PT  - JOURNAL ARTICLE
AU  - Kitching, A. Richard
AU  - Turner, Amanda L.
AU  - Semple, Timothy
AU  - Li, Ming
AU  - Edgtton, Kristy L.
AU  - Wilson, Gabrielle R.
AU  - Timoshanko, Jennifer R.
AU  - Hudson, Billy G.
AU  - Holdsworth, Stephen R.
TI  - Experimental Autoimmune Anti–Glomerular Basement Membrane Glomerulonephritis: A Protective Role for IFN-γ
AID  - 10.1097/01.ASN.0000128968.27705.5E
DP  - 2004 Jul 01
TA  - Journal of the American Society of Nephrology
PG  - 1764--1774
VI  - 15
IP  - 7
4099  - http://jasn.asnjournals.org/content/15/7/1764.short
4100  - http://jasn.asnjournals.org/content/15/7/1764.full
SO  - J. Am. Soc. Nephrol.2004 Jul 01; 15
AB  - ABSTRACT. IL-12 and IFN-γ play key roles in murine lupus and planted antigen models of glomerulonephritis. However, their roles in renal organ–specific autoimmunity are unknown. To establish the roles of endogenous IFN-γ and IL-12 in experimental autoimmune anti–glomerular basement membrane (GBM) glomerulonephritis (EAG), EAG was induced in normal C57BL/6 mice (WT), IL-12p40–deficient (IL-12p40−/−) mice, and IFN-γ–deficient (IFN-γ−/−) mice by immunization with α3-α5(IV)NC1 heterodimers. At 13 wk, WT mice developed EAG with linear mouse anti-GBM antibody deposition, histologic injury, proteinuria, and mild tubulointerstitial disease. Compared with WT mice, IL-12p40−/− mice had decreased histologic injury and trends to decreased leukocyte infiltrates. In contrast, 40% (4 of 10) of IFN-γ−/− mice developed significant crescent formation and focal or diffuse interstitial infiltrates (WT, 0 of 8). Compared with WT and/or IL-12p40−/− mice, IFN-γ−/− mice developed increased injury: histologic injury, total glomerular cell numbers, leukocytes in glomeruli, and renal expression of P-selectin and intercellular adhesion molecule 1. All groups developed similar serum anti–α3-α5(IV)NC1 antibodies and glomerular Ig deposition, but IFN-γ−/− mice had decreased anti–α3-α5(IV)NC1 IgG2a. Therefore, IFN-γ−/− mice developed increased cellular reactants despite a potentially less damaging antibody response. Dermal delayed-type hypersensitivity was increased in α3-α5(IV)NC1 immunized IFN-γ−/− mice and was suppressed by recombinant murine IFN-γ. CD4+ cells from draining nodes of immunized IFN-γ−/− mice showed increased proportions of proliferating CD4+ cells but similar numbers of apoptotic cells. These studies demonstrate that in renal organ–specific autoimmunity, IL-12 is pathogenetic but IFN-γ is protective. They lend weight to the hypothesis that depending on the context/severity of the nephritogenic immune response IFN-γ has different effects.