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Significant reduction of acute cardiac allograft rejection by selective janus kinase-1/3 inhibition using R507 and R545.
- Source :
-
Transplantation [Transplantation] 2012 Oct 15; Vol. 94 (7), pp. 695-702. - Publication Year :
- 2012
-
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.<br />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).<br />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.<br />Conclusions: Both R507 and R545 are potent novel immunosuppressants with favorable pharmacokinetics and high JAK1/3 selectivity, but only R507 synergistically interacts with Tac.
- Subjects :
- Animals
Cells, Cultured
Coculture Techniques
Drug Administration Schedule
Drug Synergism
Drug Therapy, Combination
Enzyme-Linked Immunosorbent Assay
Graft Rejection enzymology
Graft Rejection immunology
Graft Rejection pathology
Heart Transplantation adverse effects
Immunoglobulin M blood
Immunosuppressive Agents administration & dosage
Immunosuppressive Agents pharmacokinetics
Interferon-gamma metabolism
Interleukin-10 metabolism
Janus Kinase 1 metabolism
Janus Kinase 3 metabolism
Lymphocyte Activation drug effects
Lymphocyte Culture Test, Mixed
Male
Myocardium immunology
Myocardium pathology
Phosphorylation
Protein Kinase Inhibitors administration & dosage
Protein Kinase Inhibitors pharmacokinetics
Rats
Rats, Inbred BN
Rats, Inbred Lew
STAT3 Transcription Factor metabolism
T-Lymphocytes drug effects
T-Lymphocytes immunology
Tacrolimus pharmacology
Graft Rejection prevention & control
Graft Survival drug effects
Heart Transplantation immunology
Immunosuppressive Agents pharmacology
Janus Kinase 1 antagonists & inhibitors
Janus Kinase 3 antagonists & inhibitors
Myocardium enzymology
Protein Kinase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1534-6080
- Volume :
- 94
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Transplantation
- Publication Type :
- Academic Journal
- Accession number :
- 22971540
- Full Text :
- https://doi.org/10.1097/TP.0b013e3182660496