A novel JAK3 inhibitor, R348, attenuates chronic airway allograft rejection
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A novel JAK3 inhibitor, R348, attenuates chronic airway allograft rejection. / Velotta, Jeffrey B; Deuse, Tobias; Haddad, Munif; Masuda, Esteban; Park, Gary; Carroll, David; Taylor, Vanessa; Robbins, Robert C; Schrepfer, Sonja.
In: TRANSPLANTATION, Vol. 87, No. 5, 15.03.2009, p. 653-659.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A novel JAK3 inhibitor, R348, attenuates chronic airway allograft rejection
AU - Velotta, Jeffrey B
AU - Deuse, Tobias
AU - Haddad, Munif
AU - Masuda, Esteban
AU - Park, Gary
AU - Carroll, David
AU - Taylor, Vanessa
AU - Robbins, Robert C
AU - Schrepfer, Sonja
PY - 2009/3/15
Y1 - 2009/3/15
N2 - 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 (PCONCLUSIONS: R348 is an effective drug, and it is expected to be introduced into clinical transplant pharmacology soon.
AB - 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 (PCONCLUSIONS: R348 is an effective drug, and it is expected to be introduced into clinical transplant pharmacology soon.
KW - Animals
KW - Chronic Disease
KW - Enzyme Inhibitors/therapeutic use
KW - Graft Rejection/prevention & control
KW - Janus Kinase 3/antagonists & inhibitors
KW - Male
KW - Rats
KW - Rats, Inbred BN
KW - Rats, Inbred Lew
KW - Respiratory Mucosa/cytology
KW - Sirolimus/therapeutic use
KW - Transplantation, Homologous
U2 - 10.1097/TP.0b013e318196110f
DO - 10.1097/TP.0b013e318196110f
M3 - SCORING: Journal article
C2 - 19295308
VL - 87
SP - 653
EP - 659
JO - TRANSPLANTATION
JF - TRANSPLANTATION
SN - 0041-1337
IS - 5
ER -