CP-690550, a Janus kinase inhibitor, suppresses CD4+ T-cell-mediated acute graft-versus-host disease by inhibiting the interferon-γ pathway.
Transplantation
; 90(8): 825-35, 2010 Oct 27.
Article
en En
| MEDLINE
| ID: mdl-20697326
BACKGROUND: Acute graft-versus-host disease (GVHD) is a critical obstacle to bone marrow transplantation. Although numerous studies have described immunosuppression protocols to mitigate acute GVHD, the need still exists for a more efficient immunosuppressant with fewer side effects. Here, we evaluated the protective effect of CP-690550, a newly developed Janus kinase inhibitor, in an acute GVHD model. METHODS: CP-690550 was chemically synthesized. Acute GVHD was induced through the transfer of parent B6 (H-2) bone marrow and CD4 T cells into lethally irradiated (B6×bm12)F1 (H-2) mice. RESULTS.: CP-690550 treatments confined to days -3 to 11 of GVHD induction provided full protection against allogeneic, acute GVHD-related lethality and histopathology. An analysis of the initial donor-derived CD4 T-cell responses revealed that the inhibitory effects of CP-690550 were largely related to the suppression of donor CD4 T-cell-mediated interferon (IFN)-γ production. Enhanced inhibition of T helper 1 cell differentiation, rather than the inhibition of allogeneic CD4 T-cell proliferation or T helper 17 cell differentiation, was also confirmed in allogeneic mixed lymphocyte reactions. Because lethality was considerably delayed by the systemic blockade of IFN-γ, the principal protective effect of CP-690550 occurred through the modulation of IFN-γ production. CONCLUSION: The targeting of Janus kinase with a sensitive and specific inhibitor, CP-690550, conferred effective protection from acute GVHD induced by a semiallogeneic major histocompatibility complex class II-disparate combination. Protection from acute GVHD was largely mediated by the inhibition of IFN-γ production.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pirimidinas
/
Pirroles
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Linfocitos T CD4-Positivos
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Interferón gamma
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Janus Quinasa 3
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Enfermedad Injerto contra Huésped
Tipo de estudio:
Guideline
/
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Transplantation
Año:
2010
Tipo del documento:
Article
País de afiliación:
Corea del Sur
Pais de publicación:
Estados Unidos