[The Experimental Model of Autoimmune Process: the Role of Epigenetic Variation in the Population of Mice Hybrids].

BACKGROUND: At the development of graft versus host disease in genetically homogeneous population of (C57BI/6 x DBA/2) Fl mice two clinical phenotypes of SLE-like disease were revealed: lupus+ (immune complex glomerulonephritis and hemnolytic anemia) and lupus - (hemolytic anemia). The GvHD phenotypic heterogeneity is determined by the Th2-polarization: Th2 lymphocyte predominant activity, leads to the lupus+development, or prevalence activity of Th1 cells, leads to the lupus- development. OBJECTIVE: Our aim was to evaluate the possibility of using an experimental model of autoimmnune disease for studying and testing of epigenetic modifications, shifting Th1/Th2 balance in vivo. METHODS: Chronic GVHD was induced in B6D2F1 mice by the transplantation of 130x10(6) parental DBA/2 splenocytes. Anti-ds-DNA, total IgG and IgGI, IgG2a Abs were measured by ELISA. RESULTS: Six- to 8-week-old female DBA/2 and B6D2F1 mice were obtained from Biological Research Laboratory (Novosibirsk). It was established that regular moderate physical activity (unladed swimming) shifted Th1/Th2 balance towards Th1. This leads to a decrease in a population of recipients the lupus+ mice from 57 to 26% (p <0,001) with significantly reduced hypergammaglobulinemia (IgG from 2,8 to 2,0 mg/ml; p <0,047) and DNA antibodies titer from 0,18 to 0,12 OD (p =0,05). Administration of epigenetic modificator bisphenol A at low doses, which mimicking estrogen effects, enhances the proportion of lupus+ mice in experimental groups from 33 to 64% (p <0,001) and impairs their clinical status by the increasing the urine protein level from 2.8 to 4,2 mg/ml (p <0,001) in animals. CONCLUSION: Th1/Th2 - balance presumably is determined by the immune system epigenetic modification in experimental mice, formed on the previous stages of ontogeny and defines the direction of immune processes development in individual animal.

[Th1/2-balance shift during acute graft-versus-host reaction developing against the background of experimental hyperlipidemia].

AIM: Evaluate the effect of experimental hyperlipidemia on the intensity of development of acute graft-versus-host reaction (GVHR) in mice. MATERIALS AND METHODS: Half-allogenic system C57Bl/6 (C57Bl/6 x DBA/2)F1 was used as a laboratory model of acute GVHR. Experimental hyperlipidemia in mice-recipients was induced by repeated administration of poloxamer 407. RESULTS: Lethality in the group of mice with acute GVHR developing against the background of preceding hyperlipidemia was significantly higher (70% at day 50 of GVHR development) compared with control group with acute GVHR (50% lethality at day 50). Such effect on the degree of severity of acute GVHR induced under the conditions of hyperlipidemia is confirmed by a more pronounced destruction of thymus in mice of the group with previously induced hyperlipidemia. CONCLUSION: Preceding hyperlipidemia induced by administration of poloxamer 407 shifts Th1/2- balance in the development of acute GVHR towards Th1. Mechanisms of this effect and possible role of nuclear LXR receptors in regulation of immune reactions are discussed.

[Laboratory model of hyperlipidemia].

AIM: Approbation of laboratory model of hyperlipidemia induced by multiple administration of poloxamer 407 to hybrid mice (C57BL/6 x DBA/2) F1. MATERIALS AND METHODS: Two-month-old female mice (C57B1/6 x DBA/2)F1 were used for experiments. Level of dyslipidemia was assessed measuring cholesterol level in serum by method with cholesteroloxidase. RESULTS: Dosages and timing of administration of the compound for inducing stable moderate hypercholesterolemia were selected. It was discovered that dyslipidemia induced by this method accompanied by reliable increase of neutrophils count in peripheral blood of animals. CONCLUSION: Hyperlipidemia induced in mice by administration of poloxamer 407 could be used for convenient experimental model for complex studies of immune system functions during pathophysiologic conditions associated with lipid metabolism disorders.

[Influence of the activation of the immune system cells on the parameters of lipid metabolism in macrophages]. / Vliianie aktivatsii kletok immunnoi sistemy na parametry lipidnogo obmena v makrofagakh.

The influence of tumor necrosis factor a (TNF-alpha) and media, conditioned by activated macrophages and lymphocytes and containing a complex of biologically active compounds (including cytokines), on the parameters of lipid metabolism in macrophages was studied. The addition of recombinant TNF-alpha and immunocompetent cell-conditioned media to mouse peritoneal macrophages culture stimulated labelled oleate incorporation into cholesterol esters and triglycerides, as well as labelled glycerine incorporation into cholesterol esters, but inhibited labelled cholesterol incorporation into cholesterol esters. One of the mechanisms of the influence of activated immunocompetent cells on cholesterol metabolism in macrophages was, supposedly, the stimulation of sphigmomyelinase activity by a complex of anti-inflammatory cytokines produced by these cells on their activation.

[Effect of modified low density lipoproteins on humoral immune response and functional activity of macrophages in mice]. / Vliianie modifitsirovannykh lipoproteinov nizkoi plotnosti na gumoral'nyi immunyi otvet i funktsional'nuiu aktivnost' makrofagov myshi.

Intravenous injection of acetylated low density lipoproteins (acLDL) in mice in a dose of 0.5 mg per mouse decreased the intensity of humoral immune response to sheep red blood cells (SRBC) by 35%. The addition of acLDL to mouse peritoneal macrophages in vitro resulted in inhibition of Fc-dependent phagocytosis of SRBC and fourfold increased secretion of prostaglandins E2 by macrophages. Fc-dependent phagocytosis of SRBC was also found to be inhibited by oxysterols (25-hydroxycholesterol and 7-ketocholesterol), added to the incubation medium of macrophages in vitro in doses of 0.5-5 mg/ml. The conclusion was made that oxidative metabolism of cholesterol and arachidonic acid, contained in LDL, may mediate the immunomodulating effects of modified LDL.

[Benz(a)anthracene and 2,3,7,8-tetrachloro dibenzo(p)dioxin modulate mitogen-stimulated proliferation of lymphocytes]. / Benz(a)antratsen i 2,3,7,8-tetrakhlordibenzo(p)dioksin modiliruiut mitogenstimulirovannuiu proliferatsiiu limfotsitov.

The influence of benzo(a)anthracene (BA) and 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) on functional properties of peripheral blood mononuclear cells (PBC) has been investigated. Incubation of mitogen-stimulated cells in the presence of xenobiotics induced high activity of benzo(a) pyrene-hydroxylase (BH) and suppressed lymphocyte blast transformation. Preincubation of unstimulated PBC with BA and TCDD caused insignificant increase of BH activity. The results show modulated effect of xenobiotics on functional properties of PBC.

[Benzopyrene hydroxylase induction and the functioning of the immunocompetent cells in human peripheral blood]. / Induktsiia benzpirengidroksilazy i funktsional'noe sostoianie immunokompetentnykh kletok perifericheskoi krovi cheloveka.

Xenobiotics--inducers of benzo(a)pyrene hydroxylase (BPH)--exert different effects on mitogen-stimulated and mitogen-unstimulated human peripheral blood mononuclear cells (PBC). In mitogen-stimulated culture xenobiotics highly increase BPH activity and suppress cell blast transformation. The incubation of the unstimulated PBC in the presence of xenobiotics increases insignificantly BPH activity, intensifies T-cell differentiation and concanavalin A-induced proliferation. The BPH activity is mainly associated with the PBC adhered to plastic Petri dishes. However, the control and induced levels of BPH activity depend on the interaction between adhered and nonadhered cells.