Suppression of CD4+ T cell activation by a novel inhibitor of Src family kinases.
Int Immunopharmacol
; 5(4): 667-77, 2005 Apr.
Article
en En
| MEDLINE
| ID: mdl-15710336
The Src family kinases Lck and Fyn play an important role in T cell development and function. We have synthesized a novel small molecule, A-420983, which inhibits Lck and Fyn, as well as other Src family kinases, but has selectivity with respect to non-Src family kinases. A-420983 completely inhibited antigen-stimulated production of IFN-gamma and IL-4 by mouse Th1 and Th2 cells, respectively. Antigen-induced T cell proliferation was also blocked by treatment with A-420983. In contrast, IL-15-induced proliferation was unaffected by A-420983, suggesting that TCR-independent pathways of T cell activation were not impaired. When mice were dosed orally, A-420983 inhibited TCR-mediated c-jun and ZAP-70 phosphorylation in CD4+ T cells and suppressed the disease course of established EAE. Treatment with A-420983 for 7 days resulted in a block in thymocyte development at the CD4- CD8- stage, consistent with inhibition of Lck and Fyn in vivo. These results demonstrate that a small molecule inhibitor of Lck and Fyn can block TCR-induced T cell activation in vitro and in vivo. Furthermore, CNS demyelination mediated by activated encephalitogenic CD4+ T cells is dependent upon the kinase activity of these Src family members. We conclude that inhibition of Src family kinases may represent a promising strategy for the treatment of T cell-mediated disorders.
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Bases de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Pirimidinas
/
Activación de Linfocitos
/
Linfocitos T CD4-Positivos
/
Familia-src Quinasas
Límite:
Animals
Idioma:
En
Revista:
Int Immunopharmacol
Asunto de la revista:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Año:
2005
Tipo del documento:
Article
País de afiliación:
Estados Unidos