A novel JAK3 inhibitor, R348, attenuates chronic airway allograft rejection.
BACKGROUND
This study aimed at investigating the role of a novel JAK3 inhibitor, R348, in the prevention of chronic airway allograft rejection.


METHODS
The heterotopic rat trachea transplant model was used. Recipients were treated daily with R348 (10, 20, 40, 80 mg/kg) or rapamycin (0.75 or 3 mg/kg). Blood levels of R348 and of its active metabolite R333 were measured. Grafts were harvested after 28 days to analyze epithelial morphology, mononuclear infiltration, and luminal obliteration. Plasma levels of circulating donor strain-reactive IgG antibodies were quantified.


RESULTS
R348 was well tolerated at up to 40 mg/kg, but was toxic at 80 mg/kg. Blood levels of R333 at 2 and 24 hr were consistently 10 to 15 times higher than those of R348. Airway luminal obliteration after 28 days was significantly inhibited by R348 at 40 mg/kg (20.6%+/-13.2%, P<0.05) and 80 mg/kg (15.7%+/-7.6%, P<0.05) and by rapamycin at 3 mg/kg (11.6%+/-6.7% P<0.001) versus untreated controls (100%). R348 is more than or equal to 40 mg/kg but neither dose of rapamycin preserved the physiologic epithelial coverage with its prominent goblet cells population (8.8+/-1.5 goblet cells/microm circumference in syngeneic grafts and 8.0+/-0.9 and 4.3+/-1.2 with R348 80 mg/kg and 40 mg/kg, respectively). Peritracheal graft mononuclear infiltration was most effectively suppressed by R348 is more than or equal to 40 mg/kg (P<0.05) and rapamycin 3 mg/kg (P<0.01). Donor strain-reactive IgG antibodies were significantly decreased by R348 is more than or equal to 40 mg/kg (P</=0.05) and rapamycin 3 mg/kg (P<0.001). Animals treated with R348 is more than or equal to 40 mg/kg showed elevated alanine transferase (P<0.05), whereas hypercholesterolemia was only found in animals receiving rapamycin 3 mg/kg (P<0.05).


CONCLUSIONS
R348 is an effective drug, and it is expected to be introduced into clinical transplant pharmacology soon.
Velotta
Jeffrey B
JB
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Deuse
Tobias
T
Haddad
Munif
M
Masuda
Esteban
E
Park
Gary
G
Carroll
David
D
Taylor
Vanessa
V
Robbins
Robert C
RC
Schrepfer
Sonja
S
D000818:Animals; D002908:Chronic Disease; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006084:Graft Rejection / Q000517:prevention & control*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects; D020123:Sirolimus / Q000627:therapeutic use; D014184:Transplantation, Homologous
D004791:Enzyme Inhibitors; C507936:Jak3 protein, rat; D053616:Janus Kinase 3; D020123:Sirolimus