Suppression of Alloreactivity and Allograft Rejection by SP600125, a Small Molecule Inhibitor of c-Jun N-terminal Kinase

c-Jun N-terminal kinase (JNK) is reported to play crucial roles in T-cell activation and differentiation, and SP600125 is a small molecule that inhibits JNK. The aim of this study was to examine immunosuppressive action of this compound.Rat heterotopic heart transplantation, popliteal lymph node (PLN) hyperplasia bioassay and lymphocyte proliferation assay.SP600125 treatment reduced histological rejection, and dose-dependently extended median survival time of cardiac allografts from 7 days (vehicle) up to 20 days (40 mg/kg/day). Alloantigen-induced PLN hyperplasia was also inhibited by SP600125 in a similar fashion. SP600125 suppressed mixed lymphocyte reaction and OX52-positive lymphocyte proliferation (IC50: 1.5-5.7 microM). Thus, SP600125 inhibits both T-lymphocyte expansion in vitro and T-cell-mediated alloimmune responses in vivo. In addition, SP600125 interacted with cyclosporine additively to prolong cardiac allograft survival.Our data provide the first evidence indicating the potential for JNK as a therapeutic target to inhibit the alloimmune response.