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

Geraldine Rousvoal, Ming Sing Si, Macy Lau, Sally Zhang, Gerald J. Berry, Mona G. Flores, Paul S. Changelian, Bruce A. Reitz, Dominic C. Borie

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1014-1021
Number of pages8
JournalTransplant International
Volume19
Issue number12
DOIs
StatePublished - Dec 2006
Externally publishedYes

Keywords

  • Aorta transplantation
  • Chronic rejection
  • CP-690,550
  • Janus kinase 3

ASJC Scopus subject areas

  • Transplantation

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    Rousvoal, G., Si, M. S., Lau, M., Zhang, S., Berry, G. J., Flores, M. G., Changelian, P. S., Reitz, B. A., & Borie, D. C. (2006). Janus kinase 3 inhibition with CP-690,550 prevents allograft vasculopathy. Transplant International, 19(12), 1014-1021. https://doi.org/10.1111/j.1432-2277.2006.00387.x