Experimental transplantation: Novel immunosuppression using the JAK3-inhibitor R348

T. Deuse, E. Masuda, V. Taylor, G. Park, D. Carroll, H. Reichenspurner, J. Velotta, R. Robbins, S. Schrepfer

Research output: Contribution to journalArticlepeer-review


Background: Janus-kinase-(JAK)3 is crucial for signal transduction in immune cells. This is the first report on the novel JAK3 inhibitor R348 for prevention of acute and chronic rejection. Methods: Pharmacokinetic and in vitro enzyme inhibition assays were performed to characterize the drug. Heterotopic BNLew heart (n=108) and tracheal transplantations (n=48) were performed to study acute cardiac allograft rejection and the development of chronic obliterative airway disease (OAD), respectively. Immunosuppressive efficacy and drug toxicity of R348 (10-80mg/kg) was compared to tacrolimus (1-4mg/kg) and rapamycin (0.75-3mg/kg). Results: Plasma levels of R348's active metabolite R333 remained high for several hours, and in vitro enzyme assays showed selective inhibition of JAK3-dependent pathways. Acute rejection study: R348 40mg/kg was effective to preserve cardiac allograft function, significantly reduced early mononuclear graft infiltration, and decreased histologic rejection scores on day 5, similar to rapamycin 3mg/kg. R348 40mg/kg and rapamycin 3mg/kg were similarly effective to reduce the host cellular Th1/Th2 responsiveness and similarly suppressed intragraft IFN-gamma, MIP3-alpha, and IL-6 expression. Prolongation of allograft survival with R348 20-40mg/kg was similar to that of tacrolimus 2mg/kg or rapamycin 2mg/kg. R348 demonstrated highly beneficial synergistic interactions with tacrolimus. OAD study: R348 40mg/kg and rapamycin 3mg/kg similarly inhibited tracheal OAD development and inhibited donor-specific antibody production by day 28. However, only R348 preserved airway morphology and physiologic gene expression. R348 was subtherapeutic at 10mg/kg and toxic at 80mg/kg. Conclusions: R348 highly effectively diminishes acute cellular rejection and OAD development with favorable pharmakokinetics and biological activity and is suitable for combination regimens with tacrolimus.

Original languageEnglish (US)
Pages (from-to)45
Number of pages1
JournalTransplantationsmedizin: Organ der Deutschen Transplantationsgesellschaft
Issue numberSUPPL. 2
StatePublished - 2009
Externally publishedYes

ASJC Scopus subject areas

  • Transplantation


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