Dynamics of cervical Langerhans cell counts in the course of HPV-positive CIN treatment with the use of human recombinant interferon gamma

Objectives: Langerhans cells play a pivotal role as professional antigens presenting cells in cervical epithelium, thus changes in their density or/and function may profoundly influence the proper activation of the afferent arm of immune response in cases of HPV-related intraepithelial lesions.

Aim of the study: Assessment of intraepithelial Langerhans cell count changes in CIN I/CIN II after human recombinant interferon gamma (IFNgamma) application and correlation with clinical outcome.

Material & methods: The present study is a part of prospective trial on IFNgamma application in the treatment of CIN I/CINII associated with high-risk HPV infection. Seventeen subjects underwent uniform IFNgamma treatment (four intracervical injections in a two-day interval for a total dose of 6,000,000 IU). Langerhans cells were stained within cervical punch biopsy specimens with the use of polyclonal anti-S-100 antibody according to the three-step indirect peroxidase protocol, and their mean count calculated for the following groups: before IFNgamma treatment launching, immediately after completion of the treatment, and after two months of follow-up.

Results: The analysis revealed a rapid and significant increase in Lagerhans' cell count immediately after treatment completion (21.17/mm2 and 25.94/mm2, respectively, at p = 0.019) which further increased in the group of complete response (in 9 subjects; 32.22/mm2). After transient elevation of the Langerhans' cell count it returned to a level even lower than initially in the non-responder group (4 subjects; 20.25/mm2).

Conclusion: Our data strongly support the observation from static studies suggesting that regression of HPV-related cervical lesions is associated with increased density of epithelial Langerhans cells.

Langerhans cells; Cervical intraepithelial neoplasia; Interferon gamma

[1] McArdle J.P., Muller H.K.: "Quantitative assessment of Langerbans'cells in human cervical intraepithelial neoplasia and wart virus infection". Am. J. Obstet. Gynecol., 1986, 154, 509.

[2] Edwards J.N., Morris H.B.: "Langerhans'cells and lymphocyte subsets in the female genital tract". Br. J. Obstet. Gynaecol., 1985, 92, 974.

[3] Figueroa C.D., Caorsi I.: "Ultrastructural and morphometric study of the Langerhans cell in the normal human exocervix". J. Anal., 1980, 131, 669.

[4] Tay S.K., Jenkins D., Maddox P., Campion M., Singer A.: "Subpopulations of Langerhans'cells in cervical neoplasia". Br. J. Obstet. Gynaecol., 1987, 94, 10.

[5] Morris H.H., Gatter K.C., Sykes G., Casemore V., Mason D.Y.: "Langerhans'cells in human cervical epithelium: effects of wart virus infection and intraepithelial neoplasia". Br. J. Obstet. Gynaecol., 1983, 90, 412.

[6] Morelli A.E., Sananes C., Di Paola G., Paredes A., Fainboim L "Relationship between types of human papillomavirus and Langerhans'cells in cervical condyloma and intraepithelial neoplasia". Am. J. Clin. Pathol., 1993, 99, 200.

[7] Tay S.K., Jenkins D.: "Langerhans cell population in early invasive squamous cell carcinoma of the uterine cervix". Aust. NZ J Obstet. Gynaecol., 1989, 29, 38.

[8] Abdou L.A., el-Gazayerly l.M., el-Shazley L.Y., Zoheir M.A., Kholeif A.E., el-Sedfy A.S.: "Immunohistochemical and ultrastructural study of Langerhans's cells in squamous cell carcinoma of the cervix". J. Obstet. Gynaecol. Res., 1999, 25, 15.

[9] Connor J.P., Ferrer K., Kane J.P., Goldberg J.M.: "Evaluation of Langerhans'cells in the cervical epithelium of women with cervical intraepithelial neoplasia". Gynecol. Oneal., 1999, 75, 130.

[10] Cristoforoni P., Favre A., Cennamo V., Giunta M., Corte G., Grossi C.E.: "Expression of a novel beta I integrin in the dysplastic progression of the cervical epithelium". Gynecol. Oneal., 1995,5 8, 319.

[11] Barberis M.C., Vago L., Cecchini G., Bramerio M., Banfi G., D'Amico M. et al.: "Local impairment of immunoreactivity in HIV-infected women with HPV- related squamous intraepithelial lesions of the cervix". Turnori, I 998, 84, 489.

[12] al-Saleh W., Delvenne P., Arrese J.E., Nikkels A.F., Pierard G.E., Boniver J.: "Inverse modulation of intraepithelial Langerhans' cells and stromal macrophage/dendrocyte populations in human papillomavirus-associated squamous intraepithelial lesions of the cervix". Virchows Arch., 1995, 427, 41.

[13] Sikorski M., Zrubek H.: "Recombinant human interferon gamma in the treatment of cervical intraepithelial neoplasia (CIN) associated with human papillomavirus (HPV) infection". Eur. J. Gynaecol. Oncol., 2003, 24, 147.

[14] Sikorski M., Zrubek H.: "Long-term follow-up of patients treated with recombinant human interferon gamma for cervical intraepithelial neopl􀆐sia". Int. J. Gynecol. Obstet., 2003, 82, 179.

[15] Sikorski M., Zrubek H.: "Responses to intracervical recombinant interferon gamma administration in cases of CIN with HPV infection". Acta Obstet. Gynecol. Scand., 1997, 76 (suppl.), 167, 64.

[16] Sikorski M., Zrubek H., Wiktor H.: "Systemic side effects of intracervical interferon gamma administration". J. Buon., 1996, 1, 26.

[17] Munn D.H., Cheung N.K.: "Preclinical and clinical studies of macrophage colony-stimulating factor". Sernin. Oncol., 1992, 19, 395.

[18] Heufler C., Koch F., Schuler G.:'.'Granulocyte/macrophage colony-stimulating factor and interleukin I mediate the maturation of murine epidermal Langerhans cells into potent immunostimulatory dendritic cells". J. Exp. Med., 1988, 167, 700.

[19] Witmer-Pack M.D., Olivier W., Valinsky J., Schuler G., Steinman R.M.: "Granulocyte/macrophage colony-stimulating factor is essential for the viability and function of cultured murine epidermal Langerhans cells". J. Exp. Med., 1987, 166, 1484.

[20] Hubert P., van den Brule F., Giannini S.L., Franzen-Detrooz E., Boniver J., Delvenne P.: "Colonization of in vitro-formed cervical human papillomavirus-associated (pre)neoplastic lesions with dendritic cells: role of granulocyte/macrophage colony-stimulating factor". Arn. J. Pathol., 1999, 154, 775.

[21] Mota F., Rayment N., Chong S., Singer A., Chain B.: "T he antigen-presenting environment in normal and human papillomavirus (HPV)-related premalignant cervical epithelium". Clin Exp. Irnrnunol., 1999, 116, 33.

[22] Fukuda K., Hachisuga T., Nakamura S., Matsuo N., Iwasaka T., Sugimori H.: "Local immune response in persistent cervical dysplasia". Obstet. Gynecol., 1993, 82, 941.

[23] Nakano T., Oka K., Takahashi T., Morita S., Arai T.: "Roles of Langerhans'cells and T-lymphocytes infiltrating cancer tissues in patients treated by radiation therapy for cervical cancer". Cancer, 1992, 70, 2839.

[24] Nakano T., Oka K.,S ugita T.,T sunemoto H.: "Antitumor activity of Langerhans cells in radiation therapy for cervical cancer and its modulation with SPG administration". In Vivo, 1993, 7, 257.

[25] Oka K.,N akano T.,A rai T.: "Adenocarcinoma of the cervix treated with radiation alone: prognostic significance of S-100 protein and vimentin immunostaining". Obstet. Gynecol., 1992, 79, 347.

[26] Hawthorn R.J., Murdoch J.B., MacLean A.B., MacKie R.M "Langerhans'cells and subtypes of human papillomavirus in cervical intraepithelial neoplasia". Br. Med. J., 1988, 297, 643.

[27] Lehtinen M., Rantala I., Toivonen A., Luoto H., Aine R., Lauslahti K. et al.: "Depletion of Langerhans cells in cervical HPV infection is associated with replication of the virus". APMIS, 1993, 101, 833.

[28] Mota F.F., Rayment N.B., Kanan J.H., Singer A., Chain B.M "Differential regulation of HLA-DQ expression by keratinocytes and Langerhans cells in normal and premalignant cervical epithelium". Tissue Antigens, 1998, 52, 286.

[29] Lenz P., Day P.M., Pang Y.Y., Frye S.A., Jensen P.N., Lowy D.R et al.: "Papillomavirus-like particles induce acute activation of dendritic cells". J. Irnrnunol., 2001,1 66, 5346.

[30] Morelli A.E., di Paola G., Fainboim L.: "Density and distribution of Langerhans cells in the human uterine cervix". Arch. Gynecol. Obstet., 1992, 252, 65.