NOS2 MEDIATES OPPOSING EFFECTS IN MODELS OF ACUTE AND CHRONIC CARDIACREJECTION - INSIGHTS FROM NOS2-KNOCKOUT MICE

To compare regulatory effects of NOS2 in acute and chronic cardiac all ograft rejection, we used NOS2 knockout mice as recipients in a cardia c transplant model To study acute and chronic rejection separately but within the same genetic strain combination, we compared allografts pl aced into recipients without or with immunosuppression (anti-CD4/8 for 28 days). NOS2 mRNA and protein expression were compared using P-32-R T-PCR and immunohistochemistry, In our acute rejection model, NOS2 was predominately localized to graft-infiltrating immune cells. At day 7, grafts in NOS2-deficient recipients (n = 7) showed reduced inflammato ry infiltrates and myocyte damage resulting in significantly lo pc er rejection scores (1.6 +/- 0.4) compared to wild-type controls (n = 18; 2.8 +/- 0.2, P = 0.02). In contrast, in our chronic rejection model, additional NOS2 expression was localized to graft-parenchymal cells. A t day 55, grafts in NOS2-deficient recipients (n = 12) showed more par enchymal infiltration and parenchymal destruction (rejection score 3.8 +/- 0.1) than wild-type controls (n = 15; 1.6 +/- 0.2, P < 0.0001). T his was associated with a significant decrease in ventricular contract ility (palpation score 0.3 +/- 0.1 compared to 2.3 +/- 0.3 in wild-typ e, P < 0.0001). Hence, NOS2 promotes acute but prevents chronic reject ion, These opposing effects during acute and chronic cardiac allograft rejection are dependent on the temporal and spatial expression patter n of NOS2 during both forms of rejection.