PROLONGATION OF CARDIAC ALLOGRAFT SURVIVAL BY ABROGATION OF MATRIX METALLOPROTEINASE-2.

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PROLONGATION OF CARDIAC ALLOGRAFT SURVIVAL BY ABROGATION OF MATRIX METALLOPROTEINASE-2.
Andres Jaramillo , Lacey G. Campbell , Wei Lu , Robert M. Senior and Shigeyoshi Itohara . St. Louis MO, Washington University, Department of Surgery ; St. Louis MO, Washington University, Department of Cell Biology & Physiology and Wako Japan, Brain Science Institute .

Purpose: The goal of this study was to determine whether matrix metalloproteinase (MMP)-2 and MMP-9 play a role in the pathogenesis of allograft rejection.
Methods: BALB/c cardiac allografts were transplanted into MMP-2-/- (C57BL/6), MMP-9-/- (129/SvEv) mice. Then, graft survival time was determined as well as the intra-graft levels of MMP-2 and MMP-9 mRNA and enzymatic activities. Additionally, proliferative alloresponses were determined in vitro in allograft recipients.
Results: MMP-9-/- and 129/SvEv mice rejected their allografts with comparable kinetics (15.2±2.6 and 11.5±5.0 days, respectively). In contrast, MMP-2-/- mice rejected their allografts at a longer time than C57BL/6 mice (13.1±3.2 and 7.0±0.6 days, respectively, P<0.01). Treatment of C57BL/6 recipients with an MMP inhibitor doxycycline, significantly prolonged allograft survival to 27.3±1.5 days (P<0.01). Allografts rejected by C57BL/6 mice showed severe cellular infiltration and fibrosis as well as high levels of MMP-2 and, to a lesser extent, MMP-9. Analysis of graft-infiltrating cells in rejected allografts revealed that >90% expressed MMP-2 and only <3% expressed MMP-9. Functioning allografts harvested at 7 days after transplantation from MMP-2-/- and doxycycline-treated C57BL/6 recipients revealed mild cellular infiltration and no fibrosis. Also, at 7 days after transplantation, MMP-2-/- mice showed a significantly lower proliferative alloresponse as compared to C57BL/6 mice. Interestingly, high levels of MMP-2 were detected in allografts rejected by MMP-2-/- mice indicating that allograft parenchymal cells also produce MMP-2 during the rejection process.
Conclusion: Both recipient- and donor-derived MMP-2 play an important role in the pathogenesis of allograft rejection.