Reduced intragraft mRNA expression of matrix metalloproteinases Mmp3, Mmp12, Mmp13 and Adam8, and diminished transplant arteriosclerosis in Ccr5-deficient mice.
Experimental and human organ transplant studies suggest an important role for chemokine (C-C-motif) receptor-5 (CCR5) in the development of acute and chronic allograft rejection. Because early transplant damage can predispose allografts to chronic dysfunction, we sought to identify potential pathophysiologic mechanisms leading to allograft damage by using wild-type and Ccr5-deficient mice as recipients of fully MHC-mismatched heart and carotid-artery allografts. Gene expression in rejecting heart allografts was analyzed 2 and 6 days after transplantation using Affymetrix GeneChips. Microarray analysis led to identification of four metalloproteinase genes [matrix metalloproteinase (Mmp)3, Mmp12, Mmp13 and a disintegrin and metalloprotease domain (Adam)8] with significantly diminished intragraft mRNA expression in Ccr5-deficient mice at day 6. Accordingly, allografts from Ccr5-deficient mice showed less tissue remodeling and hence better preservation of the myocardial architecture compared with allografts from wild-type recipients. Moreover, survival of cardiac allografts was significantly increased in Ccr5-deficient mice. Carotid artery allografts from Ccr5-deficient recipients showed better tissue preservation, and significant reduction of neointima formation and CD3+ T cell infiltration. Ccr5 appears to play an important role in transplant-associated arteriosclerosis that may involve metalloproteinase-mediated vessel wall remodeling. We conclude that early tissue remodeling may be a critical feature in the predisposition of allografts to the development of chronic dysfunction.
Luckow
Bruno
B
Klinikum der Universität München, Medizinische Poliklinik--Innenstadt, München, Germany. bruno.luckow@med.uni-muenchen.de
Joergensen
Joanne
J
Chilla
Silvia
S
Li
Jian-Ping
JP
Henger
Anna
A
Kiss
Eva
E
Wieczorek
Grazyna
G
Roth
Lukas
L
Hartmann
Nicole
N
Hoffmann
Reinhard
R
Kretzler
Matthias
M
Nelson
Peter J
PJ
Pérez de Lema
Guillermo
G
Maier
Holger
H
Wurst
Wolfgang
W
Balling
Rudi
R
Pfeffer
Klaus
K
Gröne
Hermann-Josef
HJ
Schlöndorff
Detlef
D
Zerwes
Hans-Günter
HG
D051722:ADAM Proteins; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D001161:Arteriosclerosis / Q000517:prevention & control*; D002339:Carotid Arteries / Q000637:transplantation; D017364:Collagenases / Q000235:genetics*; D016572:Cyclosporine / Q000494:pharmacology; D016027:Heart Transplantation / Q000009:adverse effects*; D053508:Matrix Metalloproteinase 12; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008666:Metalloendopeptidases / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis*; D019713:Receptors, CCR5 / Q000502:physiology*; D014184:Transplantation, Homologous
D015703:Antigens, CD; D008565:Membrane Proteins; D012333:RNA, Messenger; D019713:Receptors, CCR5; D016572:Cyclosporine; D051722:ADAM Proteins; C489402:Adam8 protein, mouse; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases; C507081:Mmp13 protein, mouse; D019278:Matrix Metalloproteinase 3; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12