Prevention of chronic renal allograft rejection by AS2553627, a novel JAK inhibitor, in a rat transplantation model.

Abstract

BACKGROUND:

Janus kinase (JAK) inhibitors are thought to be promising candidates to aid renal transplantation. However, the effectiveness of JAK inhibitors against features of chronic rejection, including interstitial fibrosis/tubular atrophy (IF/TA) and glomerulosclerosis, has not been elucidated. Here, we investigated the effect of AS2553627, a novel JAK inhibitor, on the development of chronic rejection in rat renal transplantation.

METHODS:

Lewis (LEW) to Brown Norway (BN) rat renal transplantation was performed. Tacrolimus (TAC) at 0.1mg/kg was administered intramuscularly once a day for 10 consecutive days starting on the day of transplantation (days 0 to 9) to prevent initial acute rejection. After discontinuation of TAC treatment from days 10 to 28, AS2553627 (1 and 10mg/kg) was orally administered with TAC. At 13weeks after renal transplantation, grafts were harvested for histopathological and mRNA analysis. Creatinine and donor-specific antibodies were measured from plasma samples. Urinary protein and kidney injury markers were also evaluated.

RESULTS:

AS2553627 in combination with TAC exhibited low plasma creatinine and a marked decrease in urinary protein and kidney injury markers, such as tissue inhibitor of metalloproteinase-1 and kidney injury molecule-1. At 13weeks, histopathological analysis revealed that AS2553627 treatment inhibited glomerulosclerosis and IF/TA. In addition, upregulation of cell surface markers, fibrosis/epithelial-mesenchymal transition and inflammation-related genes were reduced by the combination of AS2553672 and TAC, particularly CD8 and IL-6 mRNAs, indicating that AS2553627 prevented cell infiltration and inflammation in renal allografts.

CONCLUSIONS:

These results indicate the therapeutic potential of JAK inhibitors in chronic rejection progression, and suggest that AS2553627 is a promising agent to improve long-term graft survival after renal transplantation.

• Authors: Koji Nakamura, Yuka Kawato, Yoko Kaneko, Kaori Hanaoka, Kaori Kubo, Tomonori Nakanishi, Masashi Maeda, Hidehiko Fukahori, Misato Ito, Takahisa Noto, Masamichi Inami, Jun Hirose, Tatsuaki Morokata
• Journal: Transplant immunology (Transpl Immunol) Vol. 46 Pg. 14-20 (02 2018) ISSN: 1878-5492 [Electronic] Netherlands
• PMID: 28988984 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• AS2553627
• Interleukin-6
• Piperidines
• Pyrroles
• Janus Kinases
• Tacrolimus

Topics

• Allografts (immunology)
• Animals
• Chronic Disease
• Disease Models, Animal
• Drug Therapy, Combination
• Glomerulosclerosis, Focal Segmental (immunology, prevention & control)
• Graft Rejection (immunology, prevention & control)
• Humans
• Interleukin-6 (genetics, metabolism)
• Janus Kinases (antagonists & inhibitors)
• Kidney Transplantation
• Piperidines (therapeutic use)
• Pyrroles (therapeutic use)
• Rats
• Rats, Inbred Lew
• Tacrolimus (therapeutic use)