Replacement of mycophenolate mofetil with a JAK inhibitor, AS2553627, in combination with low-dose tacrolimus, for renal allograft rejection in non-human primates.
Int Immunopharmacol
; 64: 201-207, 2018 Nov.
Article
in En
| MEDLINE
| ID: mdl-30195818
ABSTRACT
In renal transplant patients, using mycophenolate mofetil (MMF) with calcineurin inhibitors (CNIs; cyclosporine and tacrolimus [TAC]) has led to a significant improvement in graft survival. However, reducing or withholding MMF due to its gastrointestinal adverse events increases rejection risk. CNI-sparing strategies are important to avoid CNI-related nephrotoxicity in clinical settings. Here, we investigated AS2553627, a JAK inhibitor replacing MMF in combination with a sub-therapeutic dose of TAC to treat allograft rejection in a monkey model. AS2553627 inhibited proliferation of IL-2 stimulated T cells with little species difference between monkeys and humans. In MMF monotherapy, oral administration of 20 or 40â¯mg/kg/day prolonged graft survival with median survival times (MSTs) of 16.5â¯days and 33â¯days, respectively, whereas untreated animals showed MST of 6â¯days. In MMF/TAC (1â¯mg/kg/day, p.o.) combination therapy, pharmacokinetic analysis indicated that MMF 20â¯mg/kg/day achieved the clinical target AUC0-24h and prolonged renal allograft survival, with MST of 24â¯days. Oral administration of AS2553627 0.24â¯mg/kg/day in combination with TAC significantly prolonged renal allograft survival to MST of >90â¯days with low plasma creatinine levels. Histopathological analysis revealed that acute T cell-mediated rejection events such as vasculitis and interstitial mononuclear cell infiltration were significantly inhibited in AS2553627/TAC-treated allografts compared with MMF/TAC-treated allografts. All AS2553627/TAC-treated monkeys surviving >90â¯days exhibited less interstitial fibrosis/tubular atrophy than monkeys in the MMF/TAC group. These results suggest that AS2553627 replacing MMF is an attractive CNI-sparing strategy to prevent renal allograft rejection.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Piperidines
/
Pyrroles
/
Kidney Transplantation
/
Tacrolimus
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Graft Rejection
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Immunosuppressive Agents
/
Mycophenolic Acid
Limits:
Animals
Language:
En
Journal:
Int Immunopharmacol
Journal subject:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Year:
2018
Document type:
Article