Relevance: Early detection and treatment of HPV infection and precancerous changes in the cervical canal are most significant for reducing the incidence of cervical cancer (CC). Every year more and more patients of reproductive age are registered and there is a tendency towards a decrease in the average age among patients with dysplasia. However, only 30–50% of cases transform into invasive cervical cancer. Accordingly, the question arises of searching for additional markers of the effectiveness of the therapy. Currently, more and more data are emerging on changes in the content of cytokines, chemokines, and growth factors in the mucus of the cervical canal with varying degrees of dysplasia of the cervical mucosa. In this regard, not only general but also local determination of the content of cytokines in secretions at the tissue level is discussed as an additional method for monitoring treatment results. In this case, an important role is played by cytokines, which can reflect the activity of effector cells, regulating antitumor immunity, malignant proliferation, and signaling persistent human papillomavirus of high carcinogenic risk (HPV HCR). However, changes in the cytokine profile in secretions at the tissue level and the mechanisms of the antiproliferative effect under the influence of antiviral treatment remain poorly understood. Analysis and further study of the cytokine profile are necessary, as they can help more accurately assess the response to treatment and monitor the resulting effect.

Purpose: To evaluate changes in the content of cytokine factors in the discharge of the cervical canal after antiviral and immunomodulatory treatment.

Scientific novelty: For the first time, in healthy (control group) patients and HPV-positive patients with severe cervical intraepithelial neoplasia (study group) was comprehensively studied a wide panel of cytokines (FGF basic, Eotaxin, G-CSF, GM-CSF, IFN-γ, IL- 1ra, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL -15, IL-17A, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF) in cervical mucus before and after antiviral treatment. An analysis of the possible diagnostic and prognostic significance of the results obtained was carried out.

Study methods: This multicenter, prospective, open cohort, non-randomized interventional study included 13 patients aged 18 to 49 years infected with high-risk HPV (mainly types 16 and 18) with histologically confirmed severe cervical intraepithelial neoplasia (HSIL). The patients received Inosine pranobex orally and Diindolylmethane suppository intravaginally for 3 months in accordance with the manufacturers' instructions. Preparation of cervical mucus samples before and after treatment was carried out in accordance with the recommendations of the manufacturer of cytokine quantitation kits, Bio-Rad Laboratories, Inc. (USA). The content of cytokines, chemokines and growth factors (pg/ml) in mucus was determined using the commercial Bio-Plex Pro Human Cytokine 27-plex Assay Bio-Plex Pro™ kit (FGF basic, Eotaxin, G-CSF, GM-CSF, IFN- γ, IL-1ra, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL -13, IL-15, IL-17A, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF) produced by Bio-Rad Laboratories, Inc. (USA) on a Luminex 200 analyzer (Luminex Corporation, USA) using xMAP technology using Luminex xPONENT Version 3.1 software.

Statistical analysis: The results obtained after statistical processing were presented in the form of medians (Me) indicating the minimum (min) and maximum (max) values. The significance of differences in the content of cytokines, chemokines and growth factors between groups was determined using a two-sided Student's t-test. In all cases, the differences were considered significant (the null hypothesis was rejected) at a significance level of p<0.05.

Results and discussion: After the therapy, a clear decrease in the following cytokines was detected: IL-17A and IL-1ra, chemokines: IL-8, IP-10 and MCP-1 and growth factors: PDGF-BB, VEGF, and G-CSF.  The content of IL-1ra in cervical mucus significantly decreased (p<0.05) from 198.56 (34.775 – 384.052) to 63.67 (23.058 – 351.538); IL-8 from 12.43 (2.312 – 61.000) to 5.48 (0.533 – 29.567); IP-10 from 1.88 (0.298 – 8.619) to 0.71 (0.156 – 3.664) and VEGF from 0.78 (0.164 – 0.927) to 0.19 (0.160 – 0.750). A decreasing trend after the end of treatment (0.05

Conclusions: The results obtained not only reflect the mechanisms of the anticarcinogenic effect of the drugs used but can also be used to evaluate the effectiveness of therapy for diseases of the female reproductive system. Studying the content of cytokines in mucus in patients with cervical diseases in combination with cytology, histology, immunocytochemistry and molecular genetics can increase the accuracy of diagnosing early neoplasia of the cervical epithelium.