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

TY - JOUR

T1 - Novel immunosuppression: R348, a JAK3- and Syk-inhibitor attenuates acute cardiac allograft rejection

AU - Deuse, Tobias

AU - Velotta, Jeffrey B

AU - Hoyt, Grant

AU - Govaert, Johannes A

AU - Taylor, Vanessa

AU - Masuda, Esteban

AU - Herlaar, Ellen

AU - Park, Gary

AU - Carroll, David

AU - Pelletier, Marc P

AU - Robbins, Robert C

AU - Schrepfer, Sonja

PY - 2008/3/27

Y1 - 2008/3/27

N2 - 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.

AB - 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.

KW - Animals

KW - Enzyme Inhibitors/therapeutic use

KW - Graft Enhancement, Immunologic/methods

KW - Graft Rejection/pathology

KW - Graft Survival/drug effects

KW - Heart Transplantation/immunology

KW - Immunosuppressive Agents/therapeutic use

KW - Intracellular Signaling Peptides and Proteins/antagonists & inhibitors

KW - Janus Kinase 3/antagonists & inhibitors

KW - Male

KW - Protein-Tyrosine Kinases/antagonists & inhibitors

KW - Rats

KW - Rats, Inbred BN

KW - Rats, Inbred Lew

KW - Sirolimus/therapeutic use

KW - Syk Kinase

U2 - 10.1097/TP.0b013e318166acc4

DO - 10.1097/TP.0b013e318166acc4

M3 - SCORING: Journal article

C2 - 18360272

VL - 85

SP - 885

EP - 892

JO - TRANSPLANTATION

JF - TRANSPLANTATION

SN - 0041-1337

IS - 6

ER -