Summs~The role of nitric oxide in the immune response to allogeneic tissue was 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 aUografted heart, but not in the nonrejecting isografted heart. The enzyme was demonstrated to be biologically active by the in vitro conversion of t-arginine to t-dtrulline and was immunohistochemically localized to the infiltrating inflammatory cells. Treatment with aminoguanidine, a preferential inhibitor of the inducible nitric oxide synthase isoform, prevented the increased nitric oxide production in the transplanted organ and significantly attenuated the pathogenesis of acute rejection. Aminoguanidine treatment prolonged graft survival, improved graft contractile function, and significantly reduced the histologic grade of rejection. These results suggest an important role for nitric oxide in mediating the immune response to allogeneic tissue. Inhibition of inducible nitric oxide synthase may provide a novel therapeutic modality in the management of acute transplant rejection and of other immune-mediated processes. cute rejection is mediated by humoral and cellular immune mechanisms, and is characterized by an intense inflammatory cell infiltrate and progressive destruction of the grafted organ. Despite many recent advances in the understanding of the immune system, the regulatory and effector mechanisms underlying the rejection process remain incompletely understood. Recent reports have demonstrated production of the free radical nitric oxide (NO) 1 during organ transplant rejection (1, 2). NO is synthesized from the amino acid t-arginine by a family of enzymes, the nitric oxide syn-

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ABSTRACTvon Willebrand disease Normandy (vWD Normandy) is a recently described phenotype in which a mutant von Willebrand factor (vWF) appears structurally and functionally normal except that it does not bind to blood coagulation factor VIII. This interaction is required for normal survival of factor VIII in the circulation; consequently, vWD Normandy can present as apparent hemophilia A but with autosomal recessive rather than X chromosome-linked inheritance. A vWF missense mutation, Thr28 -* Met, was identified in the propositus in or near the factor VIII binding site. The corresponding mutant recombinant vWF(T28M) formed normal multimers and had normal ristocetin cofactor activity.