|
|
 Previous Article | Table of Contents | Next Article 
Blood, 1 September 2001, Vol. 98, No. 5, pp. 1607-1613
TRANSPLANTATION
Targeting Janus kinase 3 to attenuate the severity of acute
graft-versus-host disease across the major histocompatibility barrier
in mice
Marina Cetkovic-Cvrlje,
Bertram A. Roers,
Barbara Waurzyniak,
Xing-Ping Liu, and
Fatih M. Uckun
From the Experimental BMT Program, Parker Hughes Cancer
Center, and the Departments of Immunology, Pathology, Chemistry, and
Drug Discovery Program, Parker Hughes Institute, St Paul, MN.
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.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
T. Hayashi, S. Yamagami, K. Tanaka, S. Yokoo, T. Usui, S. Amano, and N. Mizuki
Immunologic Mechanisms of Corneal Allografts Reconstituted from Cultured Allogeneic Endothelial Cells in an Immune-Privileged Site
Invest. Ophthalmol. Vis. Sci.,
July 1, 2009;
50(7):
3151 - 3158.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. W. Sternberg and D. G. Gilliland
The Role of Signal Transducer and Activator of Transcription Factors in Leukemogenesis
J. Clin. Oncol.,
January 15, 2004;
22(2):
361 - 371.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. M. Cao, B. Lo, E. A. Ranheim, F. C. Grumet, and J. A. Shizuru
Variable hematopoietic graft rejection and graft-versus-host disease in MHC-matched strains of mice
PNAS,
September 30, 2003;
100(20):
11571 - 11576.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Goleva, K. O. Kisich, and D. Y. M. Leung
A Role for STAT5 in the Pathogenesis of IL-2-Induced Glucocorticoid Resistance
J. Immunol.,
November 15, 2002;
169(10):
5934 - 5940.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. M. Uckun, B. A. Roers, B. Waurzyniak, X.-P. Liu, and M. Cetkovic-Cvrlje
Janus kinase 3 inhibitor WHI-P131/JANEX-1 prevents graft-versus-host disease but spares the graft-versus-leukemia function of the bone marrow allografts in a murine bone marrow transplantation model
Blood,
May 13, 2002;
99(11):
4192 - 4199.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. M. Uckun, J. Thoen, H. Chen, E. Sudbeck, C. Mao, R. Malaviya, X.-P. Liu, and C.-L. Chen
CYP1A-Mediated Metabolism of the Janus Kinase-3 Inhibitor 4-(4'-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline: Structural Basis for Inactivation by Regioselective O-Demethylation
Drug Metab. Dispos.,
January 1, 2002;
30(1):
74 - 85.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
