JAK3-inhibition: Suppressing immune cells while preserving epithelial cells

Aims: Janus-kinase-(JAK)3 is crucial for cytokine signal transduction and immune cell differentiation. This is the first detailed report on the novel JAK3 inhibitor R348 for prevention of acute and chronic rejection. Methods: Heterotopic BN-Lew 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). Plasma levels of R333, the active metabolite of R348, were quantified by high-power liquid chromatography and pharmacokinetics were determined. Results: 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. R348 40mg/kg and rapamycin 3mg/kg similarly inhibited tracheal OAD development and inhibited donor-specific antibody production by day 28. R348at 40 and 80mg/kg significantly preserved respiratory epithelium compared to R348at 10 and 20mg/kg (49±35%, 76±27% vs. 0±0, 3±7%; p=0.004), which was also confirmed by qRTPCR for MUC genes. Animal weight gain over 28 days was similar between all groups with the exception that recipients treated with 80mg/kg of R348 had significantly reduced weight gain compared to the rest (p<0.0001). Conclusions: R348 highly effectively diminishes acute cellular rejection. Even more importantly, R348 effectively prevented the development of obliterative airway disease (OAD) and significantly preserved respiratory epithelium with 40mg/kg being the optimal dose. Rapamycin significantly inhibited luminal obliteration with minimal effects on respiratory epithelium preservation. R348 occupies a favorable pharmacokinetic profile compared to rapamycin, is highly effective at precluding chronic airway allograft rejection, and suitable for combination regimens with tacrolimus.