Treatment of post-bone marrow transplant acute graft-versus-host disease with a rationally designed JAK3 inhibitor.
Here we show that the Janus kinase 3 (JAK3) inhibitor 4-(3'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (JANEX-3) exhibits potent anti-GVHD activity and consequently improves the post-BMT survival outcome of C57BL/6 (H-2b) recipient mice transplanted with allogeneic bone marrow/splenocyte (BM/S) grafts from MHC disparate BALB/c mice (H-2d). One hundred percent of the vehicle-treated allograft recipients developed severe GVHD and died with a median survival of 41 days. Treatment of recipient mice with JANEX-3 (30 mg/kg/day, 3 x/day) after the onset of rapidly progressive severe GVHD in the 3rd week after BMT significantly improved the survival of BMT recipients with GVHD and prolonged the median survival time to 78 days (P < 0.0001, log-rank test). The probability of survival at two and three months post-BMT was 6 +/- 6% and 0 +/- 0% for vehicle-treated control mice and 100 +/- 0% and 38 +/- 17% for mice treated with JANEX-3. These results prompted the hypothesis that JAK3 plays a pivotal role in the pathophysiology of GVHD. To test this hypothesis, we examined if mice transplanted with allogeneic BM/S grafts from Jak3 knockout mice Jak3-/- develop GVHD. The allografts from (Jak3-/-) C57BL/6 (H-2b) mice rescued MHC-disparate recipient BALB/c mice (H-2d) of the lethal toxicity of TBI without causing fatal GVHD. Taken together, these observations establish JAK3 as a key mediator of severe GVHD after allogeneic BMT in the context of a major-HLA disparity.
Cetkovic-Cvrlje
Marina
M
Experimental BMT Program, Parker Hugher Cancer Center, St. Paul, MN 55113, USA.
Roers
Bertram A
BA
Schonhoff
Dawn
D
Waurzyniak
Barbara
B
Liu
Xing-Ping
XP
Uckun
Fatih M
FM
D000208:Acute Disease; D000818:Animals; D001835:Body Weight; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000401:mortality; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000209:etiology* / Q000401:mortality; D006648:Histocompatibility; D053616:Janus Kinase 3; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D016019:Survival Analysis; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000276:immunology / Q000401:mortality
D004791:Enzyme Inhibitors; D011799:Quinazolines; C118361:WHI P180; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3