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  • Title: Identification and characterization of two genes (MIP-1beta, VE-CADHERIN) implicated in acute rejection in human heart transplantation: use of murine models in tandem with cDNA arrays.
    Author: Roussoulières AL, Raisky O, Chalabreysse L, Dureau G, Cerutti C, Thieblemont C, Boissonnat P, Sebbag L, Obadia JF, Ninet J, Bastien O, Thivolet-Bejui F, McGregor JL.
    Journal: Circulation; 2005 May 24; 111(20):2636-44. PubMed ID: 15897346.
    Abstract:
    BACKGROUND: Genes and mechanisms of action involved in human acute rejection after allogeneic heart transplantation remain to be elucidated. The use of a murine allograft model in tandem with cDNA arrays and quantitative real-time polymerase chain reaction (Q-PCR) can greatly help in identifying key genes implicated in human heart acute rejection. METHODS AND RESULTS: Hearts from Balb/c mice were either not transplanted or transplanted heterotopically in the abdomen of Balb/c (isografts) and C57BL/6 (allografts) mice. Histological analysis showed acute rejection only in allografts. Total RNA was extracted from isografts (n=3), allografts (n=4), and not transplanted hearts (n=4); reverse transcribed; and labeled with P32. Each probe was hybridized to cDNA macroarrays. Eight genes were overexpressed and 7 genes were underexpressed in allografts compared with isografts. Macrophage inflammatory protein-1beta (MIP-1beta), an overexpressed gene, and VE-cadherin, an underexpressed gene, were validated by immunohistochemistry and Q-PCR in the murine models. Genes of interest, validated in the 3 murine groups, were then investigated in human heart tissues. Immunohistochemistry and Q-PCR performed on endomyocardial biopsies after heart transplantation showing no rejection (n=10) or grade IB (n=10) or IIIA (n=10) rejection, according to International Society of Heart and Lung Transplantation criteria, confirmed the results obtained from the murine model. CONCLUSIONS: We have demonstrated that the upregulation of MIP-1beta and downregulation of VE-cadherin may strongly participate in human acute heart rejection.
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