Targeting Janus kinase 3 to attenuate the severity of acute graft-versus-host disease across the major histocompatibility barrier in mice

Abstract

To prevent the development of acute graft-versus-host disease (GVHD) in lethally irradiated C57BL/6 (H-2b) recipient mice transplanted with bone marrow–splenocyte grafts from major histocompatibility complex (MHC) disparate BALB/c mice (H-2d), recipient mice were treated with the rationally designed JAK3 inhibitor WHI-P131 [4-(4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (20 mg/kg, 3 times a day [tid]) daily from the day of bone marrow transplantation (BMT) until the end of the 85-day observation period. Total body irradiation (TBI)-conditioned, vehicle-treated control C57BL/6 mice (n = 38) receiving bone marrow–splenocyte grafts from BALB/c mice survived acute TBI toxicity, but they all developed histologically confirmed severe multi-organ GVHD and died after a median survival time of 37 days. WHI-P131 treatment (20 mg/kg intraperitoneally, tid) prolonged the median survival time of the BMT recipients to 56 days. The probability of survival at 2 months after BMT was 11% ± 5% for vehicle-treated control mice (n = 38) and 41% ± 9% for mice treated with WHI-P131 (n = 32) (P < .0001). Notably, the combination regimen WHI-P131 plus the standard anti-GVHD drug methotrexate (MTX) (10 mg/m2 per day) was more effective than WHI-P131 or MTX alone. More than half the C57BL/6 recipients receiving this most effective GVHD prophylaxis remained alive and healthy throughout the 85-day observation period, with a cumulative survival probability of 70% ± 10%. Taken together, these results indicate that targeting JAK3 in alloreactive donor lymphocytes with a chemical inhibitor such as WHI-P131 may attenuate the severity of GVHD after BMT.