Janus kinase 3 inhibition with CP-690,550 prevents allograft vasculopathy

Abstract

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.

Targeting the Janus kinases in rheumatoid arthritis: focus on tofacitinib

“…Number of T lymphocytes in the periphery was not altered, although trend toward reduction of CD8 + T cells and NK cells was observed [17,22]. Additional studies with rodent aorta transplantation model and nonhuman primate kidney transplantation model treated with tofacitinib also showed significantly enhanced graft survival [23,24].…”

“…Administration of tofacitinib at the time of disease onset significantly reduced inflammatory cell influx and joint damage including cartilage damage [27,28]. When tofacitinib was administered into an established murine CIA, arthritis and inflammation were rapidly ameliorated by the inhibition of the JAK1 and JAK3 signaling pathways and by the suppression of STAT1-dependent gene expression in the joint [23,29]. Furthermore, tofacitinib reduced acute response to lipopolysaccharide in vivo, a model known to be dependent on IFN-g and STAT1 [20].…”

Phase 1 Dose-Escalation Study of CP-690 550 in Stable Renal Allograft Recipients: Preliminary Findings of Safety, Tolerability, Effects on Lymphocyte Subsets and Pharmacokinetics

“…CP-690 550 treatment prolonged allograft survival in mouse heart transplant and cynomolgus monkey kidney allograft models (8)(9)(10)(11)(12)(13). Patients with psoriasis treated with CP-690 550 for 14 days had a dose-dependent improvement in the severity of their psoriatic lesions (14).…”

Potential of emerging immunosuppressive strategies to improve the posttransplant cardiovascular risk profile

“…40,41 More recently, investigators involved in the phase II multicenter randomized trial of the JAK inhibitor tasocitinib (CP-690,550) tested two doses of the drug (15 mg b.i.d. or 30 mg b.i.d.)…”