CYTOKINE PRODUCTION PATTERNS IN CERVICAL INTRAEPITHELIAL NEOPLASIA - ASSOCIATION WITH HUMAN PAPILLOMAVIRUS INFECTION

Background: Genital infection with certain strains of human papillomav irus (HPV) is associated with a high risk of malignant transformation, and HPV-associated cervical intraepithelial neoplasia (CIN) can becom e invasive cancer. Host factors are critical in regulating tumor growt h, and cytokines that modulate immunologic control may be of particula r importance. The type 1 cytokines interleukin 2 (IL-2) and interferon gamma (IFN gamma) are immunostimulatory and are thus capable of limit ing tumor growth. The type 2 cytokines interleukin 4 (IL-4) and interl eukin 10 (IL-10) are immunoinhibitory and are thus capable of stimulat ing tumor growth. Purpose: We analyzed the production of cytokines by peripheral blood mononuclear cells (PBMCs) in women with CIN associate d with localized or extensively spread HPV infection. Methods: Thirty women diagnosed with CIN and 10 age- and sex-matched healthy control s ubjects were enrolled in the study conducted at Istituto Nazionale Tum ori, Milan, Italy. The following parameters were analyzed: 1) HPV infe ction of the cervix and other sites of the lower genital tract by colp oscopic, cytologic, and histologic examinations; 2) HPV typing; 3) in vitro production of IL-2 by PBMCs in response to stimulation with solu ble antigen (influenza [FLU] antigen) or to cell-associated human leuk ocyte antigen (HLA) alloantigen; and 4) in vitro production of the typ e 1 cytokines IL-2 and IFN gamma and of the type 2 cytokines IL-4 and IL-10 by PBMCs in response to mitogen stimulation. Statistical signifi cance was determined by nonparametric tests (two-sided). Results: High -grade CIN associated with HPV infection was detected in all case pati ents, and HPV type 16 or 18 infection was detected in cervical tissue of 21 (70%) of 30 case patients. HPV infection that had spread to othe r sites of the lower genital tract, thus resulting in more extensive d isease, was detected in 16 (53%) of the 30 individuals with CIN, where as HPV infection was limited to the portio in 14 (47%). IL-2 productio n by PBMCs in response to stimulation with soluble antigen or HLA allo antigen was reduced in the group with extensive disease compared with that in the group with localized disease or with that in healthy contr ol subjects. In contrast, IL-4 and IL-10 production in response to mit ogen stimulation was elevated in the group with extensive disease comp ared with that in the group with localized disease or with that in hea lthy control subjects. The highest production of IL-4 and IL-10 was de tected in patients with HPV infection that had extended beyond the gen ital tract. Conclusions: CIN is characterized by different immunologic profiles, in which HPV infection is or is not confined to the portio. Production of cytokines that mainly enhance potentially protective ce ll-mediated immunity is defective in the women in whom extended HPV in fection was observed. A pronounced shift from type 1 to type 2 cytokin e production is associated with more extensive HPV infection. Implicat ions: These data reinforce the need for detailed analyses of immune dy sregulation in CIN patients. They also suggest the potential usefulnes s of the cytokine assays for determining prognosis or deciding whether cytokine-based therapy is indicated.