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Jia-Feng Wu 1 , Chien-Hung Chen 2 , Yen-Hsuan Ni 1 , Mei-Hwei Chang 1

Interleukins 10 and 12 on Spontaneous Hepatitis B Virus e Antigen Seroconversion. Jia-Feng Wu 1 , Chien-Hung Chen 2 , Yen-Hsuan Ni 1 , Mei-Hwei Chang 1 Department of 1 Pediatrics and 2 Medicine, National Taiwan University Hospital 2009/09/28. Background.

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Jia-Feng Wu 1 , Chien-Hung Chen 2 , Yen-Hsuan Ni 1 , Mei-Hwei Chang 1

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  1. Interleukins 10 and 12 on Spontaneous Hepatitis B Virus e Antigen Seroconversion Jia-Feng Wu1, Chien-Hung Chen2, Yen-Hsuan Ni1 , Mei-Hwei Chang1 Department of 1Pediatrics and 2Medicine, National Taiwan University Hospital 2009/09/28

  2. Background ♠ HBeAg seroconversion is considered as an important indicator of subsidence of disease activity and decrease of active viral replication. Hepatology 1986; 6: 167-72 ♠ During the course of chronic HBV infection, persistent HBeAg is regarded as an important risk factor of hepatocellular carcinoma. (HBeAg(+) > 30y/o with OR 6.27 as compared with HBeAg(-) B carrier) N Engl J Med 2002; 347: 168-74.

  3. Background and Aims ♠ Difference in serum cytokine levels were identified in various stages of HBV infection in cross-sectional study. ♠ Higher serum pro-inflammatory cytokine (such as IL-12) was associated with the response of interferon-α treatment in HBV carrier. J Clin Invest 1997;99:3025-3033 Virus Res 2003;97:127-133 Hepatology 2005;42:1028-1036 ♥ Aims: Investigate the roles of Th1, Th2 cytokines (IL-2, IL-4, IL-10, IL-12, and Interferon-r) on spontaneous HBeAg seroconversion in chronic HBV infected subjects.

  4. Methods • 288 HBeAg-positive (at enrollment) chronic HBV infected patients were included • 201 subjects (70%) finished spontaneous HBeAg seroconversion furing the follow up. -Genomic DNA extraction: PUREGENE Kit • 11 SNPs of Th1 (IL-2,IL-12β,INF-γ), Th2 (IL-4, IL-10) cytokines gene determined by Beckman coulter platform. -HBV genotyping, and HBV viral load [HBeAg(+), ALT<40 IU/L] determination (tolerance phase) -HBV seromarker and serum aminotransferase levels determination every 3-6 months

  5. Methods • ELISA assays the cytokine level Part I: serum cytokine level (n=154) Tolerance phase: HBeAg(+), ALT < 40 IU/mL Inflammatory phase: HBeAg(+), ALT > 80 IU/mL Post-HBeAg seroconversion phase: HBeAg(-), ALT < 40 IU/mL Part II: supernatant from peripheral blood mononuclear cells (PBMCs) culture under HBcAg stimulation [n=115 HBeAg(-) subjects] PBMCs (1x106 cells/mL) Recombinant HBcAg (adw) (1 μg/ml)

  6. Study Subjects

  7. Survival Analysis of HBeAg Multivariate survival analysis by Cox’s survival analysis after the adjustment of HBV genotype, Gender, Peak ALT and HBV viral load at immune tolerance phase. Other 9 SNPs at IL-2, IL-4, and Interferon-r were statistically insignificant (P>0.05) in the survival analysis.

  8. Combination of these 2 favorable polymorphisms accelerated spontaneous HBeAg seroconversion (by Kaplen-Meier estimator) Gastroenteterology (in press)

  9. IL-12β -10993 polymorphism site associated with peak ALT levels C/G genotype at IL-12β -10993 SNP site associated with higher serum ALT levels before HBeAg seroconversion than G/G genotype.

  10. IL-10 -1082 SNP(rs1800896) vs. Serum IL-10 levels IL-10 -1082 G/G genotype correlated with higher serum IL-10 before and after HBeAg seroconversion. Serum IL-12 levels correlated with IL-10 levels at tolerance phase (Coeff. 0.42, P<0.001)

  11. PBMC stimulation:Genotype vs. Phenotype IL-12 secretion by PBMCs with HBcAg stimulation PBMCs from subjects carrying C/G genotype at IL-12β -10993 SNP sites were noted to have higher HBcAg inducible IL-12 secretion than G/G genotype carriers. No subjects carry CC genotype at the polymorphism site in this study population.

  12. Serum sample: Phenotype and Clinical outcome Serum IL-10 and IL-12 level at tolerance phase on HBeAg seroconversion Model adjusted with peak ALT (before HBeAg seroconversion), HBV genotype, and viral load at tolerance phase Higher serum IL-10 and IL-12 levels at tolerance phase predict earlier spontaneous HBeAg seroconversion.

  13. Discussions • IL-12 is considered as a pro-inflammatory cytokine which may activate NK cells, CTL and enhanced antiviral cytokines (Interferon-gamma) secretion. J Clin Invest 1997;99:3025-3033 • IL-12 have both cytolytic and non-cytolytic inhibition of HBV replication. Hepatology 2005;42:1028-1036 • IL-10 is generally considered to be immuno-regulation, but it is also reported to activate CTL and interferon-r secretion in the presence of IL-2, a downstream signal of IL-12, may stop the cytolytic and promote the non-cytolytic inhibition of HBV. J Virol 2000;74:4729-4737

  14. Conclusions • IL-10 -1082 G/G genotype is associated with higher serum IL-10 levels and IL-12β -10993 C/G genotype is associated with higher HBcAg inducible IL-12 secretion, and both of them associated with earlier HBeAg seroconversion. • Higher IL-10 and IL-12 serum levels at tolerance phase predict early spontaneous HBeAg seroconversion.

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