TWEAK/fn14 pathway blockade attenuates renal disease in autoantibody-induced nephritis (ICA 2012) - Mar 12, 2012 - Presentation time: 10.05.2012, 10:30-12:30; Fn14KO mice had significantly decreased levels of proteinuria as compared to Fn14 WT mice (day 7: 61+24 vs 220+42 mg/dl, p<0.01; day 14: 99+50 vs. 678+205 mg/dl, p=0.02; day 21: 101+49 vs 678+205 mg/dl, p=0.02); Moreover, crescent formation and tubular dilatation were significantly decreased in Fn14KO mice, as were MCP-1, RANTES, and IP-10 kidney mRNA expression levels
Preclinical-animal • Lupus
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8th International Congress on Autoimmunity, May 9-13 2012
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Background: TNF-superfamily members are instrumental in the pathogenesis of lupus nephritis. Previously, we found that TWEAK-mediated activation of its receptor, Fn14, stimulates the secretion of MCP-1, RANTES, IP-10 and KC by mesangial cells and podocytes. TWEAK also modulates renal cell survival and proliferation. Thus, we hypothesized that TWEAK blockade may be therapeutically beneficial in autoantibody-mediated nephritis.
Methods: Nephrotoxic serum nephritis (NTN), a model for lupus nephritis, was used to study the role of the TWEAK/Fn14 pathway in the pathogenesis of renal disease induced by pathogenic antibodies.
Results: We induced NTN by transfer of pre-formed nephritogenic rabbit antibodies into 129 Fn14 KO and WT mice. On days 7, 14, and 21 after antibody transfer, Fn14KO mice had significantly decreased levels of proteinuria as compared to Fn14 WT mice (day 7: 61+24 vs 220+42 mg/dl, p. To confirm the protective effect of TWEAK inhibition with a pharmacological approach, we induced nephrotoxic nephritis in 129 Fn14 WT mice and initiated treatment with an anti-TWEAK mAb or control Ig. Similar to results in Fn14KO mice, significant amelioration of proteinuria and improvement in renal histology was observed in mice receiving treatment with anti-TWEAK mAb. Anti-TWEAK mAb treatment did not appear to affect the systemic immune response, as no alteration in murine anti-rabbit IgG subclass antibody titers was evident.
Assigned speakers:
Dr. Chaim Putterman, Albert Einstein College of Medicine , Bronx , USA
Assigned in sessions:
10.05.2012, 10:30-12:30, Parallel Session, PS01, NOVEL THERAPIES IN SYSTEMIC LUPUS ERYTHEMATUS Supported by an unrestricted educational grant from GLAXO SMITHKLINE UK LTD, A
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