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* Institut National de la Santé et de la Recherche Médicale U643, Institut de Transplantation et de Recherche en Transplantation,
Centre Hospitalier Universitaire du Nantes, and
Université de Nantes, Faculté de Médecine, Nantes, France
In rats, tolerance to MHC-incompatible renal allografts can be induced by the administration of anti-donor class II Abs on the day of transplantation. In this study we explored the mechanisms involved in the maintenance phase of this tolerance by analyzing intragraft gene expression profiles by microarray in long-term accepted kidneys. Comparison of the gene expression patterns of tolerated to syngeneic kidneys revealed 5,954 differentially expressed genes (p < 0.05). Further analysis of this gene set revealed a key role for the wingless-type (WNT) signaling pathway, one of the pivotal pathways involved in cell regulation that has not yet been implicated in transplantation. Several genes within this pathway were significantly up-regulated in the tolerated grafts, particularly matrix metalloproteinase 7 (MMP7; fold change > 40). Analysis of several other pathway-related molecules indicated that MMP7 overexpression was the result of the noncanonical WNT signaling pathway. MMP7 expression was restricted to vascular smooth muscle cells and was specific to anti-class II Ab-induced tolerance, as it was undetectable in other models of renal and heart transplant tolerance and chronic rejection induced across the same strain combination. These results suggest a novel role for noncanonical WNT signaling in maintaining kidney transplant tolerance in this model, with MMP7 being a key target. Determining the mechanisms whereby MMP7 contributes to transplant tolerance may help in the development of new strategies to improve long-term graft outcome.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by a grant from the "Foundation Progreffe" (Nantes, France).
2 J.-P.S. and S.B. contributed equally to this study as senior authors.
3 Address correspondence and reprint requests to Dr. Sophie Brouard, Institut National de la Santé et de la Recherche Médicale U643, 30 Boulevard Jean Monnet, 44093 Nantes Cedex 01 France. E-mail address: Sophie.Brouard{at}univ-nantes.fr
4 Abbreviations used in this paper: WNT, wingless-type; Axin, axis inhibitor; Dkk3, dickkopf homologue 3; DST, donor-specific blood transfusion; FC, fold change; HPRT, hypoxanthine phosphoribosyltransferase; LEW, Lewis (rat); MMP7, matrix metalloproteinase 7; NFATc1, NFAT cytoplasmic, calcineurin-dependent 1; PKC, protein kinase C; PLC, phospholipase C; TCF7, transcription factor 7; TGF, transforming growth factor.
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