RESUMEN
The aim of this study is to characterize the role of ellagic acid, a flavonoid from a medicinal herb which blocks HBeAg secretion in a HBV infected cell line and in HBeAg transgenic mice, in immune tolerance in chronic HBV infection. Using the mouse strain C57ML/6, HBeAg-producing transgenic mice (HBeAg-Tg), under the control of metal ion-inducible promoter were generated. The effect on immune tolerance of HBeAg-Tg and the release of immune tolerance by the inhibitor of HBeAg secretion, ellagic acid, was tested using T/B cell proliferation, HBeAg/HBeAb production, cytotoxic T-lymphocyte (CTL) and cytokine assays. C57ML/6 based HBeAg-producing HBeAg-Tg mice were tolerant to HBeAg at the T and B-cell level, did not produce antibodies to HBeAg in vivo and in vitro, produced minimal levels of cytokines (IL-4 and IFN-gamma) and decreased CTL responses, while feeding mice with ellagic acid (5mg/kg body weight) blocked the immune tolerance caused by HBeAg. Our results suggest that host immune tolerance induced by HBeAg during HBV infection, a viral strategy to guarantee HBV infection, can be overcome by ellagic acid, thus it can be used as a therapeutic for HBV-carriers.
Asunto(s)
Ácido Elágico/farmacología , Antígenos e de la Hepatitis B/inmunología , Virus de la Hepatitis B/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Factores Inmunológicos/farmacología , Animales , Linfocitos B/inmunología , Células Cultivadas , Pruebas Inmunológicas de Citotoxicidad , Ácido Elágico/administración & dosificación , Anticuerpos contra la Hepatitis B/biosíntesis , Anticuerpos contra la Hepatitis B/sangre , Interferón gamma/biosíntesis , Interleucina-4/biosíntesis , Activación de Linfocitos , Ratones , Ratones Transgénicos , Plantas Medicinales , Linfocitos T/inmunología , Linfocitos T Citotóxicos/inmunologíaRESUMEN
A flavonoid molecule that showed a unique anti-HBV function was isolated from Phyllanthus urinaria. The molecular formula was determined as C14H6O8 based on FAM-MS analysis and the structure was determined by NMR. The identified flavonoid molecule, ellagic acid, showed unique anti-HBV functions. Ellagic acid did not inhibit either HBV polymerase activity, HBV replication or block HBsAg secretion. Rather, ellagic acid blocks effectively HBeAg secretion in HepG2 2.2.15 cells (IC50=0.07 microg/ml). Since HBeAg is involved in immune tolerance during HBV infection, ellagic acid, a newly identified functional anti-HBV compound, may be a new candidate therapeutic against immune tolerance in HBV-infected individuals.