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Background. During the ongoing COVID-19 pandemic and in the season of rising incidence of other respiratory infections, it is relevant to use preventive measures of non-specific prophylaxis. Synthetic peptides are widely considered as a tool. The representative of this group is the synthetic analogue of thymus regulatory peptides Thymogen, which has been used in Russia for more than 20 years in the treatment of acute and chronic infection diseases.The aim of the study. To evaluate the effect of Thymogen, a dosed nasal spray, on induced parameters of the immune system during prophylactic use in healthy volunteers.Materials and methods. Twenty healthy volunteers received Thymogen nasal dosed spray (JSC “Cytomed”, Russia) at a dose of 25 μg twice a day for 10 days. A comparative assessment of immunological parameters was carried out in dynamics: before the start of therapy, on days 6 and 11 of taking the drug and 14 days after the end of the course. Clinical observation was carried out from day 1 to day 11, registration of adverse events – the entire period of the study for 24 days. The first day was considered the day the drug was started.Results. In the course of the work, according to the data of immunological examination, a statistically significant increase in the virus-induced production of interferon alpha (INF-α) by a culture of peripheral blood cells was revealed. The growth rate was recorded on day 11 of taking Thymogen and persisted for 14 days after the end of the course. Significant differences in the dynamics of bactericidal and phagocytic activity of neutrophils, serum α- and γ-interferon were not obtained.Conclusion. The use of Thymogen spray at a dose of 25 μg for 10 days was safe and contributed to a significant induction of interferon-alpha in response to exposure to a viral pathogen, which allows us to recommend the drug for prophylactic use during the period of rising incidence of acute respiratory diseases.

Hairy cell leukemia. Clinical recommendations

Peripheral blood monocytes are heterogeneous CD14+ cell population, some of which also express CD16 molecule. Differences in phenotype between monocyte subpopulations can affect their functional activity, as well as the ability to further differentiate into dendritic cells (DCs). DCs are professional antigen-presenting cells which induce the immune response or, conversely, maintain the immunological tolerance. The aim of the present study was to analyze the relationship between monocyte subpopulations and the functional activity of monocyte-derived DCs, as well as DC sensitivity to the tolerogenic effect of dexamethasone. DCs were generated by cultivating enriched fractions of CD14+ monocytes with or without CD16+ cell depletion (CD16-Mo-DCs or CD16+Mo-DCs, respectively) in the presence of IFNα and GM-CSF. Monocyte subpopulations were obtained by immunomagnetic negative selection. CD16+Mo-DCs were characterized by lower ability to take up FITC-dextran and higher allostimulatory activity compared to CD16-Mo-DCs. In addition, CD16+Mo-DCs showed higher apoptosis-inducing activity against autologous CD4+T lymphocytes and allogeneic CD8+T lymphocytes, but were similar to CD16-Mo-DCs in their ability to induce apoptosis in allogeneic CD4+T lymphocytes. TNFa production level, similar for both types of DCs, was negatively correlated with CD16-Mo-DC allostimulatory activity and directly correlated with apoptosis-inducing activity of CD16+Mo-DCs towards allogeneic CD4+T cells. CD16-Mo-DCs and CD16+Mo-DCs were similar by their IL-10 production, which was inversely related to allostimulatory activity of both types of DCs. Dexamethasone increased endocytic activity, decreased the ability to stimulate autologous and allogeneic T cells, inhibited TNFα production of CD16-Mo-DCs and CD16+Mo-DCs. However, CD16+Mo-DCs demonstrated a more pronounced increase in endocytic activity and more dramatic decrease in their ability to stimulate the proliferation of CD4+T cells in auto-MLR. Also, addition of dexamethasone into CD16+Mo-DCs cultures led to the increase in DC pro-apoptogenic activity against autologous CD8+T lymphocytes. Thus, the presence of CD16+ cells among monocyte population affects the properties of IFNα-induced monocyte-derived DCs and DC sensitivity to the immunomodulatory effects of dexamethasone.

This publication is the Russian translation of the Plain Language Summary (PLS) of the Cochrane Systematic Review: Pasquali S, Hadjinicolaou AV, Chiarion Sileni V, Rossi CR, Mocellin S. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database of Systematic Reviews 2018, Issue 2. Art. No.: CD011123. DOI: 10.1002/14651858.CD011123.pub2

Dendritic cells (DCs) of patients with high-grade brain glioma exhibit impaired expression of membrane TNFα associated with low DC cytotoxicity against TNF-R1-expressing tumor cell line HEp-2. To assess the significance of these findings, we investigated a role of TNFα/TNF-R1-signaling pathway in DC cytotoxic activity against allogenic and autologous cell lines obtained from high-grade glioma tissues. DCs were generated by culturing of plastic-adherent peripheral blood mononuclear cells in presence of GM-CSF and IFNα for 4 d followed by LPS addition for 24 h (IFN-DCs). The tumor cell lines were obtained from tissues of 11 patients with glioblastoma multiforme. According our findings glioblastoma cells were sensitive to lysis mediated by donor IFN-DCs. The level of DC cytotoxic effect against cell lines obtained from different glioma patient tissues varied from 20 to 72.2%. DC lysis of 8 out of 11 glioblastoma cell lines exceeded 40%. Glioblastoma cell lines expressed both TNF-R1 and TNF-R2 receptors, but mostly – TNF-R1. However, rTNFα did not show cytotoxic activity towards glioblastoma cell lines. Blocking of TNFα/TNF-R1-signaling pathway by treating of donor IFN-DCs with soluble rhTNFR1 receptor led to partial decrease of DC cytotoxic activity against 5 out of 6 tested glioblastoma cell lines by 11-40% (median of suppression 24%). Glioblastoma patient IFN-DCs which were characterized by an impairment of TNFα/TNF-R1-signaling pathway lysed these glioblastoma cell lines, however median of DC cytotoxicity was 30% lower than that of donor values (31.5 vs 45.1%; р = 0.003). Cytotoxic activity of IFN-DCs of the glioblastoma patient against autologous tumor cells resistance to TNFα/TNF-R1-signaling pathway was comparable with level of cytotoxicity of donor IFN-DCs. Thus, glioblastoma cells are sensitive to cytotoxic activity of DCs mediated via TNFα/TNF-R1-signaling pathway, but the defect of this mechanism in IFN-DCs of glioblastoma patients determines significant decrease of DC cytotoxicity towards glioblastoma cells.

Granule-mediated cytotoxicity of effector cells is a universal mechanism of tumor growth inhibition and induction of tumor cell death. The aim of present study was to evaluate expression of lytic molecules in DCs generated in presence of IFNα (IFN-DCs), and to analyze the role of granule-mediated mechanism for IFN-DC cytotoxic activity against tumor cell lines. IFN-DCs were generated by culturing of plastic-adherent peripheral blood mononuclear cells in presence of GM-CSF and IFNα for 4 d followed by LPS addition for 24 h. The tumor cell lines were obtained from malignant tissues from patients with glioblastoma multiforme. Maturation of IFN-DCs in presence of LPS was accompanied by accumulation of intracellular perforin and granzyme B molecules. Perforin expression showed a direct correlation with intracellular lysosome-associated membrane protein-1 (LAMP-1/CD107a) expression in LPS-stimulated IFN-DCs. However, CD107a expression did not increase under LPS stimulation. At the same time, LPS caused upregulated degranulation in IFN-DCs, as shown by an increase of surface CD107a expression on IFN-DCs. LPS activation of DCs generated from the same donors in the presence of GM-CSF and IL-4 (IL-4-DCs) did not influence perforin and granzyme B expression in IL-4-DCs which was significantly lower than in IFN-DCs. Intracellular pool of CD107a molecules was increased in response to LPS stimulation of IL-4-DCs, but surface CD107a expression did not change on IL-4-DCs. Studies of cytotoxic activity of LPS-stimulated IFN-DCs revealed that concanamicyn A (CMA), an inhibitor of vacuolar H+-ATPase and of perforin/granzyme B-mediated signaling pathway, caused reduced cytotoxicity of donor DCs towards glioblastoma cell lines. Involvement of perforin/granzyme B-signaling pathway into the DCs cytotoxicity was confirmed with glioblastoma cell lines, since blockage of this mechanism with vacuolar H+ ATPase blocker (CMA) caused inhibition of the IFN-DC cytotoxicity. Differently reduced DC cytotoxic activity by CMA may suggest that the glioblastoma cell lysis can be mediated via perforin/granzyme B-independent mechanisms.

Atopic dermatitis remains an important medico-social problem, whose significance is determined by the steady increase in morbidity, recurrent course and often low therapeutic efficacy. In recent years, the number of patients suffering from severe forms of atopic dermatitis has increased [1–3]. One of the most important causes of the complication of an allergic disease is the combination of allergies and secondary immune deficiency syndrome characterized by reversible (as a rule) disturbances of the functions and adaptation mechanisms of the immune system [4, 5].

Abstract. The effect of cytokine preparations (Interleukin-2/IL-2/Proleukin and interferon-alpha/IFN-α 2b/ Intron A) on immune cell subpopulations has been studied in the children suffering with advanced malignancies during intensive chemotherapy cycles combined with whole body hyperthermia (thermochemotherapy). It was shown that IFN-α 2b promotes recovery of peripheral lymphocyte counts in the patients. However, no sufficient changes were observed for the lymphocyte subpopulations. Furthermore, more profound lymphopenia along with increased contents of activated (CD25+, HLA-DR+) T cells occurs in a group of children treated with IL-2, as compared to the patients who received IFN-α 2b. Besides that, some differential effects upon the CD4+/CD8+ T-cell ratios were observed in the patients treated with Proleukin or Intron A, with a tendency to increase in CD4+ T-cells for the patients treated with IL-2. It was concluded that differential immunomodulatory mechanisms mediate the effects of IL-2 and IFN-α 2b in the patients with malignancies undergoing combined chemobiotherapy with whole-body hyperthermia.

The correction of impaired functions of in vitro generated interferon-alpha-induced dendritic cells (IFN-DCs) in patients with malignant brain tumors (n = 8), malignant lymphomas (n = 14) and pulmonary tuberculosis (n = 26) was analyzed in the present study. The principal possibility of restoring reduced functional activity of patient DCs was shown. The addition of recombinant human IL-2, complex of pro-inflammatory cytokines, double-stranded human DNA or polyoxidonium to IFN-DC cultures at the stage of maturation could significantly increase the allostimulatory activity of DCs in patients with malignant lymphomas and pulmonary tuberculosis, as well as enhance the cytotoxic activity of cancer patient DCs against NK- and TRAIL-resistant tumor cell line HEp-2. These findings offer new approaches to the correction of DC dysfunctions in the pathology and justify ways of improving the treatment of infectious diseases and cancer using dendritic cell vaccines.

Aim. To investigate factors determining prognosis and efficacy of induction therapy including interferon-alpha-2b (intron-A, Schehng Plough) in patients at an early chronic stage of Ph-positive chronic myeloid leukemia (CML) as shown by histomorphological examination. Material and methods. The analysis covered 52 CML patients treated at an early chronic phase with intron-A in a standard daily dose 5 IU/m2 in combination with low-dose cytosinearabinoside (10 mg/m2, s.c. , daily for 10 days of each month). The treatment efficacy was assessed by the international criteria of complete and partial hematological remission and cytogenetic response. The cytogenetic study employed the direct method, even and G-differential staining, fluorescent hybridization in situ (FISH). The sections were stained with hematoxilin-eosine by Gomori, van Gieson. Histological samples were examined with histomorphometry. Immunohistochemical examination was made on paraffin sections using a panel of monoclonal antibodies CD3, CD4, CDS, CD20, NK, PCNA, Ki-67 (Dako, Denmark). Results. Repeated assessment of histomorphological parameters such as erythroid lineage, degree of myelofibrosis and reduction of leukemic population indicate the treatment efficacy. Estimation of the level of leukemic population proliferation in trephine biopsies from CML patients with monoclonal antibodies PCNA and Ki-67 before the treatment is prognostically significant as it further correlates with the cytogenetic response (r = 0.821, p = 0.000000). Conclusion. It is valid to study histomorphological picture of CML to prognosticate and assess treatment efficacy with standard doses of interferon-alpha with high probability.

Introduction: Chronic viral hepatitis C (CHC) is a ubiquitous infectious disease, a significant limitation of which WHO attributes to the use of a new highly effective antiviral therapy. Previously, two B-cell epitopes were identified in NS4a antigen of the hepatitis C virus (HCV). It was shown that certain titers of antibodies (ABs) to the extended C-terminal epitope (1687-1718 a.a.) can predict a high probability of achieving a sustained virological response (SVR) to standard therapy with pegylated interferon-α and ribavirin.The aim of the work was to determine immunoreactivity of two B-cell epitopes (middle and C-terminal) of NS4a antigen, and to estimate a possible association of ABs to them with the achievement of SVR after standard interferon therapy and treatment with direct antiviral drugs (DAAs) daclatasvir and sofosbuvir (velpanat)., Materials and Methods: Blood serum samples of patients with CHC (n = 113), of which 55 participants received standard interferon therapy, 50 received velpanate treatment, the remaining 8 received no therapy were examined. The middle B-cell epitope (positions 24-34 a.a.) of NS4a was synthesized by the solid-phase method, while the C-terminal epitope (34-54 a.a.) was obtained using genetically engineered techniques. Enzyme immunoassay (ELISA) testing of the sera collected before treatment was performed for the two selected epitopes according to the conventional methods., Results: The antibodies to the C-terminal epitope were detected significantly more frequently than those to the middle one (p = 0.01) when analyzing the blood sera of patients (n = 113). The presence of ABs to the C-terminal epitope in the serum samples of participants who completed standard interferon therapy was associated with the achievement of SVR (p = 0.0245). In the blood sera of participants who completed therapy with velpanate, an association of the presence of ABs to the C-terminal epitope with the achievement of SVR was also established (p < 0.0001). The presence of ABs to the middle B epitope was not associated with the achievement of SVR, regardless of the therapy used., Discussion: The observed difference in the immunoreactivity of the two B-cell determinants may be associated with the localization of the nearest Th-epitopes, the sensitivity of NS4a antigen to proteolytic enzymes, and the peculiarities of epitope presentation by antigen-presenting cells. However, it should be noted that the immunoreactivity of the middle B-epitope is poorly studied. Although the association of ABs to the C-terminal epitope with the achievement of SVR has been shown by several scientific teams, the detailed molecular mechanism of their influence on the effectiveness of therapy is unclear., Conclusion: In CHC, ABs to the C-terminal epitope of NS4a are produced more frequently than those to the median epitope. The presence of ABs to the C-terminal epitope is a predictive marker of a high probability of achieving SVR, regardless of the type of therapy and antibody titer.

Aim: To study the dynamics of anxiety-depressive disorders and peripheral blood serotonin in patients with multiple sclerosis (MS) during interferon-ß (IFN-ß) therapy., Material and Methods: The level of anxiety and depression in 227 MS patients was measured by psychometric testing at baseline and during treatment. The concentration of serotonin in serum of patients was determined by enzyme immunoassay., Results: The presence of emotional disorders in patients with MS was confirmed. Their relationship with personality characteristics of the patient, the course of the disease and social status was shown. The level of humoral serotonin was lower in patients with MS. The relationship between the serotonergic system deficiency in patients with MS and anxiety disorders was shown. Interferon-induced depression was not associated with serotonin metabolism. It is a multifactor condition influenced by the patient's initial emotional level, personality characteristics, psychological reaction to therapy and the unfavorable dynamics of the disease., Conclusion: IFN-β does not appear to induce depression in MS patients.

The main reason for the ineffectiveness of antiviral therapy in patients with chronic hepatitis C that impedes full and adequate treatment of IFN-α and ribavirin is the development of neutropenia and thrombocytopenia. The present study included 63 patients (59% men and 41% women) with chronic hepatitis C that did not previously receive antiviral therapy. All patients had HCV genotype-1 (15 patients with genotype 1a; 42 people, with genotype 1b; 6 patients, with genotypes (1a + 1b)). The patients' age was 33.8 ± 0.7 years, with term of infection 6,1 ± 0,8 years. It was shown that in the case of treatment with Peg-IFN-alpha in combination with ribavirin, a significant decrease in the number of white blood cells, neutrophils and platelets prevailed in patients with HCV-monoinfected genotype 1b in the F0-F2 stages (2,8-8,6 kPa) at METAVIR. With the development of moderate "early" (less than 12 weeks of antiviral therapy) and for the prevention of "late" (more than 12 weeks of treatment) neutropenia, appointment of immune medicine likopid (glucosaminylmuramyldipeptide) at a dosage of 1 mg, 2 times a day for 20 days, in patients with chronic hepatitis C (genotype 1b ) with

Although several years have passed since the determination of the human papilloma virus (HPV) as the causative agent for cervical cancer, a definitive treatment has not yet been found. Interferon-alpha (IFN-α) immunotherapy is one of the promising methods for tumor treatment, although numerous side effects were observed in clinical trials. Recently, a new type of interferon, lambda-interferon (IFN-λ), has been discovered with fewer side effects than IFN-α since its receptor repertoire is limited. IFN-λ has a series of activities including antiviral, anti-proliferative and anti-tumor actions. In the present study, the effects of IFN-α and IFN-λ on the TC1 papilloma tumor model in C57BL/6 mice were evaluated. TC1 cells were injected into the mice subcutaneously. Upon tumor formation, murine IFN, mIFN-α and mIFN-λ, expression plasmids were injected intratumorally in combination or alone. The survival time and tumor size as well as apoptosis in tumors and NK cytoxicity were measured after three injections. As compared with the control group, the remarkable results especially in the group which received mIFN-α and mIFN-λ together were obtained for all of the measured parameters. Although IFN-λ is a new member of the interferon family and its properties should be studied in detail, the data obtained suggests that the use of IFN-λ especially in combination with IFN-α could be considered as an effective strategy for papilloma cervical cancer immunotherapy.

The efficacy of the therapeutic, prophylactic and urgent prophylactic schemes for the use of Reaferon-ES lipint, a liposomal human recombinant alpha-interferon for oral use, was studied on mice infected with the avian influenza virus. Strain A/Chicken/Kurgan /05/2005 (subtype H5N1) of the avian influenza virus showed high virulence with respect to mice ICR. Theoretically-based calculations allowed to design an optimal therapeutic and prophylactic dose of the drug for the mice (1000 units/animal). It was observed that only after prophylactic use of Reaferon-ES lipint it was effective in protection of the mice infected with 10 LD50 of the avian influenza virus (A/Chicken/Kurgan/05/2005, H5N1). The protection coefficient was 0.35. Under such conditions the drug efficacy was comparable with that of Tamiflu. Therefore, Reaferon-ES lipint could be recommended for prophylaxis of the infection due not only to the season strains of the influenza virus, but also to the strains of the avian influenza virus.

A new method of treatment of endometriosis includes combination of surgical and hormonal therapy. Surgical method included excision of tissue with endometriosis, while the hormonal therapy involved the combination of dufaston and reaferon-EC (recombinant interferon alpha 2b). The aim of this study was to develop effective method of treatment of infertility caused by endometriosis using combination of dufaston and reaferon. There were 114 patients under observation who suffered from endometriosis and infertility. At the first stage of treatment thermokouterisation of area with endometrosis has been used. At the second stage of treatment all patients were divided into different clinical groups. To 34 patients from the study group reaferom-EC has been administered on the 5th, 8th, 10th, 12th, 14th days of menstrual cycle. The control group was represented by 80 patients, which was divided into two subgroups, 40 patients in each group. The patients from the first subgroup got hormonal therapy 20 mg dufaston from the 5th to 25th days of menstrual cycle, while the patients from the second subgroup got 20 mg dufaston from the 15th-20th to 25th days. The treatment was successful among the patients who got the combination of reaferon and dufaston, the frequency of pregnancy in the study group reached 52% vs. 27.3% in the control group (p>0.05). Those patients who had so called "small form" of endometriosis became pregnant in 34% cases in the study group and in 22.7% cases in the control group. Patients who had endometriosal cystoma became pregnant in 18.7% in the study group, but only in 9.4% in the test group, which shows that the treatment is less effective among these categories of patients. As a result of our study it is proved that the method of combination of reaferon and dufaston gives a chance to increase therapeutic effect and the number of pregnancy among the patients with endometriosis.

Aim: To examine clinical efficacy of combined therapy with reaferon and iodantipirin in patients with chronic hepatitis B and C of moderate activity., Material and Methods: 100 patients with confirmed diagnosis of chronic viral hepatitis (CVH) at the stage of replication. All the patients have undergone puncture biopsy of the liver with estimation of index of histological activity Knodell and index of fibrosis Desmeth., Results: Comparative evaluation was made of clinical efficacy of combined therapy reaferon + iodantipirin and monotherapy with reaferon in 100 patients with moderate activity CHB and C., Conclusion: Conventional scheme with reaferon turned out less effective than the above combination therapy.

The article deals with a problem of combined use of interferon (laferon) and interleukin in patients with skin melanoma. Recombinant interleukin-2 (rIL-2) was included into the worked-out scheme. Patients with primary-localized skin melanoma (T(2-4)N0M0) have been studied. Three groups were chosen. 901 patients of the control group underwent excision of tumor (e/t); 34 patients of the first study group (e/1) were given endolymphatic interferontherapy (ift); 35 patients of the second study group were subjected to excision of tumor followed by endolymphatic interferontherapy. One-year relapse-free survival among patients of the control group reached 57.6+/-1.6%, 1st study group--70.5+/-7.8% and 2nd study group--83.6+/-6.7%. Total one-year survival among patients of the control group was 92.1+/-0.9%, in the 1st study group--97.0+/-2.9%, in the 2nd study group--92.7+/-5.0%. Thus, the combined use of recombinant interferon (laferon and interleukin (ronkoleukin) in treatment schemes of malignant skin melanoma was proved to be perspective.

Aim: To elucidate the role of tumor necrosis factor alpha (TNF alpha) and interferon alpha (INF alpha) in pathogenesis of infectious-immune myocarditis (M) and myocarditic cardiosclerosis (MCS)., Material and Methods: Patients with infectious-immune myocarditis (n=27) and myocarditic cardiosclerosis with symptoms of heart failure (n=19). Blood levels of TNF alpha and INF alpha were measured by immune enzyme analysis., Results: Mean levels of INF alpha and TNF alpha in patients with M (75+/-47 and 304+/-102 rg/ml respectively) were significantly higher than in patients with MCS and healthy donors (31+/-14 and 83+/-39; 38+/-18 95+/-58 rg/ml, respectively, p<0.05). Levels of INF alpha and TNF alpha significantly differed between patients with benign and malignant course of M (99+/-46 and 354+/-100; 39+/-10 227+/-42 rg/ml, p<0.05). Phytohemagglutinine induced TNF alpha production by leucocytes in patients with malignant M (1432+/-515 rg/ml) was higher (p<0.05) while in patients with benign M (131+/-54 rg/ml) lower (p<0.01) than in healthy donors (255+/-98 rg/ml). Patients with malignant compared with those with benign course of myocarditis had lower ejection fraction (25.9+/-12.1 and 42.5+/-11,2%, respectively, p<0.003) and higher inhospital mortality (16.6 and 0%, respectively)., Conclusion: It is most probable that factors of regulation of INF alpha and TNF alpha production occupy an import place among mechanisms of malignant transformation of myocarditis.

Chronic inflammatory gynecological diseases (CIGD) in highlanders (2,100-2,200 m a.s.l.) are accompanied with the following changes in immunoregulatory parameters: strengthening in the expression of CD3+ (TCR), CD4+ (T-helpers), CD16+ (NK-cells), CD25+ (activated IL-2R), increase in CD4+/CD8+ ratio, levels of circulating cytokines--alpha-, beta-, gamma-interferon (IFN) and alpha-, beta-tumor necrotizing factor (TNF), strengthening in immune adhesion of thrombocytes (IAT), and inhibition of the oxidative metabolic way of L-arginine with redistribution of the main metabolites formed via its non-oxidative way. Complex extremely high frequency (EHF) therapy and interferon (with Laferon) therapy of CIGD normalized expression of the differentiated and functional CD-markers of immunocompetent cells (ICC), CD4+/CD8+ ratio, increased expression of CD8+, decreased IAT and levels of circulating cytokines (IFN, TNF), changed L-arginine metabolism with activation of the oxidative way. Full-value of the population signs of immune stabilization due to the treatment was complemented with increase in the ICC functional parameters--markers of mitochondrial, lysosomal and mitotic activity. We first demonstrated a high effectiveness of complex use of EHF and Laferon as an immunocorrective therapy of CIGD in highlanders.

Platelet aggregation (PA) and the content of cyclic nucleotides (CN) was studied in a group of 44 patients with chronic viral hepatitis (CVH) and liver cirrhosis (LC) in comparison to 10 healthy volunteers. The analyses were performed before and 6 h after interferon-alpha (IFN-alpha) administration. The CN content was increased in CVH cases and was maximum in LC patients, while the platelet aggregation was reduced in CVH patients and was minimum in the LC group. The CN level increased and the functional activity of platelets decreased, depending on the degree of disorder. After the first introduction of IFN-alpha, the CN content in thrombocytes decreased in LC and low-PA CVH patients, but increased in high-PA CVH cases. IFN-alpha produced a normalizing effect on the platelet functioning in the patients with CVH and LC.

Results of treatment of 160 patients, operated on for nontumoral biliary ducts impassibility, complicated by purulent cholangitis, were analyzed. In 60 patients intraoperatively and after the operation in complex of treatment laferon solution was injected into biliary ducts in dosage 500,000--1 million IU a day, permitting to reduce the frequency of the postoperative complications occurrence from 62.2 to 36% and of postoperative mortality--from 13 to 6%. Regional immune therapy using laferon stimulates the factors of organism inflammatory reaction and hepatocytes functional state restoration.

The treatment was given to 100 patients with chronic virus hepatitis of moderate activity and chronicity stage I. Of them, 50 patients received reaferon (3 IU 3 times a week) in combination with antiviral and immunomodulating drug iodantipirin (100 mg/d) given on the days of reaferon injections for 6 months. The other 50 patients received reaferon alone in the same doses and duration of the treatment course. Efficiency was assessed by the level of ALT, findings at polymerase chain reaction, index of histological activity of hepatic biopsy. The combined scheme demonstrated higher efficiency and tolerance.

Aim: To design and substantiate an effective combined therapy scheme for patients with chronic viral hepatitis (CVH) and chronic opisthorchiasis (CO)., Material and Methods: 10 patients with CHB and 12 patients with CHB + C in the presence of CO. All the patients have undergone clinical and device examinations before the treatment and in the course of therapy with biltricide and reaferon., Results: Patients with CVH at the stage of moderate activity and in the phase of virus replication received antihelminthic therapy with biltricide which caused neither complications nor deterioration, antihelminthic effect was observed in 20 of 22 patients. In a month, the patients started on reaferon given for therapy of hepatitis. As a result, all the patients improved clinically with normalization of biochemical blood parameters. Markers of viral hepatitides disappeared in 17 of 22 patients., Conclusion: Combined therapy of CVH in active process in the presence of CO may include antihelminthic and antiviral treatment and should be staged.

Aim: To ascertain regularities of development of cellular immunity in patients with Astrakhan fever (AF) with reference to AF severity, treatment and course., Material and Methods: Cellular factors of immunity--relative and absolute contents of T-lymphocytes (early and late), T-helpers and T-suppressors, B-lymphocytes, neutrophils (early and late)--were studied in 75 patients with AF (63 patients with moderate and 12 patients with severe disease) in the course of the disease progression (weeks 1-5). The patients received antibacterial treatment--doxicyclin, rifampicin and doxicycline in combination with alpha 2-realdiron and gamma-reaferon., Results: Examination of immunocompetent cells has revealed suppression of T- and B-immunity for 2 weeks in moderate AF and 3 weeks in severe AF. The number of T-helpers was low for 3 weeks while of T-suppressors rose beginning from week 2. Immunoregulatory index Tx/Tc remains low till the end of the disease. The number of early and late neutrophils increased since weeks 2 of the disease in moderate and week 3 in severe AF., Conclusion: Doxicycline efficiency was higher than that of rifampicin. Interferon preparations decrease relative number of early and late T-lymphocytes, neutrocytes and T-helpers but their absolute number is at the control level. Relative content of T-suppressors and B-lymphocytes is as in controls but their absolute content is higher.

We studied modifying potentialities of high temperatures in treatment regimens with adjuvant endolymphatic chemo- and interferontherapy of malignant melanoma of the skin. We had previously obtained enough evidence for expediency of adjuvant endolymphatic therapy of primary-localized melanoblastoma of the skin. Added to the preventive treatment regimens were sessions of local magnetothermia. The study was done in patients diagnosed as having primary-localized melanoma of the skin T(2-4) No Mo. A 3-year recurrence-free survival in the control group was (38.2 +/- 1.6)%, in the first study group--(54.2 +/- 5.8)%, in the second study group--(44.3 +/- 13.5)%. The general 3-year survival in the control group was (67.7 +/- 1.5)%, in the first study group--(70.8 +/- 5.5)%, in the second one--(91.7 +/- 5.7)%. In this way, the expediency has been proved of employment of local magnetothermia in treatment regimens to deal with malignant melanoma of the skin.

The effect of reaferon (introduced at a dose of 1 x 10(6) IU/kg over six days prior to ischemia induction) on the levels of catecholamines and the activity of succinate dehydrogenase and NADH-dehydrogenase in various structures of kidney was studied in experiments on white rats. The ischemia was modeled by 90-min ligation of renal vessels. Reaferon retained the luminescence of catecholamines in all renal structures 24 h after circulation was restored on the level of intact kidney, except for the nerve trunks where the luminescence intensity decreased by 40%. Preliminary introduction of reaferon stimulated restoration of the enzymatic activity in the Krebs cycle and mitochondrial respiratory chain after 24- and 48-h revascularization, respectively.

Identification of the type of human papilloma virus (HPV) was done by means of polymerase chain reaction in 40 children with juvenile respiratory papillomatosis (JRP). Adjuvant to surgery interferon treatment was carried out in 18 patients (study group) with severe JRP. The rest 22 patients (control group) with less severe papillomatosis received only surgical treatment. The majority of the patients from both the groups had the virus type 6/11 (72.2 and 77.3% for the study and control groups, respectively). The assessment of a relationship between HPV type and effectiveness of interferon treatment in the study group has shown that the share of patients with effective and uneffective interferon therapy in each category (by HPV type) was about the same, i.e. no correlation exists between HPV type and interferon therapy effectiveness.

Sixty-six patients with multiple myeloma were divided into four groups: treatment with alpha-2a-interferon (reaferon) 3-5 mln MU/m2 alone (group); alpha-interferon + pulsed therapy with dexamethasone (group II); reaferon at high or low dose + different regemens of polychemotherapy (group III), and polychemotherapy followed by therapeutic support with melfalan and prednisone (MP) (control). Patients in group I untreated earlier with MP showed positive response in 80% while only 20% were in partial remission. Chemoresistance was broken in 86% (complete clinico-hematological remission--18%) following administration of high doses of alpha-interferon in conjunction with cytostatics. Reaferon + dexamethasone modality proved less effective. After chemoresistance was broken in 83%, tumor process reached a plateau. Low-dose reaferon was less effective, too, with complete remission never being reported. When administered in high doses as support therapy, it proved fairly effective, with median response being double that registered at low dosage or chemotherapy + MP. Whenever high-dose alpha-interferon tolerability is poor, dosage can be decreased; the patients may continue on low dosage or switch to MP support.

The composition of liposomal lipid phase preparation was selected. The optimum ratio of liposomal lipid phase components was found to produce a a human liposomal recombinant alpha 2-interferon-containing preparation by extrusion across the polycarbonate membranes. The study gave rise to a lyophilized sterile liposomal recombinant alpha 2-interferon preparation. The agent was shown to be stable and retains its antiviral activity within a year.

Tumor necrosis factor-alpha (TNF) was shown to have an antiinfectious effect on murine and rat models of viral, bacterial and parasitic infections. The effective antiinfectious dose of TNF was determined to be 10(2)-10(3) U/kg body weight. TNF, interferon, and antibiotics were demonstrated to potentiate the antibacterial effect of each. Clinical trials of TNF in the treatment of slowly progressive, latent, and chronic infections and in the emergency prevention of acute infections are advisable.

Since 1990, 230 operations for focal pathologies in the liver have been carried out at the Center's clinics using such advanced procedures and equipment as radio-isotope examination of hepatic function, ultrasonography of the liver during surgery, ultrasound aspirator, water-flow scalpel, argon coagulator and adhesive dressing materials. The study included 75 resections for primary hepatic tumor (lethality-14.6%), 114 resections-disseminated tumor (lethality-5.2%) and 41 resections for benign tumors and non-tumor pathologies (no lethality). Preoperative chemotherapy was found to significantly increase the risk of postoperative complications in cases of liver resection. Five-year survival in such patients with primary tumor was 33.3%. The seven most significant prognostic factors in primary hepatic carcinoma were: portal invasion by tumor cells, number of tumor nodes in the liver, alpha-fetoprotein concentration, tumor node size, concomitant cirrhosis, age and extent of surgery. In patients with hepatic resection for solitary metastasis of the large bowel, 5-year survival was 28.6%. A regimen of adjuvant chemotherapy for solitary metastasis of colorectal cancer into liver is suggested. The data on 37 surgical patients with hepatic metastasis of non-colorectal cancer are presented. It was demonstrated that the liver should be resected in cases of solitary metastasis of renal carcinoma, adrenal gland, ovary, tests, breast, gallbladder and carcinoid.

Administration of IL-1 beta and 125-129 fragment of alpha 2-interferon improved learning and retention of active avoidance behaviour in memory in rats. It also improved the correlation between intersignal runs and success of the avoidance behaviour learning. The data obtained suggest that an activation of the intersignal retention process is one of the mechanisms of the immunomodulators effect on learning and memory.

Clinicoimmunological characteristics were followed up in the course of laryngeal papillomatosis (LP) in 96 children. It was found that they had suppressed T-cell immunity, phagocytosis which still worsen with the disease aggravation and recurrences. A decrease in nonspecific resistance, properdin, lysozyme, complement and secretory IgA indicated impairment of nasopharyngeal and laryngeal local immunity. A scheme of combined treatment is proposed incorporating basic therapy with reaferon, systemic immunomodulators (thymalin, T-activin) and local immunocorrection. Such approach reduced the time of basic treatment and prolonged remission 2.5-3-fold.

Children with juvenile respiratory papillomatosis given alpha 2-INF had antibodies to alpha 2-INF in 67.7% of cases. In children treated with intramuscular recombinant alpha 2-INF (reaferon) alone antibodies to INF occurred in 92.3% of patients. The proportion of such patients fell to 28.5% if the children used recombinant alpha 2-INF as rectal suppositories viferon. The level of the antibodies in 4-48 hours decreased 2 times maximally and returned to the baseline on day 3 since intramuscular injection of alpha 2-INF. It is stated that interferon therapy had a positive effect on juvenile respiratory papillomatosis. Antibodies to INF had no negative effects on the treatment results.

500 patients with hepatitis B have been followed up from the acute onset to long-term outcome. As for chronic transformation of the disease, at higher risk are patients with mild form, progredient run and inadequate immune response. Of the highest value for identification and prognostication was a dynamic quantitative control over the system HBeAg-anti-HBe providing separate prognosis of establishment of replicative or integrative variants of chronic hepatitis B. In progredient infection an early administration of reaferon in combination with thymogen is thought valid which in many patients is sufficient to prevent the disease transformation into a chronic form.

Data on long-term interferon-alpha (reaferon) therapy in 6 patients with CML (5 in chronic phase, 1 in acceleration phase) are presented. Clinicohematological remission was achieved in all the patients in a chronic phase irrespective of their group of risk. Cytogenetic improvement occurred only in one patient from a low-risk group. Reaferon had no effect in the patient in the acceleration phase. Tumor necrosis factor neither influenced viability of mononuclear bone marrow cells of patients before treatment nor suppressed proliferation. Dose independent reduction of cell viability was revealed in a patient in remission after reaferon therapy. There were no cases of apoptosis induction. Mechanisms of CML pathogenesis and interferon action in CML chronic phase are discussed.

The investigation of the prevention and treatment action of some immunomodulators (ridostin, reaferon and polyribonate) used alone and in combinations was conducted on laboratory animals infected aerogenically by Venezuelan equine encephalitis (VEE) virus. A lower death rate of the aerogenically infected mice (10-30 respiratory LD50) was observed after intramuscular injection of ridostin. The preventive affect of ridostin and ridostin + reaferon administered intranasally and intramuscularly was achieved in the aerogenically infected guinea pigs (10 respiratory LD50). The results of the study on the early virus reproduction in the animals were used for the choice of the treatment scheme. The immunomodulators had no effect when the treatment was started 1 day after the VEE virus infection.

The study of the preventive and therapeutic action of some immunomodulators (ridostin, reaferon and polyribonate) used alone and in combinations was conducted on laboratory animals infected aerogenically by Marburg or Ebola virus. It was found that special preventive intranasal and intramuscular administration of ridostin provided protection of the animals infected by Marburg virus (p = 0.1) and an increase in their mean lifespan by 2.4 days (p = 0.15). In the Ebola infection combined administration of ridostin and reaferon caused an essential increase in the mean lifespan of the animals by 2.9 days (p = 0.04). None of the tested drugs had any significant positive effect when used in various combinations according to the treatment schemes in Marburg and Ebola infections in guinea pigs.

Chronic alcoholic intoxication is followed by a fall in 3H-(D-ala-2,D-leu-5)-enkephalin affinity of mu-opioid receptors with their unchanged concentrations in the rat brain cortex, by reductions in the tissue and plasma levels of beta-endorphine and met-enkephalin. A daily administration of reaferon in a dose of 10,000 IU during two fortnights completely restored both the binding affinity of the receptors and the concentrations of the peptides tested: those of beta-endorphine in the adenohypophysis and plasma and those of metenkephalin in the adrenals and plasma.

Reaferon administered to outbred young mice with experimental influenza had a positive effect on morphologic changes in pulmonary tissues and on lipid peroxidation in the blood plasma and pulmonary tissues. Combined use of reaferon and alpha-tocopherol in mice infected with influenza A virus reduced the mortality rate, boosted the antiviral effect of reaferon proper, and led to virtually complete normalization of lipid peroxidation processes in the blood plasma and pulmonary tissues.

The effectiveness of domestic alpha 2-interferon preparation reaferon was studied in vivo and in vitro for eradication of pathological hemopoietic clone in chronic myeloid leukemia. Reaferon administration for 1-30 months produced cytogenetic remission in 7%, hematological remission in 21%, partial hematological remission in 36% of the patients. Reaferon is indicated in chronic myeloid leukemia without splenomegaly. In the disease progression reaferon is uneffective. Mechanism of reaferon therapeutic action comprises three components: a direct antiproliferative effect on hemopoietic precursor cells, activation of cellular immunity, an effect on stem cell microenvironment.