The issues of immune pathogenesis in autoimmune pathology are discussed in this review. The main attention is drawn to potential pathogenetic role of various suppressor cell populations, including T-regulatory cells, mesenchymal stem cells, myeloid lineage-derived suppressors. Homeostatic lymphocyte proliferation is considered to be of great importance for pathogenesis of autoimmune disorders. Recent data from literature suggest that the autoimmune diseases are characterized by reduced activity of the mentioned suppressor cell populations, thus being a possible prerequisite for development of autoaggressive clones of cytotoxic lymphocytes, increased synthesis of autoantibodies leading to evolving autoimmune pathology. It should be, however, noted, that all these processes are accompanied by changes in the immune system induced by homeostatic proliferation of lymphoid cells.

Increased incidence of allergic diseases worldwide reflects some mangles of the existing pharmacotherapy concept which ignores some etiopathogenetic aspects of clinical atopy. Meanwhile, understanding cellular and molecular mechanisms of allergy may create prerequisites for development of new therapeutic areas, in order to effectively influence pathogenesis points of allergic inflammation and, thus, leading to therapeutic success. The review article concerns an antagonism between the two populations of T-helper cells (Th1 and Th2) carried out mainly by the action of IFNγ produced by activated Th1, and IL-4 secreted by activated Th2 which is at the heart of modern concept on the regulation of adaptive immunity. The prospects of immunotherapy of allergic diseases based on the polarization of the immune response are discussed, i.e., an activation of Th1 responses and Th2 suppression. This functional polarization can be mediated by the innate immune receptor agonist, i.e., synthetic and natural minimally-sized biologically active fragments (MBAF) with pathogen-associated molecular patterns. In this respect, a very promising drug registered in Russia is based on the synthetic MBAF, glucosaminylmuramyldipeptide (GMDP), The liсopid immunomodulator. This is due to the fact that GMDP, being an active substance of Liсopid, is a highly specific ligand for the NOD2 receptor of innate immunity factors; it may cause activation of the NF-kB transcription factor, and production of multiple immunoregulatory cytokines. Clinical and immunological efficacy of Licopid application in conventional therapy of atopic allergic diseases (asthma, atopic dermatitis, atopic variant of acute obstructive bronchitis) is presented as an overview of pre-clinical and clinical trials.

A leading role of phagocytes in prevention of M. tuberculosis infection is well established. Various clinical variants of tubercular inflammatory process necessitate further studies of functional and metabolic features of blood phagocytes in the patients with different forms of lung tuberculosis, being the main goal of this study. We have observed a total of 124 persons including 25 healthy subjects, and 99 patients with tuberculosis who manifested with different types of tubercular inflammatory process, i.e., 31 patients had a limited specific process (tuberculoma); in 44 patients, an infiltrative lung tuberculosis was diagnosed, and 24 patients had fibro-cavernous tuberculosis of lungs. We studied activation markers of neutrophils and monocytes (phagotest, burst-test, CD11b+, CD11c+, HLA-DR-Ag), as well as main indicators of cellular immunity (CD45+CD3+, CD45+CD19+, CD45+CD3- CD16+56+). Statistical evaluation was carried out in the «Microsoft Office Excel 2007» and «Statistica for Windows v. 6.1» environment.

A considerable decrease in proportion of superoxide anion-producing monocytes was found in 10% of the patients with fibro-cavernous tuberculosis as compared to the patients with tuberculoma and infiltrative tuberculosis. Similarly, the fibro-cavernous tuberculosis was characterized by higher expression of adhesion markers, e.g., CD11b, by 49%, and CD11c, by 73.5%, when compared with the two other groups of patients. A considerable decrease of absorbing granulocyte function was found in the patients with active forms of tuberculosis, as compared with limited clinical forms (tuberculoma). Fibro-cavernous tuberculosis was associated with increased absolute numbers of granulocyte that produce both superoxide anion, and express surface CD11b+ and CD11c+. We have revealed a relative decrease in lymphocyte quantities in the patients from tuberculoma which corresponded to increased granulocyte quantities of granulocytes and monocytes in the patients’ blood. The conducted study allowed us to make a conclusion that each clinical form of tuberculosis id characterized by a specific immunological pattern.

In the patients with tuberculoma, we have revealed a decrease of phagocytic, functional and metabolic activities of monocytes is noted, along with increased quantities of CD11b+ and CD11c+ adhesion molecules on granulocytes, increased numbers of T-lymphocytes, and decreased amounts of NK-cells. Infiltrative tuberculosis is characterized by increased contents and higher HLA-DR expression of the monocytes, with enhanced expression of CD11b+ and CD11c+ adhesion molecules on the granulocytes, and decreased number of T-lymphocytes. In the fibro-cavernous tuberculosis we observed leukocytosis, monocytosis, granulocytosis. The main functional feature of this clinical form is an increased amount of CD 11b+ and CD 11с+-bearing leukocytes, higher functional and metabolic activity of granulocytes, as well as expansion of CD11b+ expressing cell population and increased numbers of B-cells in peripheral blood.

The study included 120 patients with acute coronary syndrome (ACS), which were divided: in two groups, respectively, with ACS-ST segment elevation (group 1, n = 80), and without this clinical sign (group 2, n = 40). The levels of interleukins (IL)-6, -8, -10, and tumor necrosis factor-α (TNFα) were determined by quantitative ELISA test on the 1st and 10th days of the study. In both groups, the IL-8 and TNFα values on day 1 were similar to the reference level, whereas IL-10 levels were significantly reduced as compared to the standard values. IL-6 level was increased in patients with ACS-ST elevation only in acute phase of ACS, while the patients from group 2 showed normal IL-6 values. On the day 10, TNFα levels in the both groups of patients were significantly increased as compared to the 1st day, whereas IL-6 and IL-10 levels were significantly decreased by the day 10 in both groups of patients. Differential dynamics of IL-8 was observed for these groups of the patients from the day 1 to day 10, i.e., the IL-8 concentration showed a tendency to increase (by 40%) for the group 1 and decrease by 54% in the group 2. In conclusion, the patient grouped by different clinical ACS variants exhibit a similar dynamics of cytokine concentrations, but an increase of IL-8 by the day 10 of the disease was seen only in patients with ACS segment elevation. It may be indicative of different intensity of the inflammatory response.

Some genetic polymorphisms of CYP and GST enzymes metabolizing low-molecular weight xenobiotics may represent endogenous risk factors for carcinogenesis. However, possible relationships between the enzyme activities, amounts of carcinogen adducts and synthesis of anticarcinogen antibodies in humans (including cancer patients) are still poorly studied. The purpose of this study was to identify possible associations between occurrence of antibodies against benzo[a]pyrene, and frequency of genetic polymorphisms of CYP1A1*2A, CYP1A2*1F, GSTT1, GSTM1 in healthy men and in lung cancer patients. Materials and methods. We have examined 203 men with non-small cell lung cancer and 267 apparently healthy donors without respiratory diseases. A non-competitive solid phase immunoassay of antibodies to benzo[a]pyrene was performed. Analysis of polymorphic loci within CYP1A1 (rs4646903), CYP1A2 (rs762551), GSTP1 (rs1695, rs1138272) was performed by means of real-time PCR using TaqMan technology. Null-alleles of GSTM1 (del), GSTT1 (del) genes were detected by multiplex PCR with real-time fluorescent assay. Results. Among the lung cancer patients, the proportion of cases with a high level of IgG antibodies to benzo[a]pyrene in carriers of GSTT1+ and GSTM1+ in conjunction with the CYP1A2*1F C allele was significantly greater than in AA homozygotes CYP1A2*1F. The risk of lung cancer was increased to 5.5 in carriers of CYP1A2*1F C allele combined with GSTT1+ and GSTM1+ at high levels of IgG antibodies to benzo [a] pyrene. In healthy male donors, we have not found differences between the incidence of low and high levels of IgG anti-benzo[a]pyrene antibodies in the carriers of certain CYP1A1*2A, CYP1A2*1F, GSTT1 and GSTM1 genotypes. Conclusions. We have first reported a relationship between CYP1 and GST gene polymorphisms and specific immune response to chemical carcinogens in lung cancer patients. Immunoassays of IgG antibodies to benzo[a]pyrene combined with molecular biology studies of CYP1 and GST are recommended for the cancer risk assessment.

The development of HIV vaccine remains an important goal in prophylaxis and therapy of HIV/ AIDS epidemics. There are various approaches for development of а candidate vaccine based on induction of neutralizing antibodies and cell-mediated immunity. Synthetic peptides are considered promising vaccine antigens since they are capable of activating both humoral and cellular immune response. HIV-1 envelope gp120 is the target for neutralizing antiviral antibodies. The V3 region of the HIV-1 gp120 is highly immunogenic and important for the virus-coreceptor interaction. In a RV144 vaccine trial, the levels of vaccine-induced IgG antibodies recognizing V1V2 regions from multiple HIV-1 subtypes show inverse correlations with a risk for HIV-1 infection. Meanwhile, HIV is characterized by high diversity. The consensus and mosaic immunogens are complete but artificial proteins, which are computationally designed to elicit immune responses with improved cross-reactive broadness. We have been studied immunogenic properties of synthetic peptides derived from V1, V2, V3 loop regions of the consensus M HIV1 (CON-S) sequence group of the gp 120 envelope protein and V3 loop derived from a Russian RUA022a2 isolate. These peptides specifically reacted to HIV-positive sera in ELISA, thus indicating their similarity to appropriate HIV proteins. The peptides proved to be weakly immunogenic. Therefore, Freund complete adjuvant was used to enhance peptide immunogenicity. To assess the immunogenicity, the mice were immunized with a peptide mixture. Antibodies have been developed to every peptide from the mixture, being, predominantly, of IgG isotype. The antibody titers depended on the length of peptide sequences. However, the sera from immunized mice did not have a HIV neutralizing activity. The serum neutralization was assessed by pseudovirus-based assay, using a molecular clone of virus isolates CAP 45.2.00.G3 and QH.209.14.M.EnvA2. The virus neutralization is a complex process and may be influenced by several factors, such as antibody titer, isotype, or antibody structure. Probably, to induce neutralizing antibodies by this peptide mixture, it is necessary to choose appropriate adjutants and immunization schedule. Moreover, it was shown that peptides could increase in vitro virus infectivity in pseudovirus-based model, using the CAP 45.2.00.G3, QH209.14M.ENV.A2, QD435.100M.ENV.E1 molecular clone. These viral isolates belong to different HIV-1 subtypes.

The objective of the present study was to assess the level of 26 cytokines secreted by peripheral blood cells of the patients with liver cirrhosis (LC; n = 20) during the cell therapy (CT). All the patients were administered with intravenously injected autologous bone marrow-derived mononuclear cells (MNCs) in a dose of 1.3±0.3 × 109 (Ме 1.0 × 109 ) followed by 14 days later intravenous injection of ex vivo generated mesenchymal stromal cells (MSCs) in a dose of 22.3±5.0 × 106 (Ме 16.0 × 106 ). The patients were examined before the CT, 2-3 days after the administration of MNCs and, then, 2-3 days after the introduction of MSCs. Cytokine-secretory function of peripheral blood cells was evaluated in a 24-hour whole blood cultures both in the absence of any stimulation and in response to lipopolysaccharide (LPS). The control group consisted of 10 healthy donors. The administration of patients’ bone marrow cells (both MNCs and MSC) was safe and well tolerated and caused no any adverse (toxic or allergic) events. Compared with donors, LC patients (especially, with class B+C by Child-Pugh) differed by an initially increased production of several cytokines and chemokines. Actually, there was a statistically significant increase of the spontaneous production of IL-9, MIP-1β, and IP-10, as well as a distinct trend to an increase in TNFα, IL-1ra, IL-4, IL-5, IL-6, IL-13, of MCP-1, MIP-1α, RANTES and Eotaxin. Moreover, the blood cells of LC patients were susceptible to the stimulatory effect of LPS, and the LPS-induced production of 11 out of 26 cytokines (IL-1ra, IL-6, IL-9, IL-15, IL-17, IL-7, IL-8, IP-10, MIP-1α, MIP-1β, Eotaxin) significantly exceeded the normative values. Transplantation of bone marrow MNCs had minimal impact on cytokine production. Meanwhile, the MSCs introduction resulted in a significant decrease in spontaneous and LPS-induced production of, respectively, 20 and 18 analytes including pro-/anti-inflammatory and immunoregulatory cytokines, chemokines and growth factors. The normalization of cytokine-secretory function following transplantation of MSCs revealed in the patients with LC indicates the weakening of an inflammatory activity of circulating blood cells and the decrease in their reactivity to endotoxin. MSC suppressive effect on cytokine production was dose-dependent, and most pronounced in patients with decompensated LC (class B+C by Child-Pugh) of viral etiology.

Our objective was to study in vitro response of blood leukocytes to IFNα2 in children with infectious mononucleosis, caused by the Epstein-Barr virus, during the acute phase of disease. Patients and methods. Sixty-five children at the age of 4 to 6 years, being in acute phase of infectious mononucleosis caused by the Epstein-Barr virus (EBV) were under study. The control group consisted of 36 healthy children. In vitro response of blood leukocytes to IFNα2 was determined by the original technique (L.M. Kurtasova et al., 2007). Chemiluminescence of the blood leukocytes was studied according to De Sole et al. (1989). Results. We observed that clinical condition of the children with EBV infection in acute phase of the disease was characterized by decreased ranges of blood leukocyte response to IFNα2, and dependence of the cellular response on the dose, as well as severity of the disease. In conclusion, these data suggest a need for individual strategy of interferon therapy for the children with infectious mononucleosis caused by the Epstein-Barr virus.

Emergence and development of pulmonary tuberculosis is often accompanied by the signs of immune system dysfunction. The key enzymes of purine metabolism, e.g., adenosine deaminase (ADA and its isoforms, i.e. ADA1, ADA1 protein complex, and ADA-2), ecto-5’-nucleotidase (5’-NC) controlling adenosine levels, may play an important role in regulation of cell-mediated immunity. We have correlated the parameters of purine metabolism with cytokine production in patients with fibro-cavernous pulmonary tuberculosis (FCT) with a severe specific process. Our studies have revealed an association between cytokine production and purine metabolism indexes, thus reflecting an important role of the latters in immunopathogenesis of the hyperchronic specific disorder. It is mainly referred to adenosine deaminase (ADA1 and ADA2) which are antagonistic in regulation of IL-17 and IL-18. A significantly decreased activity of intracellular ADA1, lowered CD26 concentrations, with lacking intercorrelation, along with increased activity of ecto-ADA-2 is, generally, typical to patients with fibrous-cavernous tuberculosis, thus being a possible marker for prediction of unfavorable hyperchronic specific process, being consistent with functional depletion of immunocompetent cells. Lack of the ADA/ectopeptidase complexes leads to an imbalance between adenosine supply and its deamination. Increased extracellular adenosine concentrations in the patients with severe specific processes may cause metabolic alterations of immunocompetent cells, thus complicating clinical course of the disease, e.g., contributing to enhancement and progression of pulmonary fibrosis.

An experimental model of post-traumatic arthritis of knee was developed in a series of 105 white non-inbred rats. Time-dependent changes of some cytokines were studied upon combined treatment with oral nimesulide and intra-articular etoxydole injections. It was found that the knee joint injury we observed increased levels of pro- and anti-inflammatory cytokines, which may reflect a development of local immunological response. Combined application of nimesulide and etoxydole contributed to significant reduction in all cytokine pools at the end of observation, bringing their levels to normal ranges typical to the intact animals.