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Enhanced Allograft Survival and Modulation of T‐Cell Alloreactivity Induced by Inhibition of MMP/ADAM Enzymatic Activity
Author(s) -
Eaton V. L.,
Lerret N. M.,
VelásquezLopera M. M.,
John R.,
Caicedo M.,
DeCresce R. P.,
Jaramillo A.
Publication year - 2008
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2007.02097.x
Subject(s) - matrix metalloproteinase , medicine , pathogenesis , transplantation , immunology , chemokine , cytokine , disintegrin , ex vivo , in vitro , cd8 , inflammation , metalloproteinase , immune system , biology , biochemistry
Recent studies have shown significantly increased expression of matrix metalloproteinases (MMP) and disintegrin‐type metalloproteinases (ADAM) during allograft rejection. In this regard, our previous studies have demonstrated contrasting roles for MMP‐2 and MMP‐9 during allograft rejection: MMP‐2‐deficiency enhanced allograft survival while MMP‐9‐deficiency decreased allograft survival. The aim of this study was to determine the effect of broad‐spectrum MMP/ADAM inhibition on the pathogenesis of allograft rejection. Toward this, heterotopic BALB/c cardiac allografts were transplanted into C57BL/6 recipients treated with MMP/ADAM inhibitors, GM6001 or doxycycline. Systemic MMP/ADAM inhibition significantly enhanced allograft survival. Functioning allografts recovered from MMP/ADAM inhibitor‐treated recipients showed lower cellular infiltration and tissue remodeling than rejected allografts recovered from control recipients. In addition, decreased chemotaxis of CD4+ and CD8+ T cells, B cells and macrophages was observed in vitro in the presence of MMP/ADAM inhibitors. Enhanced T‐cell alloreactivity was also observed ex vivo in MMP/ADAM inhibitor‐treated recipients and in vitro in the presence of MMP/ADAM inhibitors. These observations were associated with enhanced cytokine, chemokine and growth factor production. These results indicate that MMPs and ADAMs play a critical role in the pathogenesis of allograft rejection and may represent novel therapeutic targets for the treatment and/or prevention of this disease.