MODULATION OF IN-VIVO ALLOREACTIVITY BY INHIBITION OF INDUCIBLE NITRIC-OXIDE SYNTHASE

The role of nitric oxide in the immune response to allogeneic tissue w as explored in an in vivo cardiac transplant model in the rat. Nitric oxide production during organ rejection was demonstrated by elevations in systemic serum nitrite/nitrate levels and by electron paramagnetic resonance spectroscopy. Messenger RNA for the inducible nitric oxide synthase enzyme was detected in the rejecting allografted heart, but n ot in the nonrejecting isografted heart. The enzyme was demonstrated t o be biologically active by the in vitro conversion of L-arginine to L -citrulline and was immunohistochemically localized to the infiltratin g inflammatory cells. Treatment with aminoguanidine, a preferential in hibitor of the inducible nitric oxide synthase isoform, prevented the increased nitric oxide production in the transplanted organ and signif icantly attenuated the pathogenesis of acute rejection. Aminoguanidine treatment prolonged graft survival, improved graft contractile functi on, and significantly reduced the histologic grade of rejection. These results suggest an important role for nitric oxide in mediating the i mmune response to allogeneic tissue. Inhibition of inducible nitric ox ide synthase may provide a novel therapeutic modality in the managemen t of acute transplant rejection and of other immune-mediated processes .