Clear suppression of Th1 responses but marginal amelioration of autoimmune manifestations by IL-12p40 transgene in MRL-FAS(lprcg)/FAS(lprcg) mice.
To investigate the effects of overproduction of IL-12p40, a potent antagonist against IL-12, on lupus-like autoimmune disease in vivo, we generated p40 transgenic MRL-Fas(lprcg)/Fas(lprcg) mice. Serum p40 and IL-12 levels were 600- to 8000-fold and 3- to 20-fold higher in transgenic (p40-lpr(cg)) than nontransgenic (lpr(cg)) mice, respectively. Serum IFN-gamma levels increased after 3 months of age in lpr(cg) and this age-related increase was completely abrogated in p40-lpr(cg). Serum IL-4 levels were the same in both mice. Production of IgM and IgG anti-double-stranded DNA (dsDNA) antibodies was significantly lower in p40-lpr(cg). Anti-dsDNA antibodies decreased in Th1-dependent IgG2a but increased in the Th2-dependent IgG1 subclass significantly in p40-lpr(cg). Proteinuria, glomerulonephritis, and survival were only marginally ameliorated in p40-lpr(cg). The results suggest that excess p40 production in vivo may suppress Th1 responses in autoantibody and IFN-gamma production but lead to minimal improvement of clinical manifestations of autoimmune disease in this mouse model.
Yasuda
T
T
Laboratory Animal Research Center, University of Tokyo, Minato-ku, Tokyo, Japan. takuwa@med.toho-u.ac.jp
Yoshimoto
T
T
Tsubura
A
A
Matsuzawa
A
A
D000375:Aging / Q000276:immunology; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000974:Antibodies, Antinuclear / Q000096:biosynthesis* / Q000235:genetics; D000918:Antibody Specificity; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003433:Crosses, Genetic; D004247:DNA / Q000276:immunology; D019281:Dimerization; D004195:Disease Models, Animal; D005260:Female; D005813:Genes, Synthetic; D015316:Genetic Therapy; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D015847:Interleukin-4 / Q000097:blood; D007668:Kidney / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008181:Lupus Nephritis / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D021122:Protein Subunits; D011507:Proteinuria / Q000209:etiology; D012737:Sex Factors; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology; D019076:Transgenes; D019014:fas Receptor / Q000235:genetics
D000888:Antibodies, Anti-Idiotypic; D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D021122:Protein Subunits; D019014:fas Receptor; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D004247:DNA