SELECTIVE INHIBITION OF JANUS TYROSINE KINASE (JAK3) INDUCES APOPTOSIS OF T CELLS AND TRANSPLANTATION TOLERANCE:

P924 Aims: Since Janus kinase (Jak)3 activated by common γ-chain cytokines (IL2, IL4, IL7, IL9, IL13, IL15 and IL21) is expressed exclusively in lymphoid tissues it provides a unique target for immunosuppression. Our previous results showed that novel Jak3 inhibitor, NC1153, inhibits allograft rejection and is synergistic with cyclosporine. Present study examined whether extended therapy with NC1153 induces transplantation tolerance Methods/Resuls: Addition of NC1153 to PHA-activated human T cells induced apoptosis (60%), as measured by TUNUL assay. Untreated ACI (RT1Aa) recipients acutely rejected Lewis (LEW; RT1l) kidney allografts at a mean survival time (MST) of 8.8±0.5 days. A 14-day oral therapy with 40-240 mg/kg NC1153 produced dose-dependent effects with 240 mg/kg dose producing a mean survival time of 50.6 ± 14.3 days. However, when a 14-day course of 160 mg/kg was combined with subsequent thrice-weekly continuous drug administration up to 90 days, 75% of recipiects displayed graft survivals beyond 200 days. Induction of tolerance was confirmed by acceptance of LEW donor- (>100 days; n=3) but not third-party BUF (7.0±1.0 days; n=3) heart allografts by long-term surviving recipients. In order to examine the mechanism, irradiated (400 rads) ACI recipients of LEW heart allografts were adoptively transferred with 30x106 purified T cells or 1 ml serum from tolerant recipients. Recipients transferred with tolerant T cells displayed significantly delayed rejection of LEW heart allografts (40.0±15.0 days; n=6 vs 15±1.0 days; n=5 in irradiated controls) with 2 hearts beating well for >100 days, but rejected third-party heart allografts (12±1.0 days; n=2). These results document that therapy with NC1153 alone induces transplantation tolerance to kidney allografts. Structure your abstract in aims, methods, results and conclusions. The text should be in justified alignment. Please make sure that the body of your abstract does not exceed 3100 characters. Abstracts will be reproduced exactly as submitted and not be edited in any way. You may include any symbols or tables necessary in the body of your abstract, however, you do so at your own risk. Every effort will be made to maintain the formatting of the submitted abstract. Abstracts must be written and presented in English. Linguistic accuracy is the responsibility of the authors. Conclusions: A new and selective Jak3 inhibitor, NC1153, induces transplantation tolerance to organ allografts.