Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates.
Transplantation
; 79(7): 791-801, 2005 Apr 15.
Article
en En
| MEDLINE
| ID: mdl-15818321
ABSTRACT
BACKGROUND:
Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common chain (gammac). Because mutations in genes encoding gammac or JAK3 result in immunodeficiency, we investigated the potential of a rationally designed inhibitor of JAK3, CP-690,550, to prevent renal allograft rejection in nonhuman primates.METHODS:
Life-supporting kidney transplantations were performed between mixed leukocyte reaction-mismatched, ABO blood group-matched cynomolgus monkeys. Animals were treated with CP-690,550 (n = 18) or its vehicle (controls, n = 3) and were euthanized at day 90 or earlier if there was allograft rejection.RESULTS:
Mean survival time (+/- standard error of mean) in animals treated with CP-690,550 (53 +/- 7 days) was significantly longer than in control animals (7 +/- 1 days, P=0.0003) and was positively correlated with exposure to the drug (r = 0.79, P < 0.01). Four treated animals were euthanized at 90 days with a normal renal function and low-grade rejection at final pathology. Occurrence of rejection was significantly delayed in treated animals (46 +/- 7 days from transplantation vs. 7 +/- 1 days in controls, P = 0.0003). Persistent anemia, polyoma virus-like nephritis (n = 2), and urinary calcium carbonate accretions (n = 3) were seen in animals with high exposure. Natural killer cell and CD4 and CD8 T-cell numbers were significantly reduced in treated animals. Blood glucose, serum lipid levels, and arterial blood pressure were within normal range in treated animals, and no cancers were demonstrated.CONCLUSIONS:
CP-690,550 is the first reported JAK3 inhibitor combining efficacy and good tolerability in a preclinical model of allotransplantation in nonhuman primates and thus has interesting potential for immunosuppression in humans.
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Bases de datos:
MEDLINE
Asunto principal:
Pirimidinas
/
Pirroles
/
Proteínas Tirosina Quinasas
/
Trasplante de Riñón
/
Péptidos y Proteínas de Señalización Intracelular
/
Rechazo de Injerto
/
Supervivencia de Injerto
/
Inmunosupresores
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Transplantation
Año:
2005
Tipo del documento:
Article
País de afiliación:
Estados Unidos