Novel immunosuppression: R348, a JAK3- and Syk-inhibitor attenuates acute cardiac allograft rejection

Tobias Deuse, Jeffrey B. Velotta, Grant Hoyt, Johannes A. Govaert, Vanessa Taylor, Esteban Masuda, Ellen Herlaar, Gary Park, David Carroll, Marc P. Pelletier, Robert C. Robbins, Sonja Schrepfer

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

BACKGROUND. Janus kinase (JAK)3 is crucial for signal transduction downstream of various cytokine receptors in immune cells. This is the first report on the novel JAK3 inhibitor R348. METHODS. (1) Detailed pharmacokinetic data were obtained in rats; (2) multiple in vitro enzyme inhibition assays were performed to characterize the drug; (3) prevention of acute rejection was investigated in animals treated with different doses of R348 or rapamycin for 5 days; and (4) cardiac allograft survival after a 10-day treatment period was studied for various regimens of R348, tacrolimus, or rapamycin; combination indices were calculated to evaluate drug interactions. RESULTS. (1) Plasma levels of R348's active metabolite R333 sustained high for 8 hr or more, depending on the dose. (2) In vitro enzyme assays showed potent inhibition of JAK3- and Syk-dependent pathways. (3) R348 40 mg/kg preserved graft function, significantly reduced graft infiltration, and decreased histologic ISHLT rejection scores on postoperative day 5. Results were similar to those of rapamycin 3 mg/kg. Likewise, both drugs significantly reduced the cellular Th1 and Th2 immune responses, as determined by enzyme-linked immunosorbent assays. Intragraft inflammatory cytokine upregulation was similarly suppressed by R348 and rapamycin. R348 10 mg/kg was subtherapeutic. (4) Allograft survival was similar for R348 20 and 40 mg/kg, which was comparable with therapeutically dosed tacrolimus or rapamycin. In combination regimens, R348 demonstrated highly beneficial synergistic interactions with tacrolimus. CONCLUSIONS. R348 is a promising novel JAK3/Syk-inhibitor with favorable pharmacokinetics and biological activity. It effectively diminishes acute cardiac allograft rejection and is suitable for combination regimens with tacrolimus.

Original languageEnglish (US)
Pages (from-to)885-892
Number of pages8
JournalTransplantation
Volume85
Issue number6
DOIs
StatePublished - Mar 2008
Externally publishedYes

Keywords

  • Heart allograft rejection
  • JAK-inhibitor
  • Novel immunosuppression

ASJC Scopus subject areas

  • Transplantation

Fingerprint

Dive into the research topics of 'Novel immunosuppression: R348, a JAK3- and Syk-inhibitor attenuates acute cardiac allograft rejection'. Together they form a unique fingerprint.

Cite this