Adjuvant treatment with a dialyzable leukocytes extract contributes to maintain HPV-infected women free of low-grade cervical lesions

Purpose of investigation: To investigate if adjuvant treatment with a dialyzable extract of leukocytes (DLE), may help HPV-infected patients with low-grade intraepithelial squamous cervical lesions (LIS) to get free of HPV infection and cervical lesions. Materials and Methods: Patients with untreated, low-grade cervical lesions were treated either with surgery (Group A) or with DLE (Group B). Patients with low-grade but recurrent cervical lesions were newly treated with surgery plus DLE (Group C). Results: A decreased or absent cervical lesion correlated with a diminished or absent HPV viral load at one year of treatment (r = 0.6, p < 0.05). Seventy-nine percent of Group B but only 50 % of Group C and 38 % of Group A patients were free of cervical lesion after 24 months of treatment (p < 0.05). Conclusion: The present data support the benefit of adding DLE as adjuvant for treating HPV-infected women with LIS.

Dialyzable leukocytes extract, low-grade cervical lesions, HPV.

[1] Carter J.R., Ding Z., Rose B.R.: “HPV infection and cervical dis-ease: a review”. Aust. N. Z. J. Obstet. Gynaecol., 2011, 51, 103.

[2] Piersma S.J.: “Immunosuppressive tumor microenvironment in cer-vical cancer patients”. Cancer Microenviron., 2011, 4, 361.

[3] Bhat P., Mattarollo S.R., Gosmann C., Frazer I.H., Leggatt G.R.: “Regulation of immune responses to HPV infection and during HPV-directed immunotherapy”. Immunol. Rev., 2011, 239, 85.

[4] Orozco-Colin A., Carrillo-Garcia A., Mendez-Tenorio A., Ponce-de-Leon S., Mohar A., Maldonado-Rodriguez R., et al.: “Geographical variation in human papillomavirus prevalence in Mexican women with normal cytology”. Int. J. Infect. Dis., 2010, 14, 1082.

[5] Elit L., Krzyzanowska M., Saskin R., Barbera L., Razzaq A., Lofters A., et al.: “Sociodemographic factors associated with cervical can-cer screening and follow-up of abnormal results”. Can. Fam. Physi-cian, 2012, 58, e22.

[6] Kasap B., Yetimalar H., Keklik A., Yildiz A., Cukurova K., Sovlu F.: “Prevalence and risk factors for human papillomavirus DNA in cervical cytology”. Eur. J. Obstet. Gynaecol. Reprod. Biol., 2011, 159, 168.

[7] Yetimalar H., Kasap B., Cukurova K., Yildiz A., Keklik A., Sovlu F.: “Cofactors in human papillomavirus infection and cervical car-cinogens”. Arch. Gynaecol. Obstet., 2012, 285, 805.

[8] Lopez-Revilla R., Martinez-Contreras L.A., Sanchez-Garza M.: “Prevalence of high-risk human papillomavirus types in Mexican women with cervical intraepithelial neoplasia and invasive carci-noma. Infect”. Agent Cancer, 2008, 3, 3.

[9] Illades-Aguiar B., Alarcon-Romero L.C., Antonio-Vejar V., Zamu-dio-Lopez N., Sales-Linares N., Flores-Alfaro E., et al.: “Prevalence and distribution of human papillomavirus types in cervical cancer squamous intraepithelial lesions and with no intraepithelial lesions in women from southern Mexico”. Gynecol. Oncol., 2010, 117, 291.

[10] Velazquez-Marquez N., Paredes-Tello M.A., Perez-Terron H., San-tos-Lopez G., Reyes-Leyva J., Vallejo-Ruiz V.: “Prevalence of human papillomavirus genotypes in women from a rural region of Puebla, Mexico”. Int. J. Infect. Dis., 2009, 13, 690.

[11] Insinga R.P., Perez G., Wheeler C.M., Koutsky L.A., Garland S.M., Leodolter S., et al.: “Incident cervical HPV infections in young women: transition probabilities for CIN and infection clearance”. Cancer Epidemiol. Biomarkers Prev., 2011, 20, 287.

[12] Jayshree R.S., Sreenivas A., Tessy M., Krishna S.: “Cell intrinsic & extrinsic factors in cervical carcinogenesis”. Indian J. Med. Res., 2009, 130, 286.

[13] Ronco G., Volante R., Giubilato P.: “Cervical cancer screening in Italy: quality of colposcopy and treatment”. Epidemiol. Prev., 2011, 35, 78.

[14] Lewis K., Sellors J., Dawa A., Tsu V., Kidula N.: “Report on a cryotherapy service for women with cervical intraepithelial neopla-sia in a district hospital in western Kenya”. Afr. Health Sci., 2011, 11, 370.

[15] Wu D., Zheng Y., Chen W., Guo C., Yu J., Chen G., Huang Y.: “Pre-diction of residual/recurrent disease by HPV genotype after loop ex-cision procedure for high-grade cervical intraepithelial neoplasia with negative margins”. Aust. N. Z. J. Obstet. Gynaecol., 2011, 51, 114.

[16] Persson M. Brismar W.S., Ljungblad L., Johansson B., Weiderpass E., Andersson S.: “High-risk human papillomavirus E6/E7 mRNA and L1 DNA as markers of residual/recurrent cervical intraepithe-lial neoplasia”. Oncol Rep., 2012, 28, 346. doi: 10.3892/or.2012. 1755.

[17] Machado F.A., Janssens J.P., Michelin M.A., Murta E.F.: “Immune response and immunotherapy in intraepithelial and invasive lesions of the uterine cervix”. Clin. Exp. Obstet. Gynecol., 2012, 39, 27.

[18] Russomano F., Paz B.R., de Camargo M.J., Grinstejn B.G., Fried-man R.K., Tristao M.A., Oliveira C.A.: “Recurrence of cervical in-traepithelial neoplasia in human immunodeficiency virus-infected women treated by means of electrosurgical excision of the transfor-mation zone (LLETZ) in Rio de Janeiro, Brazil”. Sao Paulo Med. J., 2013, 13, 405. doi: 10.1590/1516-3180.2013.1316578.

[19] Malapati R., Chaparala S., Cejtin H.E.: “Factors influencing per-sistence or recurrence of cervical intraepithelial neoplasia after loop electrosurgical excision procedure”. J. Low Genit. Tract Dis., 2011, 15, 177. doi: 10.1097/LGT.0b013e3181fee61d.

[20] Lee Y.S., Lee C.W., Song M.J., Ho E.M., Kim C.J., Park T.C., et al.: “Cell-mediated immune response to human papillomavirus 16 E7 peptide pools in patients with cervical neoplasia”. Acta Obstet. Gynecol. Scand., 2011, 90, 1350.

[21] Ramos M.C., Mardegan M.C., Peghini B.C., Adad S.J., Michelin M.A., Murta E.F.: “Expression of cytokines in cervical stroma in patients with high-grade cervical intraepithelial neoplasia after treatment with intralesional interferon alpha-2b”. Eur. J. Gynaecol. Oncol., 2010, 31, 522.

[22] Bermudez-Morales V.H., Peralta-Zaragoza O., Alcocer-Gonzalez J.M., Moreno J., Madrid-Marina V.: “IL-10 expression is regulated by HPV E2 protein in cervical cancer cells”. Mol. Med. Report, 2011, 4, 369.

[23] Ovestad I.T., Gudlaugsson E., Skaland I., Malpica A., Munk A.C., Janssen E.A., Baak J.P.: “The impact of epithelial biomarkers, local immune response and human papillomavirus genotype in the re-gression of cervical intraepithelial neoplasia grades 2-3. J”. Clin. Pathol., 2011, 64, 303.

[24] Lawrence H.S., Borkowsky W.: “Transfer factor. Current status and future prospects”. Biotherapy, 1996, 9, 1.

[25] Kirkpatrick C.H.: “Transfer factor: identification of conserved se-quences in transfer factor molecules”. Mol. Med., 2000, 6, 332.

[26] Fujisawa T., Yamaguchi Y., Kimura H.: “Transfer factor in restora-tion of cell mediated immunity in lung cancer patients”. Jpn. J. Surg., 1987, 13, 304.

[27] Lukacs K., Kavai M., Berenyi E., Frendl G., Schröder I., Szegedi G.: “Effect of dialyzable leukocyte extract on the mononuclear leuko-cytes in Hodgkin’s disease”. Haematologia (Budap.), 1985, 18, 105.

[28] Wagner G., Knapp W., Gitsch E., Selander S.: “Transfer factor for adjuvant immunotherapy in cervical cancer”. Cancer Detect Prev., 1987, S1, 373.

[29] Vezendi S., Schröder I.: “Transfer factor therapy of thoracic sar-coidosis”. Allergol. Immunopathol., 1989, 1, 35.

[30] Pizza G., Amadori M., Ablashi D., De Vinci C., Viza D.: “Cell me-diated immunity to meet the avian influenza A (H5N1) challenge”. Med. Hypotheses, 2006, 67, 601.

[31] Fabre R., Pérez T.M., Aguilar L.D., Rangel M.J., Estrada-Garcìa I., Hernández-Pando R., Estrada Parra S.: “Transfer factor im-munotherapy and supplement of chemotherapy in experimental pul-monary tuberculosis”. Clin. Exp. Immunol., 2004, l35, 215.

[32] Pineda B., Estrada-Parra S., Pedraza-Medina B., Rodriguez-Ropon A., Pérez R., Arrieta O.: “Interstitial transfer factor as adjuvant im-munotherapy for experimental glioma”. J. Exp. Clin. Cancer Res., 2005, 4, 207.

[33] Estrada-Parra S. Nagaya A., Serrano E., Rodriguez O., Santamaria V., Ondarza R., et al.: “Comparative study of transfer factor and acy-clovir in the treatment of herpes zoster”. Int. J. Immunopharmacol., 1998, 20, 521.

[34] Voss J.S., Kipp B.R., Campion M.B., Sokolova I.A., Henry M.R., Halling K.C., Clayton A.C.: “Assessment of fluorescence in situ hy-bridization and hybrid capture 2 analyses of cervical cytology spec-imens diagnosed as low grade squamous intraepithelial lesion for the detection of high grade cervical intraepithelial neoplasia”. Anal. Quant. Cytol. Histol., 2010, 32, 121.

[35] Grabowska A.K., Riemer A.B.: “The invisible enemy – how human pa-pillomaviruses avoid recognition and clearance by the host immune sys-tem”. Open Virol. J., 2012, 6, 249. doi: 10.2174/1874357901206010249

[36] Amador-Molina A., Hernandez-Valencia J.F., Lamoyi E., Contreras-Paredes A., Lizano M.: “Role of innate immunity against human pa-pillomavirus (HPV) infections and effect of adjuvants in promoting specific immune response”. Viruses 2013, 5, 2624. doi: 10.3390/v5112624

[37] Canul Canche J., Rosado Lopez I., Suarez N.G., Colli Acosta G., Conde-Ferraez L., Canto de Cetina T., Gonzalez Losa M.R.: “High prevalence and low E6 genetic variability of human papillomavirus 58 in women with cervical cancer and precursor lesions in South-east Mexico”. Mem. Inst. Oswaldo Cruz., 2010, 105, 144.

[38] Bernal-Silva S., Granados J., Gorodezky C., Alaez C., Flores-Aguilar H., Cerda-Flores RM., et al.: “HLA-DRB1 Class II antigen level al-leles are associated with persistent HPV infection in Mexican women; a pilot study”. Infect. Agent Cancer, 2013, 8, 31. doi: 10.1186/1750-9378-8-31

[39] Kaplan K.J., Dainty L.A., Dolinsky B., Rose G.S., Carlson J., McHale M., Elkas J.C.: “Prognosis and recurrence risk for patients with cervical squamous intraepithelial lesions diagnosed during preg-nancy”. Cancer, 2004, 102, 228.

[40] Passmore J.S., Milner M., Denny L., Sampson C., Allan B., Gumbi P. P., et al.: “Comparison of cervical and blood T-cell responses to human papillomavirus-16 in women with human papillomavirus-associated cervical intraepithelial neoplasia”. Immunology, 2006, 119, 507.

[41] Van der Burg S.H., Piersma S.J., de Jong A., van der Hulst J.M., Kwappenberg K.M., van den Hende M., et al.: “Association of cer-vical cancer with the presence of CD4+ regulatory cells specific for human papillomavirus antigens”. PNAS USA, 2007, 104, 12087

[42] Zoodsman M., Nolte I.M., Schipper M., Oosterom E., Steege V.D., De Vriess E.G.E., Meerman G.J., Steege V.D.: “Interleukin-10 and Fas polymorphisms and susceptibility for (pre) neoplastic cervical disease”. Int. J. Gynecol. Cancer, 2005, 15, 282.

[43] Scott M.E., Shvetsov Y.B., Thompson P.J., Hernandez B.Y., Zhu X., Wilkens L.R., et al.: “Cervical cytokines and clearance of incident human papillomavirus infection: Hawaii HPV cohort study”. Int. J. Cancer, 2013, 133, 1187. doi: 10.1002/ijc.28119

[44] Bencomo-Alvarez A.E., Limones-Perches I., Suarez-Rincon A.E., Ramirez-Jirano L.J., Borrayo-Carbajal E., Sanchez-Corona J., Mon-toya-Fuentes H.: “Human papillomavirus viral load in cervical in-traepithelial neoplasia as a prognostic factor in a Mexican population”. Genet. Mol. Res., 2012, 11, 4720. doi: 10.4238/2012

[45] Origoni M., Carminati G., Sideri M., Clementi M., Rolla S., Candi-ani M.: “Low grade positivity of HPV viral load after atypical squa-mous cells of undetermined significance (ASCUS) cytology identifies women at low risk for cervical intraepithelial neoplasia grade 2 and 3”. Eur. J. Gynaecol. Oncol., 2012, 33, 261.