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The Journal of Immunology, 2003, 170: 3915-3925.
Copyright © 2003 by The American Association of Immunologists

IL-12 Deficiency in MRL-Faslpr Mice Delays Nephritis and Intrarenal IFN-{gamma} Expression, and Diminishes Systemic Pathology1

Eriya Kikawada, Deborah M. Lenda and Vicki R. Kelley2

Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women’s Hospital, Boston, MA 02115

Autoimmune disease in MRL-Faslpr 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-Faslpr mice deficient in the IFN-{gamma} receptor were spared from nephritis. Therefore, we hypothesized that eliminating IL-12 in MRL-Faslpr mice reduces IFN-{gamma}-secreting cells and thereby prevents systemic pathology. For this purpose, we constructed an IL-12p40-deficient MRL-Faslpr(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-Faslpr 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-Faslpr 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-Faslpr kidneys. Of note, survival was modestly extended in the IL-12-/- MRL-Faslpr mice. While lung and lacrimal and salivary gland pathology remained reduced in moribund IL-12-/- MRL-Faslpr 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.




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