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DIFFERENT ROLES FOR MATRIX METALLOPROTEINASE-2 AND -9 IN THE PATHOGENESIS OF CARDIAC ALLOGRAFT REJECTION.
Andres Jaramillo, Lacey G. Campbell, J. Michael Shipley, Robert M. Senior and Shigeyoshi Itohara. St. Louis MO, USA, Washington University, Surgery; St. Louis MO, USA, Washington University, Medicine and Wako Japan, RIKEN Brain Science Institute.

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Purpose: Increased expression of several matrix metalloproteinases (MMP) has been shown during cardiac and renal allograft rejection. This study was designed to define the roles of MMP-2 and MMP-9 in the pathogenesis of cardiac allograft rejection.
Methods: BALB/c cardiac allografts were transplanted into MMP-2-deficient (-/-), MMP-9-/-, and wild-type mice treated with MMP inhibitors: doxycycline and GM6001.
Results: Systemic inhibition of MMP activity with doxycycline or GM6001 significantly prolonged allograft survival time (p < 0.01). Similarly, MMP-2-deficiency significantly prolonged allograft survival time (p < 0.01). Functioning allografts harvested from MMP-2-/- mice showed significantly lower cellular infiltration and collagen deposition than rejected allografts harvested from MMP-2+/+ mice at the same time. In contrast, MMP-9-deficiency significantly decreased allograft survival time (p < 0.01). Functioning allografts harvested from MMP-9+/+ mice showed significantly lower cellular infiltration and collagen deposition than rejected allografts harvested from MMP-9-/- mice at the same time. Interestingly, MMP-2-/- recipients showed significantly decreased T cell alloreactivity mediated by a defect in dendritic cell stimulatory and T cell responsive capacities. In contrast, MMP-9-/- recipients showed significantly increased T cell alloreactivity mediated by increased dendritic cell stimulatory and T cell responsive capacities.
Conclusion: MMP2 and MMP-9 play significantly different roles in the processes of T cell activation and infiltration during cardiac allograft rejection.