Targeting Janus kinase 3 to attenuate the severity of acute graft-versus-host disease across the major histocompatibility barrier in mice.
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.
Cetkovic-Cvrlje
M
M
Experimental BMT Program, Parker Hughes Cancer Center, and the Department of Immunology, Parker Hughes Institute, St Paul, MN 55113, USA.
Roers
B A
BA
Waurzyniak
B
B
Liu
X P
XP
Uckun
F M
FM
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D017690:Cell Transplantation / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000276:immunology / Q000628:therapy*; D006183:H-2 Antigens / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D053616:Janus Kinase 3; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010835:Phytohemagglutinins / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use*; D011828:Radiation Chimera; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000201:enzymology; D014916:Whole-Body Irradiation
D004791:Enzyme Inhibitors; D006183:H-2 Antigens; D007166:Immunosuppressive Agents; D010835:Phytohemagglutinins; D011799:Quinazolines; C116180:WHI P131; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D008727:Methotrexate