title: Significant reduction of acute cardiac allograft rejection by selective janus kinase-1/3 inhibition using R507 and R545.
abstract: BACKGROUND
  Selective inhibition of lymphocyte activation through abrogation of signal 3-cytokine transduction emerges as a new strategy for immunosuppression. This is the first report on the novel Janus kinase (JAK)1/3 inhibitors R507 and R545 for prevention of acute allograft rejection.
  
  
  METHODS
  Pharmacokinetic and in vitro enzyme inhibition assays were performed to characterize the drugs. Heterotopic Brown Norway-Lewis heart transplantations were performed to study acute cardiac allograft rejection, graft survival, suppression of cellular host responsiveness, and antibody production. Therapeutic and subtherapeutic doses of R507 (60 and 15 mg/kg 2 times per day) and R545 (20 and 5 mg/kg 2 times per day) were compared with those of tacrolimus (Tac; 4 and 1 mg/kg once per day).
  
  
  RESULTS
  Plasma levels of R507 and R545 were sustained high for several hours. Cell-based enzyme assays showed selective inhibition of JAK1/3-dependent pathways with 20-fold or greater selectivity over JAK2 and Tyrosine kinase 2 kinases. After heart transplantation, both JAK1/3 inhibitors reduced early mononuclear graft infiltration, even significantly more potent than Tac. Intragraft interferon-γ release was significantly reduced by R507 and R545, and for interleukin-10 suppression, they were even significantly more potent than Tac. Both JAK1/3 inhibitors and Tac were similarly effective in reducing the host Th1 and Th2, but not Th17, responsiveness and similarly prevented donor-specific immunoglobulin M antibody production. Subtherapeutic and therapeutic R507 and R545 doses prolonged the mean graft survival and were similarly effective as 1 and 4 mg/kg Tac, respectively. In combination regimens, however, only R507 showed highly beneficial synergistic drug interactions with Tac.
  
  
  CONCLUSIONS
  Both R507 and R545 are potent novel immunosuppressants with favorable pharmacokinetics and high JAK1/3 selectivity, but only R507 synergistically interacts with Tac.
authors.affiliation: Transplant and Stem Cell Immunobiology Laboratory, University Heart Center Hamburg, Hamburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Deuse
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Hua
authors.forename: Vanessa
authors.initials: V
authors.lastname: Taylor
authors.forename: Mandy
authors.initials: M
authors.lastname: Stubbendorff
authors.forename: Muhammad
authors.initials: M
authors.lastname: Baluom
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Gary
authors.initials: G
authors.lastname: Park
authors.forename: Joachim
authors.initials: J
authors.lastname: Velden
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichenspurner
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.forename: Sonja
authors.initials: S
authors.lastname: Schrepfer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology*; D007075:Immunoglobulin M / Q000097:blood; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; C507936:Jak3 protein, rat; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D016753:Interleukin-10; D007371:Interferon-gamma; C507906:Jak1 protein, rat; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D016559:Tacrolimus