[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.

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.

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.