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.
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Authors | M Cetkovic-Cvrlje, B A Roers, B Waurzyniak, X P Liu, F M Uckun |
Journal | Blood
(Blood)
Vol. 98
Issue 5
Pg. 1607-13
(Sep 01 2001)
ISSN: 0006-4971 [Print] United States |
PMID | 11520814
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Enzyme Inhibitors
- H-2 Antigens
- Immunosuppressive Agents
- Phytohemagglutinins
- Quinazolines
- WHI P131
- Protein-Tyrosine Kinases
- Jak3 protein, mouse
- Janus Kinase 3
- Methotrexate
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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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