IL-12 drives IFN-gamma-dependent autoimmune kidney disease in MRL-Fas(lpr) mice.
IL-12 is secreted by kidney tubular epithelial cells in autoimmune MRL-Fas(lpr) mice before renal injury and increases with advancing disease. Because IL-12 is a potent inducer of IFN-gamma, the purpose of this study was to determine whether local provision of IL-12 elicits IFN-gamma-secreting T cells within the kidney, which, in turn, incites injury in MRL-Fas(lpr) mice. We used an ex vivo retroviral gene transfer strategy to construct IL-12-secreting MRL-Fas(lpr) tubular epithelial cells (IL-12 "carrier cells"), which were implanted under the kidney capsule of MRL-Fas(lpr) mice before renal disease for a sustained period (28 days). IL-12 "carrier cells" generated intrarenal and systemic IL-12. IL-12 fostered a marked, well-demarcated accumulation of CD4, CD8, and double negative (CD4-CD8- B220+) T cells adjacent to the implant site. We detected more IFN-gamma-producing T cells (CD4 > CD8 > CD4-CD8- B220+) at 28 days (73 +/- 14%) as compared with 7 days (20 +/- 8%) after implanting the IL-12 "carrier cells;" the majority of these cells were proliferating (60-70%). By comparison, an increase in systemic IL-12 resulted in a diffuse acceleration of pathology in the contralateral (unimplanted) kidney. IFN-gamma was required for IL-12-incited renal injury, because IL-12 "carrier cells" failed to elicit injury in MRL-Fas(lpr) kidneys genetically deficient in IFN-gamma receptors. Furthermore, IFN-gamma "carrier cells" elicited kidney injury in wild-type MRL-Fas(lpr) mice. Taken together, IL-12 elicits autoimmune injury by fostering the accumulation of IFN-gamma-secreting CD4, CD8, and CD4-CD8- B220+ T cells within the kidney, which, in turn, promote a cascade of events culminating in autoimmune kidney disease in MRL-Fas(lpr) mice.
Schwarting
A
A
Laboratory of Molecular Autoimmune Disease, Renal Division, and Center for Neurological Disease, Brigham and Women's Hospital, Boston, MA 02115, USA.
Tesch
G
G
Kinoshita
K
K
Maron
R
R
Weiner
H L
HL
Kelley
V R
VR
D000818:Animals; D002465:Cell Movement / Q000276:immunology; D005260:Female; D018014:Gene Transfer Techniques; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology*; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000209:etiology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
D019014:fas Receptor; D018664:Interleukin-12; D007371:Interferon-gamma