lacked reactivity. Notably, the four patients without an objective clinical response also lacked HPV16-specific type 1 T-cell immunity.
  
  
  CONCLUSIONS
  HPV16-specific IFNgamma-associated CD4+ T-cell immunity, although not essential for imiquimod-induced regression of VIN lesions, may increase the likelihood of a strong clinical response (P = 0.03).
authors: Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Mariëtte I E
authors: MI
authors: van Poelgeest
authors: Manon
authors: M
authors: van Seters
authors: Marc
authors: M
authors: van Beurden
authors: Kitty M C
authors: KM
authors: Kwappenberg
authors: Claudia
authors: C
authors: Heijmans-Antonissen
authors: Jan W
authors: JW
authors: Drijfhout
authors: Cornelis J M
authors: CJ
authors: Melief
authors: Gemma G
authors: GG
authors: Kenter
authors: Theo J M
authors: TJ
authors: Helmerhorst
authors: Rienk
authors: R
authors: Offringa
authors: Sjoerd H
authors: SH
authors: van der Burg
mesh_terms: D000276:Adjuvants, Immunologic; D000328:Adult; D000368:Aged; D000634:Aminoquinolines; D015496:CD4-Positive T-Lymphocytes; D002278:Carcinoma in Situ / Q000188:drug therapy* / Q000276:immunology / Q000821:virology*; D005260:Female; D006801:Humans; D000077271:Imiquimod; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000276:immunology; D008875:Middle Aged; D027383:Papillomaviridae; D016896:Treatment Outcome; D014846:Vulvar Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000821:virology*
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D007371:Interferon-gamma; D000077271:Imiquimod