Abstract. The lecture presents modern data on systemic inflammation, as well as an original concept of its genesis. This disorder is considered a typical pathological process being fundamental to pathogenesis of the most critical states of different origin. Distinct features of “classical” and systemic inflammation are discussed, whereas the underlying immunological and pathophysiological mechanisms of inflammation are subject to classification. Main constitutive processes, phases of systemic inflammation, and certain variants of their proceeding are characterized as well. A definition of “systemic alteration” has been specified.

Abstract. Galectins comprise a family of β-galactoside-binding animal proteins, which are defined by
common homologies of their carbohydrate-recognizing domaine (affinity for poly-N-acetyllactosamine). These lectins bind to cell surface glycans and extracellular matrix, thus influencing various cellular events, including cell cycle, adhesion, migration, proliferation and apoptosis. Moreover, galectins are able to exert intracellular effects, and participate, e.g., in signal transduction, by interacting with other nuclear and cytoplasmic proteins. Galectin-1 is considered to play a special role in functional regulation of immune cell activity. Thus protein is a factor of immunocompetent cell cooperation, thus being able to modulate immune reactions. In this respect, galectin-1 is considered as a potential agent or a target for new methods aimed to correct pathological processes associated with imbalance of immune system. This article provides an overview of works devoted to a possible role of galectin-1 in development of typical features of innate and adaptive immunity.

Abstract. This review presents a summary of our data concerning in vivo and in vitro effects of recombinant TNF-binding protein from variola virus (VARVCrmB) upon TNF-induced functional changes of human and murine cells. VARV-CrmB protein blocks TNF-induced production of IL-1β and IL-6 by human mononuclear cells, and their in vitro oxidation-related metabolic (OM) activity. VARV-CrmB protein restores TNF-induced reduction of BFU-E+CFU-E colony-forming activity and normalizes TNF-induced effects upon CFU-GM formation in a colony-forming model of human and murine bone morrow cells (BMC). VARV-CrmB protein displays a pronounced in vivo alleviation of LPS-induced endotoxic shock symptoms in SPF BALB/C mice thus significantly increasing survival of experimental animals. Moreover, VARV-CrmBprotein decreases intensity of collagen-induced arthritis at early terms. Application of VARV-CrmB protein results in normalization of TNF-induced increase of migratory and OM activity of murine leukocytes, and exerts corrective effects upon colony-forming ability of murine hematopoietic precursors. Skin application of VARV-CrmB protein decreases leukocyte migration from a skin scrap in afferent phase of DNCB-induced contact reaction, as well as “ear oedema” index. Our results demonstrate TNF-blocking properties of VARVCrmB protein. In summary, our data allow to consider a recombinant variola virus VARV-CrmB as a new potential TNF-antagonist. Its effects can be explained by its ability of neutralizing TNF-induced activation of oxidation-related metabolic, cytokine-producing and migratory functions of effector cells in therapy of pathological inflammatory processes.

Abstract. Cytotoxic/pro-apoptogenic effects of IFNα-induced dendritic cells (IFN-DCs) directed against Т-lymphocytes and NK cells were investigated in healthy donors. Using an allogenic MLC system, it was revealed that IFN-DCs induce apoptosis of both activated CD4+ and CD8+ T-lymphocytes, and NK cells. Apoptosis of CD4+ and CD8+ T-lymphocytes induced by their interaction with IFN-DCs was mediated by various signaling pathways. In particular, activated CD4+Т-lymphocytes were most sensitive to TRAIL- и Fas/ FasL-transduction pathways, whereas activated CD8+ T-lymphocytes were induced to apoptosis via TNFα-mediated pathway. PD-1/B7-H1-signaling pathway also played a distinct role in cytotoxic activity of IFNDCs towards both types of T lymphocytes and activated NK cells. The pro-apoptogenic/cytotoxic activity of IFN-DC against activated lymphocytes may be regarded as a mechanism of a feedback regulation aimed at restriction of immune response and maintenance of immune homeostasis. Moreover, upregulation of proapoptogenic molecules on DCs under pathological conditions may lead to suppression of antigen-specific response, thus contributing to the disease progression.

Abstract. Involvement of dendritic cells (DC) into switching of immune response to T-independent type 2 antigens (TI2 antigens) is poorly studied. The present study addressed some interactions between DCs and TI2-type antigens, i.e., with Streptococcus pneumoniae polysaccharide type 3 (S3), and polyvinylpyrrolidone (PVP, mw. of 360 kDa), as well as a role of antigen-loaded DCs for triggering the immune response. Shortterm treatment of DCs with TI-2 antigens induced their activation manifesting as an increase in numbers of CD80- and CD86-positive cells under the cell culture conditions. DCs loaded with TI-2 antigens were then mixed with normal murine splenocytes and cultured in complete RPMI 1640 medium for 4 days. The numbers of antibody- and immunoglobulin-forming cells (AFCs and IFCs, respectively) were determined by ELISPOT assay. Supplementation with TI2-treated DCs induced a 2.0 to 2.7-fold increase in specific immune response. Antigen-induced polyclonal response was enhanced by 40%. These data suggest a direct interaction between DCs and TI-2 antigens, and their presentation to murine splenocytes, thus leading to both specific and polyclonal B cell activation. B-1 cells are shown to play a main role in such response. Separation of loaded DC and splenocytes by semi-permeable membranes caused inhibition of this immune response.

Abstract. The aim of present study was to investigate PD-1/B7-H1-mediated induction of T-cell apoptosis/ anergy, a suggested mechanism of reduced antigen-specific immune response against M. tuberculosis. We examined 76 patients with pulmonary tuberculosis (PT) who differed in levels of proliferative response to specific antigen (purified protein derivative, PPD). It was revealed that in vitro generated dendritic cells (DCs) from the patient’s blood monocytes with GMCSF+IFNα, were characterized by increased B7-H1 expression, upregulation of IL-10 production, and reduced allostimulatory activity in mixed lymphocyte culture (MLC). Moreover, DCs of PT patients were able to enhance T-cell apoptosis, and to block T-cell division in MLC. Thus, the patients’ DCs exhibited the higher tolerogenic potential since these DCs could induce apoptosis/anergy in responsive T-cells via PD-1/B7-H1-mediated pathway combined with IL-10 effects. It was shown that neutralizing anti-PD1-antibodies partially abolished the pro-apoptogenic/tolerogenic effect of DCs. The revealed phenomenon of PD-1/B7-H1-mediated pro-apoptogenic activity should be of obvious clinical significance, since the cytotoxic/tolerogenic potential of DCs was especially pronounced in the patients with low antigen-specific response to PPD.

Abstract. Induction of chronic GVHD in the DBA/2→(C57Bl/6xDBA/2) F1 semi-allogeneic murine model results into development of Th1- and Th2-dependent immunopathological conditions that are characterized by different cytokine profiles. Chronic GVHD is accompanied by a sharp increase in IgE levels, thus presuming considerable IL-4 production. In recipients with Th2-dependent GvHD variant, elevated contents of serum IL-6, IL-7 and TNFα were also observed, which, along with other effects, may support polyclonal activation of B cells, thus leading to development of autoimmune pathology.

Abstract. Possible interactions between psychophysiological and immunological parameters are documented in healthy persons and bronchial asthma patients, as based on our own data and other sources. A role of functional asymmetry of brain is regarded as a basic phenomenon determining main features of psychical activity, as well as functions of autonomous nervous system and immunological activity.

Abstract. Prevalence of TNFα gene promoter polymorphism at -857 position was investigated in normal persons and among patients with rheumatoid arthritis. We detected a relation of this polymorphism to the levels of TNFα production by mononuclear cells of healthy donors. Changes in relative frequencies of the TNFα genotypes have been shown in rheumatoid arthritis. The -857С>T polymorphism of TNFα gene proved to be informative as a molecular marker reflecting efficiency of anti-TNFα therapy in rheumatoid arthritis.

Abstract. Angiogenesis plays the major role in growth, progression and metastasis of different solid umors. Vascular endothelium growth factor (VEGF) is a basic factor of angiogenesis regulation. The aim of present study was to evaluate possible correlations between C-2578A and C+936T VEGFА gene functional polymorphisms, and risk of breast cancer development. An association of -2578AA and -2578СС /+936СС VEGFA polymorphisms with incidence of breast cancer was revealed in our study. Distinct features of VEGFA genotype distribution were found for women with lymphogenic metastases and differences in menstrual status.

Abstract. Antistaphylococcal immunoglobulins (ASIg) are widely used for treatment of staphylococcal infections. However, Russian literature sources still lack any evidence-based data justifying clinical efficiency of this preparation. Taking into account a key role of phagocytosis for a macro-organism resistance to staphylococci, and importance of microbial opsonization in this response, a trial of antistaphylococcal immunoglobulinmediated opsonizing activity was performed with S. aureus Wood 46 and S. aureus Cowan I strains. A normal human Ig preparation was used as a reference substance. Both preparations influenced oxygen-dependent bactericidal effects of phagocytes to a similar degree. Normal immunoglobulin proved to be more active than ASIg, with respect to neutrophil ingestion properties and bacterial aggregation. Hence, present results, along with relevant data from Russian and foreign literature put in question the ASIg expediency for medication of staphylococcal infections.

Abstract. Thirty-nine patients with a progredient clinical form of chronic multiple sclerosis (MS) were subject to multiple immunization with autologous polyclonal T-cell vaccines. Two years after initiating the vaccine therapy, no evidence for disease progression was noted in 16 patients (41% of total). Neurological improvement was observed in five cases (13%) from the vaccine-treated group. Of 22 control MS patients who did not receive the immunotherapy, only 6 persons (27%) exhibited stabilization of their clinical state. Clinical improvement was not detectable among this group of MS patients. A group of twenty-six MS patients was treated with Rebif, without evidence of disease progression in eleven cases (42%), and distinct neurological improvement noted in one patient (4%) from this group. One year after starting the vaccine therapy, a rise in serum IL-10 was detected in vaccine-treated patients, whereas IL-17 and IL-18 serum levels remained within the initial ranges. A correlation between the serum levels of anti-myelin antibodies and appropriate anti-idiotypic antibodies was revealed in these patients. In general, the results obtained suggest polyclonal T-cell vaccination as a potentially effective treatment approach, both at early and more advanced stages of the disorder.

Abstract. A group of patients with bronchial asthma (BA) was under investigation, being classified according to their disease activity, and exacerbation risk factors. We studied expression of specific mRNAs for chemokines and their receptors in nasopharyngeal mucosa (n = 70) and amounts of those chemokines in blood serum (n = 59). In the patients with BA exacerbations after acute respiratory infections, an increased expression of eotaxin, MIP-1α, MIP-1β, CXCR1 mRNAs was observed, along with decreased CCR3 mRNA, as compared to a control group. In blood serum of these patients, a decreased levels of eotaxin and MIP-1β mRNA was accompanied by increase of MIP-1β and eotaxin-2 amounts. For the patients with allergen-provoked BA attacks, an increased expression of eotaxin, eotaxin-2, MIP-1β, CXCR1, CXCR1 was revealed, as well as decreased CCR1 mRNA expression, whereas serum samples showed significantly decreased contents of eotaxin and MIP-1β, along with increase in MIP-1α, RANTES and eotaxin-2 mRNAs. In BA remission state, a decreased mRNA expression was found for eotaxin, CCR1 and CXCR2 was observed, with increased serum contents of MIP-1α, RANTES and eotaxin-2. Hence, the changes of chemokine system detected in BA may be sought as markers of the disease exacerbation, depending on its primary origin, as well as potential biomarkers of the disease itself.

Abstract. The work concerned some parameters of proliferation and apoptosis in peripheral blood lymphocytes in patients with primary pulmonary tuberculosis (Tbc), as dependent on clinical form of the disease and sensitivity of M. tuberculosis to specific medical drugs. It was shown that, in patients with infiltrative and disseminated Tbc, as well as in cases of multi-drug resistance of M. tuberculosis, an increased apoptosis of lymphocytes is observed, accompanied by inhibition of their proliferative activity. The numbers of apoptotic and proliferating lymphocytes remain within normal ranges in patients with fibrous/cavernous form of the disease, and in cases of drug-sensitive M. tuberculosis.

Abstract. Macrophages are among key players of inflammatory events, acquiring either pro-inflammatory M1, or anti-inflammatory M2 phenotype, dependent on their microenvironment. Some endogenous macrophagereprogramming factors (MRFs), e.g., TGF-β (an M2-inducing agent), are found in blood serum. This work confirms a hypothesis on in vitro M1-to-M2 phenotype reprogramming of cultured macrophages, by means of decrease or increase in serum concentration. Noteworthy, the macrophages from C57BL/6 и BALB/c mice strains did not differ with their reprogramming capacity. In general, our results allow of extending present knowledge about a role of environmental factors in regulation of macrophage activities.

Abstract. It has been widely accepted that routine psychophysiological stressors may influence immune functioning via their close interactions between nervous, autonomic, endocrine and immune regulatory systems. The aim of this study was to evaluate immune reactions to acute psychophysiological stress in 203 medical students before and after academic exams. The results showed significant decrease of absolute and relative contents CD3+ T cells, natural killer (NK) cell subpopulations and T-NK cells (CD3-CD16+CD56+ and CD3+CD16+CD56+), as well as declined NK cell activity were revealed immediately after exams, as compared to initial values for these indices. Moreover, a significant decrease in CD19+ B cells, CD4+ T-helpers and CD8+ T-cytotoxic lymphocyte counts was found after exams, in comparison with parameters assessed under stress-free conditions, but no differences were observed, when compared with pre-examination values. Serum concentrations of IgA, IgM, IgG were within normal physiological limits. Changes in immunological parameters during acute examination-associated stress depend on characteristics of autonomous and hormonal reactions in humans, and, under particular extreme conditions, such psycho-emotional stress may cause general disturbances of immune reactions. We conclude that acute psycho-physiological stress during the exams causes significant changes in some lymphocyte subpopulations, in particular, natural killers.

Abstract. A comparative analysis of endotoxinemia grade, tumor necrosis factor α, C-reactive protein, sEselectin, matrix metalloproteinase-9 (MMP) and tissue inhibitor of metalloproteinases-4 (TIMP) levels was performed in a group of patients with chronic heart failure (CHF). An association has been shown between CHF progression and activation of systemic inflammation, like as with an imbalance in MMP/TIMP system. These alterations may represent a factor of structural disturbances in myocardial extracellular matrix, and promote a compartmental heart remodeling in this disorder.

Abstract. We investigated levels of spontaneous and mitogen-induced cytokine production (IL-1β, IL-4, IL-6, IL-10 and IFNγ) by peripheral blood cells of 24 men with unstable angina (UA), including indigenous population (n = 12, Yakuts), and a group of Russian migrants to the Republic of Sakha (n = 12). Activation of inflammatory response was revealed in the total group of patients with UA, manifesting by increase of spontaneous and induced production of the pro-inflammatory IL-1β, IL-6 cytokines, and mitogen-induced production of IFNγ. As compared with healthy individuals, spontaneous and induced production of anti-inflammatory IL-4 was decreased in UA patients, whereas the mitogen-induced production of IL-10 proved to be enhanced. Therefore, it is highly possible that a pro-atherogenic Th1-immune response is developing during UA, along with suppression of Th2-driving response. The differences revealed for different ethnic groups suggest that severity and prevalence of atherosclerotic disease, which is more common in the non-native patients, is associated with increased production of pro-inflammatory IL-1β and IL-6 cytokines.

Abstract. Progressive loss of dopaminergic neurons from substantia nigra is the major pathomorphologicasign in Parkinson’s disease (PD). Neuronal death is suggested to occur by programmed cell death (apoptosis) in PD patients, thus being involved into the mechanisms of neurodegeneration. Indirect signs of apoptosis may be revealed in peripheral blood lymphocytes (PBL) from PD patients. Using flow cytometry and annexin V-binding kit (PI + Annexin V FITC), we estimated PBL apoptosis in nine patients with PD (four untreated cases and five persons treated with L-DOPA), as compared with nine control persons. Spontaneous apoptosis at 24 h was higher in PD patients, as compared with controls (p < 0.01). Apoptosis rate was lower in patients receiving therapy with L-DOPA, than in untreated patients (p < 0.01). Our results support a possible role of apoptosis in PD pathogenesis, and suggest some effects of L-DOPA treatment upon apoptotic rates of peripheral blood lymphocytes.

Abstract. The changes of cytokine profile revealed in viral influenza-associated pneumonia (A/H1N1) were shown to exceed appropriate parameters for the cases of bacterial outpatient pneumonia. The most expressed hyperproduction of proinflammatory cytokines (IFNγ, TNFα), and a marker of pathological endothelial activation (sICAM-1) was registered in more severe cases, including those with ALI/ARDS, thus confirming a prognostic value of these parameters. An increased level of IL-10 and decreased IFNγ and TNFα concentrations in the non-severe flu-like pneumonia are indicative for a more balanced immune response. Increased IFNγ concentrations at six months after influenza-associated pneumonia (A/H1N1) may be caused by prolonged use of interferon inducers, as well as persistent antiviral immunity.

Abstract. The article presents data on some changes of immunological parameters in women with missed abortion. The indices of humoral and cellular immunity were studied in pregnant women at the terms of 4 to 15 weeks, as compared with a group of women with missed abortion within the same terms.

Abstract. Functional activity of thymus in normal donors and patients with various clinical forms of bronchial asthma was evaluated by means of assessing TREC-positive T-cell numbers. In spite of well-known alterations in parameters of T-cell homeostasis, TREC levels in CD4+and CD8+ lymphocytes from the patients with asthma did not differ significantly from those in donors. There were also no significant differences in TREC-containing cell numbers, dependent on clinical types of bronchial asthma and IgE levels. However, the patients with a recent disease onset (duration of several days to one year) showed increased TREC positivity in CD4+ and CD8+ lymphocytes, as compared with donors and those patients who underwent basal therapy with glucocorticoids, and during long-term disorder (> 1 year). Enhanced thymopoiesis at initial stages of the disease may be associated with thymic stromal lymphopoietin which contributes to development of bronchial asthma, and normally participates in the process of T cell production.

Abstract. We studied expression of transcription factor T-bet protein in allergic (ABA) versus non-allergic bronchial asthma (NABA), depending on severity grade and clinical phase of the disease. A Western blotting technique was applied, according to the standard protocol (Amersham), using polyclonal anti-T-bet antibodies at a 1:500 dilution (Santa Cruz Biotechnology, UK). The protein levels were quantified, using β-actin as a reference. It is shown for the first time that T-bet expression in ABA patients, as compared to healthy controls, was reduced with increasing disease severity, but did not correlate with clinical phase of the disease. In NABA patients, no sufficient differences in T-bet expression were revealed, as compared with healthy controls. The work was supported by St.Petersburg governmental grant PD04-4.0-102 (Certificate № ASP604079).