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Invariant Natural Killer T Cells and TGF-β Attenuate Anti-GBM Glomerulonephritis

Laurent Mesnard^*,, Alexandre D.C. Keller^,, Marie-Laure Michel, Sophie Vandermeersch^*, Cédric Rafat^*,, Emmanuel Letavernier^*, Yves Tillet^||, Eric Rondeau^*, and Maria C. Leite-de-Moraes

^* INSERM, UMR S 702, Hôpital Tenon, Paris, France; AP-HP, Hôpital Tenon, Urgences Néphrologiques & Transplantation Rénale, France; Université Paris Descartes, Faculté de Médecine, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Paris, France; Universidade Federal de São Paulo (UNIFESP), Nephrology Division, Brazil; and ^|| INRA, UMR85, Unité de Physiologie de la Reproduction et des Comportements, Nouzilly, France; CNRS, Nouzilly, France; Université François Rabelais, Tours, France; Haras Nationaux, Nouzilly, France; IFR 135, Imagerie Fonctionnelle, France

Correspondence: Dr. Maria C. Leite-de-Moares, Unité Mixte de Recherche 8147, Centre National de la Recherche Scientifique, Faculté de Médecine René Descartes, Paris V, Hôpital Necker, 75743 Paris, Cedex 15, France. Phone: +33 (0) 1 44 49 53 92; Fax: +33 (0) 1 44 49 06 76; E-mail: leite.de.moraes{at}necker.fr; and Pr. Eric Rondeau, AP-HP, Hôpital Tenon, Urgences Néphrologiques & Transplantation Rénale, UPMC Univ Paris 06, UMR S 702, F-75020, Paris, France. Phone: +33 (0) 1 56 01 83 17; Fax: +33 (0) 1 56 01 79 68; Email: eric.rondeau{at}tnn.aphp.fr

Received for publication April 28, 2008. Accepted for publication January 28, 2009.

Invariant natural killer T (iNKT) cells represent a particular subset of T lymphocytes capable of producing several cytokines, which exert regulatory or effector functions, following stimulation of the T cell receptor. In this study, we investigated the influence of iNKT cells on the development of experimental anti-glomerular basement membrane glomerulonephritis (anti-GBM GN). After injection of anti-GBM serum, the number of kidney iNKT cells rapidly increased. iNKT cell-deficient mice (J18^–/–) injected with anti-GBM serum demonstrated worse renal function, increased proteinuria, and greater glomerular and tubular injury compared with similarly treated wild-type mice. We did not detect significant differences in Th1/Th2 polarization in renal tissue that might have explained the severity of disease in J18^–/– mice. Interestingly, expression of both TGF-β and TGF-β-induced (TGFBI) mRNA was higher in wild-type kidneys compared with J18^–/– kidneys, suggesting a possible protective role for TGF-β in anti-GBM GN. Administration of an anti-TGF-β neutralizing antibody significantly enhanced the severity of disease in wild-type, but not J18^–/–, mice. In conclusion, in experimental anti-GBM GN, iNKT cells attenuate disease severity and TGF-β has a renoprotective role.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673