[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.

Proliferative activity and subpopulation pattern of cells in murine thymus and spleen on the model of graft-versus-host chronic reaction under various diurnal regimens of IL-2 administration.

We studied the effects of IL-2 administration at different times of day to female B6D2F1 mice with experimental immunopathology, graft-versus-host chronic reaction induced by the administration of lymphoid cells from parental female DBA/2 mice. Recombinant murine IL-2 was injected subcutaneously at 10.00 (group 1) or 16.00 (group 2) after the first cell transfer. Evening administration of IL-2 in contrast to its morning injection prevented cell proliferation in the thymus and spleen, decreased the number of apoptotic splenocytes, significantly stimulated differentiation processes in the thymus, increased the amount of CD4 (+) 25 (high) thymocytes, and decreased the number of CD4 (+) 27 (low) splenocytes. These findings can serve as a prerequisite for the development of chronotherapeutic schemes for immunocorrection.

Effect of regular physical training on hemopoiesis in experimental animals.

Regular physical activity of moderate intensity over a long period (swimming at water temperature of 33-35°C without load, 2 h per day, 5 days a week for 4 months) activated hemopoiesis in mice: stimulation of myelopoiesis in the bone marrow and increase in the percentage of erythropoietic elements in the spleen were observed. In the peripheral blood, the relative content of lymphocytes increased, that of granulocytes decreased, and plasma cells appeared. Stimulation of erythropoiesis in the spleen can be partially responsible for suppression of immune responses during physical exercise.

Processes of homeostatic proliferation in the pathogenesis of autoimmune glomerulonephritis induced by chronic graft-versus-host reaction.

Lymphopenia developing at the early stage of chronic graft-versus-host reaction is associated with increased content of IL-7 in the peripheral blood and leads to an increase of the CD4(+)and CD8(+)cell subpopulations in the spleen of the recipient. After 3 months, some animals develop autoimmune glomerulonephritis (lupus recipients). High levels of IL-7 and T-cells with the memory cell phenotype (CD4(+)CD45RB(low)and CD8(+)CD45RB(low)) persist in these animals, in contrast to nonlupus recipients without signs of autoimmune disease. This can attest to the involvement of homeostatic proliferation processes in the formation of autoimmune disease in this model.

Stimulation of immune response: resistance to proliferation inhibitors.

Additional dose of the antigen at the end of the log phase of developing IgM response to T-dependent antigen leads to a drastic increase in the counts of IgM and IgG antibody-producing cells in the spleens of experimental animals. The effect is dose-dependent and more pronounced after the first immunization with the antigen in the suboptimal dose. Elimination of proliferating antibody producers has an ambiguous effect on IgM and IgG antibody production in the spleen: it limits the increase in the count of IgM-producing cells, but does not abolish the stimulation of IgG response. It seems that the increase in the count of IgG producers is not linked with simultaneous active proliferation of IgG producing cell precursors.

Effect of oxidized dextrans on NO synthase and arginase activities of mouse macrophages.

We studied the effect of oxidized dextrans with molecular weights of 30-35 kDa and 60-65 kDa on NO synthase and arginase activities of mouse peritoneal macrophages in vivo and in vitro. Oxidized dextrans irrespective of molecular weight shifted the NO synthase/arginase balance towards predominance of NO production under in vivo and in vitro conditions. Administration of the test compounds to intact mice considerably increased NO synthase activity, while culturing of peritoneal macrophages in the presence of modified dextrans reduced arginase activity in these cells. These effects of oxidized dextrans create conditions for predominant stimulation of Th1-mediated immune reactions.

[Screening of new derivatives of arylheteroalkanecarboxylic acid on the immune system].

The screening of 13 original compounds from the group of derivatives of arylheteroalkanecarboxylic acid on immunity were performed. The compounds exhibit strong myelostimulating/myelosuppressive property, increased or decreased influence on the: PFC (IgM and IgG), DTH at the sheep erythrocytes in CBF1 in vivo. In contrast, in vitro the compounds had no effect or inhibited the spontaneous, ConA or PWM induced proliferation of the splenocytes from normal mice. The problems of the universal methods of the screening of immunoactive properties of compounds are discussed.

Effects of preparations modifying Th1/Th2 ratio on the incidence of clinical variants of chronic graft-versus-host reaction.

Induction of chronic graft-versus-host reaction in a semiallogenic DBA/2- (DBA/2xC57Bl/6) F1 system leads to the development of Th1- or Th2-dependent immunopathologies. Modification of the Th1/Th2 ratio during induction with preparations acting on the immune system cells via different mechanisms and shifting the Th1/Th2 balance towards Th2 (bisphenol A, pentoxifylline, muramyl dipeptide) increases the incidence of Th2-dependent autoimmune lupus-like glomerulonephritis.

[Effect of stimulation and depression of macrophages on development of paracetamol-induced acute toxic hepatitis in rats]. / Vliianie stimuliatsii i depressii makrofagov na razvitie ostrogo toksicheskogo gepatita u krys, vyzvannogo paratsetamolom.

The role of macrophage (Kupffer cell) stimulation and suppression in the development of a toxic liver damage was studied in rats with acute hepatitis induced by paracetamol (acetaminophen, 1000 mg/kg). Pretreatment with carboxymethylated (1-->3)-beta-D-glucan (25 mg/kg, i.p., 48 h before paracetamol) for the macrophage stimulation or with gadolinium chloride (GdCl3, 7.5 mg/kg, i.v., 24 h before paracetamol) for the macrophage suppression has a protective effect manifested by normalization of the liver function test parameters and by a decrease in the degree of morphological changes in the liver cells. A relation between these positive effects and the TNF-alpha secretion by macrophages is discussed.

Contribution of interleukin-1 to Th1- and Th2-dependent variants of chronic graft-versus-host reaction.

Semiallogenic transfer of lymphoid cells from parental DBA/2 strain to (C57Bl/6xDBA/2)F1 hybrids induces two variants of chronic graft-versus-host reaction with predominant activation of donor Th1 or Th2 cells [2] in genetically homologous recipients: first, severe inhibition of the humoral immune response, or second, autoimmune disease (lupus nephritis) against the background of suppressed cell and humoral immunity. These variants of chronic graft-versus-host reaction are characterized by different changes in interleukin-1 level.

[Immunopoiesis- and erythropoiesis-modulating properties of trecresan in experimental immune deficiency]. / Immunopoézmoduliruiushchie i éritropoézmoduliruiushchie svoistva trekrezana pri éksperimental'nom immunodefitsite.

The effect of trecrezan, a new immunoactive biostimulator, was studied in (C57BL/6 x DBA/2)F1 mice with immunodeficiency and anemia syndromes induced by a chronic guest-versus-host reaction. The drug combines immuno- and erythromodulant properties, being capable of eliminating anemia, decreasing the number of erythrokaryocytes and BFUs in bonemarrow of ill mice, and normalizing primary humoral immune response. Possible mechanisms of trecrezan action are discussed.

Combined disorders in erythro- and immunopoiesis in (C57Bl/6xDBA/2)F1 mice with immunodeficiency induced by graft-versus-host reaction and immunocomplex glomerulonephritis.

Disorders in erythro- and immunopoiesis were studied in B6D2F1 mice with immunodeficiency induced by graft versus host reaction and with immunocomplex glomerulonephritis. By the 6th-7th months of the disease the animals developed anemia accompanied by enhanced phagocytic activity of macrophages and production of tumor necrosis factor. Macrophage dysfunction is presumed to be a cause of anemia.

[Immuno- and erythropoiesis in mice with graft vs host disease against a background of immunodeficiency]. / Sostoianie immuno- i éritropoéza u myshei s bolezn'iu transplantat protiv khoziaina na fone immunodefitsita.

In BALB/c mice immunodeficiency was induced by the transfer of lymphocytes immune to alloantigen. This model is one of experimental models of AIDS. The work was aimed at the study of disturbances in the immuno--and erythropoiesis in immunodeficient mice. The state of erythropoiesis was evaluated by the level of level of hemoglobin, hematocrit and the content of reticulocytes in peripheral blood, by the number of erythroid bursitis-forming units and the percentage of erythrokaryocytes in the marrow, as well as by the number of colony-forming units in the spleen by days 5 and 8. The study revealed that in BALB/c mice hypoplastic anemia, accompanied by the decreased phagocytic activity of macrophages and the reduced production of interleukin 1 and tumor necrosis factor, developed on months 5-6 of the disease. Macrophagal dysfunction was supposed to be one of the causes of hypoplastic anemia in immunodeficient mice.

[The immunoactive properties of trekrezan]. / Immunoaktivnye svoistva trekrezana.

It was shown that in vivo trecrezan possessed strong immunoactive properties: it decreased the spot-forming activity of polypotent stem blood cells, stimulated lympho- and hemopoesis, antibody formation, possessed steady antiinflammatory activity. It stimulated in vitro mononuclear cell proliferation in man due to its direct action on B lymphocytes and increase in lymphokine and monokine production.

[The immunomodulating properties of the diuretic bufenoks]. / Immunomoduliruiushchie svoistva diuretika bufenoksa.

Bufenox, a diuretic with a sodium-uretic and light potassium--uretic effect, has an immediate but short-term effect, stimulates IgM antibody production, depressed delayed-type hypersensitivity. The immunomodulating effect of bufenox may be due to changes in Na+ ions concentrations since sodium load abrogates immunoactive properties of the drug.

[Indicators of erythro- and immunopoiesis in the development of autoimmune disease induced by graft vs host reaction]. / Pokazateli éritro- i immunopoéza v razvitii autoimmunnogo zabolevaniia, indutsirovannogo reaktsiei transplantant protic khoziaina.

Erythropoiesis and immunity are evaluated in (C57BL/6xDBA/2) F1 mice with immune complex glomerulonephritis induced by GVHR as compared to the genetically determined models of systemic lupus erythematosus. Elevated content of serum blood antinuclear antibodies, polyclonal activation during early disease periods, immune complex deposition in kidney tissues indicate the presence of the autoimmune syndrome in (C57BL/6xDBA/2)F1 mice, similar to that in mice with genetic lupus nephritis. The findings of a decrease of CFUs on days 5 and 8 at early times of disease, a reduction of hematocrit in combination with the enhancement of stem cell proliferation on the 6th-7th month of disease, an increase of the absolute leukocyte count and relative monocyte count in the peripheral blood of diseased mice may attest to the depression of stem cell differentiation in erythropoiesis and to the enhancement of stem cell differentiation in granulocyto-monocytopoiesis, that needs, however, further research and confirmation.