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Experimental Autoimmune Anti–Glomerular Basement Membrane Glomerulonephritis: A Protective Role for IFN-

A. Richard Kitching^*, Amanda L. Turner^*, Timothy Semple^*, Ming Li^*, Kristy L. Edgtton^*, Gabrielle R. Wilson^*, Jennifer R. Timoshanko^*, Billy G. Hudson and Stephen R. Holdsworth^*

*Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia; and Departments of Biochemistry and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee

Correspondence to Dr. A. Richard Kitching, Monash University Department of Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. Phone: 61-3-9594-5520; Fax: 61-3-9594-6495; E-mail: richard.kitching{at}med.monash.edu.au

ABSTRACT. IL-12 and IFN- 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- 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-–deficient (IFN-–/–) mice by immunization with 3-5(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-–/– mice developed significant crescent formation and focal or diffuse interstitial infiltrates (WT, 0 of 8). Compared with WT and/or IL-12p40–/– mice, IFN-–/– 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–3-5(IV)NC1 antibodies and glomerular Ig deposition, but IFN-–/– mice had decreased anti–3-5(IV)NC1 IgG2a. Therefore, IFN-–/– mice developed increased cellular reactants despite a potentially less damaging antibody response. Dermal delayed-type hypersensitivity was increased in 3-5(IV)NC1 immunized IFN-–/– mice and was suppressed by recombinant murine IFN-. CD4+ cells from draining nodes of immunized IFN-–/– 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- is protective. They lend weight to the hypothesis that depending on the context/severity of the nephritogenic immune response IFN- has different effects.

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