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 d etermine whether local provision of IL-12 elicits IFN-gamma-secreting T cel ls 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-sec reting 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 i ntrarenal and systemic IL-12, IL-12 fostered a marked, well-demarcated accu mulation of CD4, CD8, and double negative (CD4(-)CD8(-) B220(+))T cells adj acent to the implant site. We detected more IFN-gamma-producing T cells (CD 4 > 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 o f these cells were proliferating (60 -70 %). By comparison, an increase in systemic IL-12 resulted in a diffuse acceleration of pathology in the contr alateral (unimplanted) kidney, IFN-gamma was required for IL-12-incited ren al injury, because IL-12 "carrier cells" failed to elicit injury in MRL-Fas (lpr) kidneys genetically deficient in IFN-gamma receptors, Furthermore, IF N-gamma "carrier cells" elicited kidney injury in wild-type MRL-Fas(lpr) mi ce. Taken together, IL-12 elicits autoimmune injury by fostering the accumu lation of IFN-gamma-secreting CD4, CD8, and CD4(-)CD8(-) B220(+) T cells wi thin the kidney, which, in turn, promote a cascade of events culminating in autoimmune kidney disease in MRL-Fas(lpr) mice.