Imiquimod is effective in the treatment of vulvar intraepithelial neoplasia. (Current Controlled Trials number, ISRCTN11290871 [controlled-trials.com].).
Background: A shifted balance between T helper 1 (Th1)-type and Th2-type cytokines has been hypothesised in cervical dysplasia Aims: To evaluate possible deregulation of the cytokine network by estimating the expression of peripheral cytokines in different stages of cervical disease and in relation to the presence or absence of high risk human papillomavirus (HR-HPV). Methods: Twenty one HR-HPV positive women with high grade cervical intraepithelial neoplasia (CIN II-III) and 12 patients with invasive cervical carcinoma formed the study groups. Two control groups consisted of 10 HR-HPV positive and 11 HR-HPV negative women without CIN. Differences in leucocyte subgroups were evaluated by a differential leucocyte count. Plasma concentrations of tumour necrosis factor a (TNFa), TNFa receptors TNFRI and TNFRII, interferon c (IFNc), interleukin 2 (IL-2), IL-12, IL-4, and IL-10 were determined by enzyme linked immunosorbent assays. Results: Leucocyte counts in patients with CIN III and carcinoma were significantly higher than in controls. Plasma IFNc concentrations were significantly lower in patients with CIN III and carcinoma than in women with CIN II or controls. Plasma concentrations of IL-12, IL-2, IL-4, and TNFa did not differ significantly between groups, but significantly lower plasma concentrations of TNFRII were found in CIN III and carcinoma compared with CIN II. IL-10 was detected with increased frequency in the plasma of patients with CIN III and carcinoma. Conclusions: These results indicate that a shift to a Th2-type cytokine pattern during the carcinogenesis of cervical cancer occurs in women with CIN III lesions.
Recently, we reported on the efficacy of imiquimod for treatment of usual type vulvar intraepithelial neoplasia (uVIN). A histologic regression of uVIN to normal tissue was observed in 58% of patients. As success of treatment is related to clearance of high-risk human papilloma virus (HPV), the aim of our study was to assess differences in immune cell counts and in the expression of p16 INK4a in VIN tissue before and after imiquimod treatment, in relation to HPV clearance and clinical response. Vulvar tissue samples taken prior to imiquimod treatment and 4 weeks after treatment were tested for the presence of HPV. Previously determined immune cell counts (CD1a, CD207, CD208, CD123/CD11c, CD94, CD4, CD8 and CD25/HLA-DR) in epidermis and dermis of 25 VIN patients and 19 healthy controls were completed with the counts for CD14 and CD68. The expression of p16 INK4a was investigated by immunohistochemistry in 15 patients. Before imiquimod treatment, both HPV cleared and HPV noncleared patients showed mainly in the dermis significantly upregulated immune cell counts compared to healthy controls. However, in patients that cleared HPV and showed histologic regression already 4 weeks after imiquimod treatment, immune cell counts and p16 INK4a expression were normalized. In conclusion, our data indicate that imiquimodinduced clearance of HPV results in normalization of counts for certain immune cells and is strongly correlated with histologic regression of the disease.Vulvar intraepithelial neoplasia (VIN) is a premalignant disorder that is classified into differentiated type VIN, which is associated with lichen sclerosus, and usual type VIN (uVIN), 1 which is caused by a persistent infection with a high-risk or oncogenic HPV (hrHPV, usually HPV-type 16, 18 or 33). 2 Over the last decades, the incidence of uVIN has increased, most likely due to a rise in the incidence of HPV infections. 3 Lifetime risk to become infected with HPV in western societies is around 80% and $40% of all sexually active, female adolescents are at least once infected with hrHPV. [4][5][6][7] When hrHPV persists (in less than 10% of cases), premalignant disorders of the anogenital tract, such as uVIN, can develop. 8-10 uVIN has invasive potential (10% of untreated cases will progress in 1-4 years) and needs to be treated proactively. 11,12 The host immune response is of critical importance in determining clearance or persistence of an HPV-infection. In natural life, during the early stages of a viral infection, CpGrich regions in the viral DNA are recognized by toll-like receptor (TLR) 7 and 9 on the cell surface of immature dendritic cells (DCs). Upon binding, TLRs activate kinase cascades eventually activating NFjB, which will result in the production of cytokines, adhesions molecules and other effectors of the innate immune response. 13 Other receptor and adhesion molecules at the DC surface can bind viral antigen and will internalize and digest the antigen, which is followed by expression on the cell membrane in major histocompatibility complex...
Genital infection with human papillomavirus (HPV) is usually transient, as the immune system is capable of eliminating the virus. When immunity ''fails'' and the infection persists, vulvar intraepithelial neoplasia (VIN) may develop. In this study, we examined the distribution of inflammatory cells in 51 patients with HPV-associated usual-type VIN and in 19 healthy controls. Frozen vulvar tissue samples were tested for the presence of HPV-DNA, and immunohistochemical staining for the markers CD1a, CD207, CD208, CD123/CD11c, CD94, CD4, CD8, and CD25/HLA-DR was performed. Cells were counted in both the epidermis and dermis over at least 2 mm of basal membrane length. + T cells. In the dermis, inflammatory activation is reflected by the influx of mature mDCs and pDCs, NK cells, and T cells, suggesting that the cellular immune response on viral HPV infection occurs in the dermis of VIN patients. [Cancer Res 2008;68(16):6617-22]
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