CP-690,550 is the first reported JAK3 inhibitor combining efficacy and good tolerability in a preclinical model of allotransplantation in nonhuman primates and thus has interesting potential for immunosuppression in humans.

Potent in vitro and in vivo immunomodulatory effects of the JAK3 inhibitor CP-690,550 likely contribute to its efficacy in the prevention of organ allograft rejection.

Addition of CP-690,550 to MMF significantly improved allograft survival. The observed side effects appear amenable to improvements upon alteration of dosing strategies. Efficacy of this combination regimen suggests that it could become the backbone of calcineurin inhibitor-free regimens.

Summary Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common γ chain. The rationally designed inhibitor of JAK3, CP‐690,550, prevents acute allograft rejection in rodents and in nonhuman primates. Here we investigated the ability of CP‐690,550, to prevent allograft vasculopathy in a rodent model of aorta transplantation. Aortas from AxC Irish (RT1a) or Lewis (RT1l) rats were heterotopically transplanted into the infra‐renal aorta of Lewis recipients and harvested at 28 or 56 days. Treated recipients received CP‐690,550 by osmotic pumps (mean drug exposure of 110 ± 38 ng/ml). Significant intimal hyperplasia was demonstrated in untreated allografts when compared with isografts at 28 days (2.08 ± 0.85% vs. 0.43 ± 0.2% luminal obliteration, respectively, P = 0.001) and 56 days (5.3 ± 2.4% vs. 0.38 ± 0.3%, P = 0.002). Treatment caused a 51% reduction in intimal hyperplasia at day 56. CP‐690,550‐treated animals also had a significant reduction of donor‐specific IgG production and of the gene expression for suppressor of cytokine signaling‐3 and with unchanged levels of expression of RANTES, IP‐10 and transforming growth factor‐β1. These results are the first to show that JAK3 blockade by CP‐690,550 effectively prevents allograft vasculopathy in this rat model of aorta transplantation.

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