IL-12 deficiency in MRL-Fas(lpr) mice delays nephritis and intrarenal IFN-gamma expression, and diminishes systemic pathology.
Autoimmune disease in MRL-Fas(lpr) mice is characterized by fatal nephritis, systemic pathology, and autoantibodies, mimicking human lupus. We previously reported that 1) intrarenal IL-12 elicits nephritis by fostering the accumulation of intrarenal IFN-gamma-secreting T cells, and 2) MRL-Fas(lpr) mice deficient in the IFN-gamma receptor were spared from nephritis. Therefore, we hypothesized that eliminating IL-12 in MRL-Fas(lpr) mice reduces IFN-gamma-secreting cells and thereby prevents systemic pathology. For this purpose, we constructed an IL-12p40-deficient MRL-Fas(lpr)(IL-12(-/-)) strain. We determined that glomerular and interstitial, but not perivascular, renal pathology were decreased in IL-12(-/-) mice vs the wild-type (WT) strain (5 mo of age). Similarly, systemic pathology (lung, lacrimal and salivary glands, skin, and lymphadenopathy) was diminished. The intrarenal accumulation of T cells (CD4(+), CD8(+), CD4(-)CD8(-)B220(+)) and macrophages was dramatically reduced in IL-12(-/-) MRL-Fas(lpr) kidneys. We determined that there were fewer IFN-gamma transcripts (>70%) in the IL-12(-/-) protected kidneys compared with the WT kidneys. Similarly, cells propagated from IL-12(-/-) MRL-Fas(lpr) kidneys generated substantially less IFN-gamma when stimulated with IL-12 and IL-18 compared with those from WT kidneys, and we detected fewer CD8 and B220 T cells producing IFN-gamma in these IL-12(-/-) MRL-Fas(lpr) kidneys. Of note, survival was modestly extended in the IL-12(-/-) MRL-Fas(lpr) mice. While lung and lacrimal and salivary gland pathology remained reduced in moribund IL-12(-/-) MRL-Fas(lpr) mice, renal pathology and IFN-gamma expression were equivalent to those in the WT strain. Thus, we suggest that IL-12 is a therapeutic target for multiple tissues in lupus; however blocking IL-12 alone is not sufficient to confer enduring protection from lupus nephritis.
Kikawada
Eriya
E
Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Lenda
Deborah M
DM
Kelley
Vicki R
VR
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003176:Complement C3 / Q000172:deficiency; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D017099:IgG Deficiency / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007132:Immunoglobulin Isotypes / Q000097:blood; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000172:deficiency* / Q000235:genetics*; D020382:Interleukin-18 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D007678:Kidney Glomerulus / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007765:Lacrimal Apparatus / Q000276:immunology / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D007970:Leukopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D012469:Salivary Glands / Q000276:immunology / Q000473:pathology; D012867:Skin / Q000276:immunology / Q000473:pathology; D015996:Survival Rate; D019014:fas Receptor / Q000235:genetics*
D003176:Complement C3; D007132:Immunoglobulin Isotypes; D020382:Interleukin-18; D019014:fas Receptor; D018664:Interleukin-12; D015847:Interleukin-4; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017493:Leukocyte Common Antigens