Fundamental immunobiology of proinflammatory cytokines and MIF

There are a lot of similarity as well as differences when we compare cytokines with MIF according their biological properties. MIF characteristics are unique structure, organs and tissues ubiquity, extremely wide variety of functions (proinflammatory cytokine, enzyme, hormone), ability to be induced by glucocorticoid hormones and affects as their immunosuppressive effects antagonist. MIF exists in preformed condition in lymphocytes, macrophages and endothelium cells. It secrets by these cells and operates as a mobilizing defense system factor in the first minutes of foreign invasion. MIF exhibits the properties of super-ligand binding with many biologically important molecules. This factor carries out the functions that are important for cell activation, proliferation and death, using a variety of intracellular signaling pathways. Some of MIF homologues exists in plants and bacteria earlier than innate and adaptive immune systems appears in evolution. In ontogenesis MIF appears at the stage of firsts cell divisions. MIF has a lot of functions, variety of ligand bindings, many effector pathways, it appears early in ontogeny and phylogeny. MIF takes part into protective reactions at any levels – from cell up to whole organism. All these MIF features taking together into account make it possible to possess it as a particular type of cytokine – eocytokine (from Greek word “eo” – early). It is assumed that MIF may function as some kind of cells and organisms "natural stability" key factor.

Abstract. Natural catalytic autoantibodies (abzymes) posessing proteolytic (protoabzymes) and DNA-hydrolysing (DNA-abzymes) activities are detectable in clinical and experimental autoimmune disorders. Catalytic activity of abzymes is revealed in the patients with different forms of systemic (nonspecific) and organ-specific autoimmune pathology. The opportunity of assaying the abzymes for intensity monitoring of autoimmune disease is also described.

Abstract. Post-infection immunity represents an immunogenicity standard for antiviral vaccines, including those against influenza. To estimate the immunogenic properties of vaccine preparations, it is necessary to compare the quantitative and qualitative parameters of immune responses to the vaccine strain and the virulent virus from which it is prepared. However, for ethical reasons, such human studies are difficult, because there is the possibility of pathogenic viral infection.

The aim of this experimental work was to compare systemic immune responses to the pathogenic mouse influenza virus A (H1N1), and an attenuated reassortant virus, genetic formula 2/6 (R 2/6), an experimental analogue to the live influenza vaccine.

It was shown, that R 2/6 lagged behind the pathogenic parental virus (PPV) in activated induction of circulating IgG-antibodies, secretion of a marker Th1-cytokine IFN-γ by splenocytes, and CTL (CD8+) production in the spleen. On the other hand, R 2/6 was highly competitive with PPV, with regard to quantitative proliferative parameters of pooled splenocytes, stimulation of Th (CD4+) cells, B-cells (CD19+), and Th2-cytokine IL-2. IL-6 production in the spleen was poorly induced by both viruses.

Thus, attenuation of influenza A (H1N1) virus by the 2/6 genetic reassortment differentially influences the induction of systemic immunity constituents. i.e., some parameters of immune response may be reduced, while others are not altered. When preparing vaccine strains for live influenza vaccines, an attention should be given first of all to increased induction of circulating antibodies that comprise the major components of antiviral immunity.

Abstract. In glioblastoma (GB), it is necessary to take into consideration GB-associated secondary immunodeficiency (SID), so-called syndrome of tumor-associated SID (STASID). Cell subsets having effector and regulatory functions, play an important role in developing STASID, and their proportions in patients with different forms of GB can be of pathogenetic importance and have clinical value for treatment and rehabilitation scheduling as well. The most pathogenically and clinically important features of cell subsets profile of peripheral blood were analyzed in patients with different clinical and morphological types of GB. The patients were divided into three groups, i.e., groups I and II were formed by patients with STASID (marked and slightly marked SID, accordingly); group III – patients with SIDTAS (tumor-associated autoimmune syndrome, associated with SID). Marked suppression of cell immunity is typical of group I - imbalance in T-lymphocytes, in a number of specific subsets, and in subsets clusters, as well as disproportions in the immunoregulatory indexes. In group II, the subset profiles of blood were slightly different from the norm. In patients with SIDTAS, activation of cell immunity was evident, forming SID with signs of autoimmune syndrome, affecting effector and regulatory chains of immunity, and influencing the severity and forecast of the disease. Specific features of the immune status in patients with GB identified can be resulted from different clinicalmorphological types of the tumor; the latter are to be considered in differential diagnostics of clinical course of GB and in scheduling of clinical-immunological efficient anti-tumor pharmacotherapy in pre- and postoperative periods.

Abstract. Present work aims to investigate functioning of the regulatory T-cells with suppressor activity in surgical sepsis. It has been shown that the septic patients with decreased T cell proliferation are characterized by enhanced relative contents of СD4+СD25+ lymphocytes, including СD4-CD25high. Moreover, a reverse correlation has been revealed between СD4+CD25+high and anti-CD3-induced proliferative response of mononuclear cells (MNC).

Increased ratio of СD4+СD25+ cells is associated with arising suppressive activity of MNC, which is partially abrogated by addition of rIL-2. It should be noted that the depletion of CD25+ subpopulation is accompanied by increased T cell proliferation. Hence, a decrease in T cell proliferative activity in surgical sepsis is coupled with naturally occurring СD4+СD25+ regulatory T-cells (Trn).

Furthermore, it has been demonstrated that the suppressive activity of MNCs in septic patients is mediated by soluble factors, in particular, IL-10. Indeed, septic patients are characterized by increased level of IL-10 production and enhanced number of CD4+IL-10+ T-cells. Addition of neutralizing anti-IL-10 antibody partially abrogated the suppressive activity of MNC supernatants. Thus, our study demonstrated that inducible regulatory T cells (Tr1) coupled to the naturally occurring СD4+СD25+ regulatory T-cells (Trn) actively contribute to genesis of immune pathology in sepsis.

Abstract. The study was carried out in the patients with bulky masses in the liver. Acute hepatic failure was initiated by resection of the liver. In the patients with bulky masses in the liver, increased serum levels of the common cytokines were detected during postoperative period. The blood contents of IL-1β and IL-6 are directly dependent on the surgery-related factors (extent of resection, duration of hepatoduodenal ligation, blood loss volume), that may be employed for prediction of disease course and planning surgical treatment. Determination of a level IL-1β and IL-6 levels is a diagnostic index of liver damage, and it may be used for evaluation of the postresection hepatic failure.

Abstract. Thirty-seven patients with stage colorectal cancer stage IV were subjected to immunotherapy using a polyantigenic vaccine, prepared, basically, from lyzed cells of murine melanoma (B16) and murine carcinoma (LLC) cells. The inducing course of xenovaccine therapy consisted of 10 subcutaneous immunizations (5 injections weekly followed by 5 bi-weekly). Consolidating treatment included monthly vaccinations. Ther xenovaccine therapy was not associated with any serious adverse effects, and did not influence the composition of blood lymphocyte subsets. Significant increase in cellular immune reactions to vaccinal carcinoma-associated antigens occurred in the patients after an inducing treatment, as determined by both skin and antigen-driven blastogenesis test. The overall 2-year survival of thirty-seven stage IV colorectal cancer patients was shown to be significantly better, than in control group (37 clinically comparable patients), with median survival rates of 17 and 7 months, respectively.

Abstract. Immunological efficiency of the tick-borne encephalitis (TBE) vaccine Encepur® Adult (Chiron Behring GmbH, Germany) was studied according to the sex- and age stratification of inoculated persons. The group under observation consisted of 117 residents of Vladivostok, Russian Far East, 17 to 68 years old, in whom anti-TBE antibodies were not detectable. Vaccination was performed according to the classical schedule, i.e., 0 days-28 days-12 months. Specific immune response was evaluated before vaccination, a month after first inoculation, 1 month following second vaccination, 1 year after two inoculations, and a month after third vaccination. Total index of marked immunological protection reached 100% after the 3rd vaccination. The highest response rates were revealed in young subjects and women. It was shown that the male persons from young and mature age groups travel to the forest more commonly than females, as opposed to the appropriate groups at older ages. However, in the older age group we have reversed situation. These data substantiate application of the tick-borne encephalitis vaccine Encepur® Adult as an effective mean for TBE prevention in endemic areas of Russia, where different strains of TBE virus are encountered.

Abstract. Hepatitis C virus (HCV) is the leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Liver damage in chronic viral hepatitis C is caused by both direct cytopathic viral effects, and indirect immune-mediated mechanisms. The cytokines locally produced in the liver, as well as those circulating in the blood circulation, play an important role in the control of viral replication and sufficiently contribute to hepatocellular damage. The goal of present study was to investigate the contents of some cytokines in blood serum and their local levels, being in interrelation with indices of necrotic inflammatory changes in the liver tissue. Correlations established between systemic and local contents of studied cytokines, and morphological indices indicate that, among immunological tests checked, the contents of IL-4, IL-10, IL-12p70, and TNFα in blood serum and supernatants of liver biopsies were of the greatest significance for determining the stage of fibrosis. Quantitative assays of abovementioned cytokines in blood serum represent, therefore, an alternative approach in order to perform noninvasive screening of liver fibrosis.

Abstract. Present study deals with size measurements of telomeric DNA from the human peripheral mononuclear immune cells in rheumatoid arthritis (RA). A method for measuring the relative telomere length by in situ hybridization followed by flow cytometric analysis (flow-FISH) was used. Relative telomere length (RTL) in monocytes was estimated as mean fluorescence intensity (MFI) of test cells divided by MFI values of internal control cells. Hybridization conditions for analysis of telomere length in monocytes have been optimized in advance. It has been shown that RTL of monocytes was significantly lower in RA patients compared to donors. Significant differences in telomere length of monocytes between RA patients and donors were revealed for the young persons under 30 years old. The findings obtained may be considered as an additional argument confirming the hypothesis on genetic defects of hematopoietic stem cells determining RA development.

Abstract. In present work, we studied some interrelations between tobacco smoking and the processes of immune system stimulation in healthy blood donors. In our opinion, this issue is especially important for the big industrial center, with rather strong antigenic exposure of the organism. The levels of circulating immune complexes (CIC) were used as a marker index which reflects specific antigen-antibody interactions during inflammation. According to the results obtained, the majority of persons who have high CIC levels were tobacco smokers (53.76%). Moreover, the percentage of persons with high CIC content, like as the mean values of this index is increased proportionally to the duration of smoking. A mixture of tobacco smoke components seems to exert direct toxic effect upon various compartments of the immune system and causes local irritation of bronchial tree, thus producing local and systemic inflammatory reaction. It is, possibly, an additional factor which determines activation of immune system, with a background of adverse antropogenic exposures typical to industrial centers. The data obtained allow us to affirm a toxic action of tobacco smoke upon the organism of smokers, with development of inflammatory reactions that are displayed as increased CIC levels at preclinical stage.

Abstract. A number of studies provide evidence for significant disturbances of immune, cytokine and antioxidant conditions in the patients with chronic salpingoophoritis. The own studies of combined effects produced by some medications, with respect to correction of altered laboratory parameters in such patients, have shown higher efficiency of ridostine/lipoic acid combination, as compared to derinate/tocopherol treatment. The revealed correlations between the clinical signs and immune status of the patients with a salpingoophoritis, suggest that only some of immunological parameters could be used for predictive purposes. The established positive influence of studied drugs on the disturbed functions of immune and antioxidant systems suggests a need to introduce immunocorrector drugs and antioxidants into complex therapy of the patients by chronic salpingoophoritis.

Abstract. Analysis of clinical and anamnestic findings has been performed for 105 children 2 to 6 years old, and 101 adolescents 10-12 years old has been performed. Clinico-anamnestic data of children and addescents with and without chronic diseases were compared within mentioned age groups. As a result, 3 groups of risk factors for developing chronic pathology have been distinguished, i.e., (1) predisposing; (2) potentiating, and (3) consolidating. For chronic pathology to be developed, the presence of factors from all three groups is obligatory.