IL-12 drives IFN-γ-dependent autoimmune kidney disease in MRL-Fas(lpr) mice

A. Schwarting, G. Tesch, K. Kinoshita, R. Maron, H. L. Weiner, V. Rubin Kelley

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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-γ, the purpose of this study was to determine whether local provision of IL-12 elicits IFN-γ-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 'carder 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-γ-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-γ 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-γ receptors. Furthermore, IFN-γ '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-y- 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.

Original languageEnglish
Pages (from-to)6884-6891
Number of pages8
JournalJournal of Immunology
Issue number12
Publication statusPublished - 28 Dec 1999
Externally publishedYes

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