Implication of matrix metalloproteinase 7 and the noncanonical wingless-type signaling pathway in a model of kidney allograft tolerance induced by the administration of anti-donor class II antibodies.
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.
Jovanovic
Vojislav
V
INSERM U643, Institut de Transplantation et de Recherche en Transplantation, Centre Hospitalier Universitaire du Nantes, 30 Boulevard Jean Monnet, Nantes, France.
Dugast
Anne-Sophie
AS
Heslan
Jean-Marie
JM
Ashton-Chess
Joanna
J
Giral
Magali
M
Degauque
Nicolas
N
Moreau
Anne
A
Pallier
Annaick
A
Chiffoleau
Elise
E
Lair
David
D
Usal
Claire
C
Smit
Helga
H
Vanhove
Bernard
B
Soulillou
Jean-Paul
JP
Brouard
Sophie
S
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D015870:Gene Expression; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000187:drug effects* / Q000276:immunology; D007108:Immune Tolerance; D007668:Kidney / Q000187:drug effects / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000502:physiology*; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction; D014019:Tissue Donors; D051153:Wnt Proteins / Q000235:genetics / Q000502:physiology*
D000906:Antibodies; D000949:Histocompatibility Antigens Class II; D051153:Wnt Proteins; D020783:Matrix Metalloproteinase 7