RESUMEN
Janus kinases (Jaks) play an important role in signal transduction via cytokine receptors. Tyk2 is a Janus kinase, and we developed tyk2-deficient mice to study the requirement for tyk2 in vivo. Tyk2-deficient mice show no overt developmental abnormalities; however, they display a lack of responsiveness to a small amount of IFNalpha, although a high concentration of IFNalpha can fully transduce its signal even in the absence of tyk2. Furthermore, IL-12-induced T cell function is defective in these mice. In contrast, these mice respond normally to IL-6 and IL-10, both of which activate tyk2 in vitro. These observations demonstrate that tyk2 plays only a restricted role in mediating IFNalpha-dependent signaling while being required in mediating IL-12-dependent biological responses.
Asunto(s)
Interferón-alfa/fisiología , Interleucina-12/fisiología , Proteínas Tirosina Quinasas/fisiología , Proteínas/fisiología , Transducción de Señal/inmunología , Linfocitos T/inmunología , Animales , Embrión de Mamíferos , Marcación de Gen , Interleucina-10/fisiología , Interleucina-6/fisiología , Ratones , Ratones Endogámicos , Ratones Noqueados , Mutagénesis Insercional , Proteínas Tirosina Quinasas/deficiencia , Proteínas Tirosina Quinasas/genética , Proteínas/genética , Células Madre , Linfocitos T/enzimología , Linfocitos T/metabolismo , TYK2 Quinasa , TransfecciónRESUMEN
BACKGROUND: Viral myocarditis has been strongly implicated in the pathogenesis of dilated cardiomyopathy as well as acute myocarditis. Among the antiviral therapies, interferons (IFNs) have been widely studied and become very important in clinical practice. METHODS AND RESULTS: To investigate the possibilities of IFN therapy in viral myocarditis, we analyzed the effects of recombinant murine interferon (mIFN)-gamma and natural mIFN-alpha/beta by the intranasal and intramuscular routes on the development of acute murine myocarditis caused by encephalomyocarditis virus. Both mIFN-gamma and mIFN-alpha/beta treatment by either route significantly increased the survival rate; none of the mIFN-gamma-treated mice died. The effect of mIFN-gamma was significantly greater than that of mIFN-alpha/beta. Furthermore, intranasal administration of mIFN-gamma significantly suppressed virus replication and inflammation in the heart. CONCLUSIONS: Our data demonstrate that IFN therapy, especially intranasal administration of IFN-gamma, dramatically improved the prognosis of acute murine viral myocarditis by suppressing virus replication and raises the possibility of antiviral therapy with IFN-gamma in patients with acute myocarditis.
Asunto(s)
Infecciones por Cardiovirus/tratamiento farmacológico , Virus de la Encefalomiocarditis , Interferón gamma/administración & dosificación , Miocarditis/tratamiento farmacológico , Administración Intranasal , Animales , Infecciones por Cardiovirus/virología , Virus de la Encefalomiocarditis/fisiología , Ratones , Miocarditis/virología , Proteínas Recombinantes , Replicación Viral/efectos de los fármacosRESUMEN
With the aim of developing an effective cancer immunotherapy for common epithelial cancer, a new class of bifunctional antibody (BFA) was developed; one arm of this BFA recognized c-erbB-2 gene product, and the other arm recognized CD3 epsilon, a T-cell specific surface antigen. Application of this BFA with human peripheral blood lymphocytes exhibited specific anti-tumor activity in vitro on a breast tumor cell line, ZR-75-1, which expressed abundant c-erbB-2 gene product on its cell surface. These results indicate that BFA recognizing an oncogene product on cell surface is a potential new agent for cancer immunotherapy.
