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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.
AuthorsM Cetkovic-Cvrlje, B A Roers, B Waurzyniak, X P Liu, F M Uckun
JournalBlood (Blood) Vol. 98 Issue 5 Pg. 1607-13 (Sep 01 2001) ISSN: 0006-4971 [Print] United States
PMID11520814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • H-2 Antigens
  • Immunosuppressive Agents
  • Phytohemagglutinins
  • Quinazolines
  • WHI P131
  • Protein-Tyrosine Kinases
  • Jak3 protein, mouse
  • Janus Kinase 3
  • Methotrexate
Topics
  • Acute Disease
  • Animals
  • Bone Marrow Transplantation (adverse effects)
  • Cell Transplantation (adverse effects)
  • Drug Evaluation, Preclinical
  • Drug Therapy, Combination
  • Enzyme Inhibitors (administration & dosage, therapeutic use)
  • Graft vs Host Disease (immunology, therapy)
  • H-2 Antigens (immunology)
  • Immunosuppressive Agents (administration & dosage, therapeutic use)
  • Janus Kinase 3
  • Lymphocyte Activation (drug effects)
  • Lymphocyte Culture Test, Mixed
  • Male
  • Methotrexate (administration & dosage, therapeutic use)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Phytohemagglutinins (pharmacology)
  • Protein-Tyrosine Kinases (antagonists & inhibitors)
  • Quinazolines (administration & dosage, therapeutic use)
  • Radiation Chimera
  • Signal Transduction (drug effects)
  • Spleen (cytology)
  • T-Lymphocytes, Cytotoxic (drug effects, enzymology)
  • Whole-Body Irradiation

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