Cytokine and chemokine signatures associated with hepatitis B surface antigen loss in hepatitis B patients

Yoshio, Sachiyo; Mano, Yohei; Doi, Hiroyoshi; Shoji, Hirotaka; Shimagaki, Tomonari; Sakamoto, Yuzuru; Kawai, Hironari; Matsuda, Michitaka; Mori, Taizo; Osawa, Yosuke; Korenaga, Masaaki; Sugiyama, Masaya; Mizokami, Masashi; Mita, Eiji; Katayama, Keiko; Tanaka, Junko; Kanto, Tatsuya

doi:10.1172/jci.insight.122268

Cited by 34 publications

(39 citation statements)

References 34 publications

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“…( 15,21 ) Moreover, the frequency of circulating T FH and systemic levels of T FH ‐associated cytokines and chemokines (IL‐21, chemokine [C‐X‐C motif] ligand 13 [CXCL13]) are associated with immune control in patients with HBV. ( 16,17,22 ) Because TLR8 agonists promote T FH differentiation through production of IL‐12 ( 9 ) and directly inhibit Treg function, ( 4 ) our data suggest that GS‐9688 may induce effective antiviral immunity by augmenting a preexisting T FH response in the liver (Supporting Fig. ).…”

Section: Discussionmentioning

confidence: 89%

“…Various studies have identified a potential role for IL-21 in the immune control of HBV infection (14)(15)(16), and it is therefore striking that baseline intrahepatic IL21 expression was significantly elevated in antiviral responders (Fig. 7D).…”

Section: Baseline Intrahepatic Transcriptional Profile Differentiatesmentioning

confidence: 88%

“…are associated with immune control in HBV patients (15,16,21). Since TLR8 agonists promote T FH differentiation via production of IL-12 (9) and directly inhibit Treg function (4), our data suggest that GS-9688 may induce effective antiviral immunity by augmenting a pre-existing T FH response in the liver ( Supplementary Fig.…”

Section: Accepted Articlementioning

confidence: 90%

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Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B

et al. 2020

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GS-9688 (selgantolimod) is an oral selective small molecule agonist of toll-like receptor 8 (TLR8) in clinical development for the treatment of chronic hepatitis B (CHB). In this study, we evaluated the antiviral efficacy of GS-9688 in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to hepatitis B virus (HBV). WHV-infected woodchucks received eight weekly oral doses of vehicle, 1 mg/kg GS-9688 or 3 mg/kg GS-9688. Vehicle and 1 mg/kg GS-9688 had no antiviral effect, whereas 3 mg/kg GS-9688 induced a >5 log 10 reduction in serum viral load and reduced WHV surface antigen (WHsAg) levels to below the limit of detection in half of the treated woodchucks. In these animals, the antiviral response was maintained until the end of the study (>5 months after the end of treatment). GS-9688 treatment reduced intrahepatic WHV RNA and DNA levels by >95% in animals in which the antiviral response was sustained after treatment cessation, and these woodchucks also developed detectable anti-WHsAg antibodies. The antiviral efficacy of weekly oral dosing with 3 mg/kg GS-9688 was confirmed in a second woodchuck study. The antiviral response to GS-9688 did not correlate with systemic GS-9688 or cytokine levels but was associated with transient elevation of liver injury biomarkers and enhanced proliferative response of peripheral blood mononuclear cells (PBMC) to WHV peptides. Transcriptomic analysis of liver biopsies taken prior to treatment suggested that T follicular helper cells (T FH) and various other immune cell subsets may play a role in the antiviral response to GS-9688. Conclusion: Finite, short-duration treatment with a clinically relevant dose of GS-9688 is well tolerated and can induce a sustained antiviral response in WHV-infected woodchucks. The identification of a baseline intrahepatic transcriptional signature associated with response to GS-9688 treatment provides insights into the immune mechanisms that mediate this antiviral effect. Approximately 260 million individuals are chronically infected with hepatitis B virus (HBV), and over half a million people are estimated to die each year due to liver diseases associated with chronic hepatitis B (CHB), such as cirrhosis and hepatocellular carcinoma (HCC). Immunological control of CHB ("functional cure") is defined as sustained loss of HBV surface antigen (HBsAg) off treatment, with or without seroconversion to anti-HBs antibody. Several nucleos(t)ide analogs, as well as interferon-alpha (IFN-α), are approved for the treatment of CHB. These therapies reduce viremia and

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Section: Discussionmentioning

confidence: 89%

Section: Baseline Intrahepatic Transcriptional Profile Differentiatesmentioning

confidence: 88%

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Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B

et al. 2020

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“…Thus, in progressive AHB there were very low to undetectable circulating cytokine levels in spite of persistently high levels of viremia since the very first weeks postinoculation, with values of HBV DNA higher than 8 log 10 IU/ml. In a recent study conducted in acute resolving versus acute progressing hepatitis B in humans, Yoshio et al found that resolving hepatitis was associated with higher levels of CXCL9, CXCL10, CXCL11, CXCL13, and IL-21 at ALT peak (39). They also showed that levels of the same cytokines were remarkably lower during a flare of hepatitis in chronic HBV infection, which is characterized by an exhaustion of HBV-specific T cells (40).…”

Section: Discussionmentioning

confidence: 98%

Distinct Cytokine Profiles Correlate with Disease Severity and Outcome in Longitudinal Studies of Acute Hepatitis B Virus and Hepatitis D Virus Infection in Chimpanzees

Engle

Battista

Danoff

et al. 2020

mBio

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Historical studies conducted in chimpanzees gave us the opportunity to investigate the basis for the different severities of liver damage and disease outcome associated with infection with wild-type hepatitis B virus (HBV) versus a precore HBV mutant, HBV/hepatitis D virus (HDV) coinfection, and HDV superinfection. Weekly samples from 9 chimpanzees were studied for immune responses by measuring plasma levels of 29 cytokines in parallel with alanine aminotransferase (ALT) levels and viral kinetics. Comparison of classic acute hepatitis B (AHB) with severe or progressive AHB and HBV/HDV coinfection or superinfection identified distinct cytokine profiles. Classic AHB (mean ALT peak, 362 IU/liter) correlated with an early and significant induction of interferon alpha-2 (IFN-α2), IFN-γ, interleukin-12 p70 (IL-12 p70), and IL-17A. In contrast, these cytokines were virtually undetectable in severe AHB (mean ALT peak, 1,335 IU/liter), characterized by significant elevations of IL-10, tumor necrosis factor alpha (TNF-α), and MIP-1β. In progressive AHB (mean ALT peak, 166 IU/liter), there was a delayed and lower-magnitude induction of cytokines. The ALT peak was also delayed (mean, 23.5 weeks) compared to those of classic (13.5 weeks) and severe AHB (7.5 weeks). HBV/HDV coinfection correlated with significantly lower levels of IFN-α2, IFN-γ, and IL-17A, associated with the presence of multiple proinflammatory cytokines, including IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-15. Conversely, HDV superinfection induced the highest ALT peak (1,910 IU/liter) and was associated with a general suppression of cytokines. Our data demonstrate that the most severe liver damage, caused by an HBV precore mutant and HDV, correlated with restricted cytokine expression and lack of Th1 response, raising the question of whether these viruses are directly cytopathic. IMPORTANCE Studies performed in chimpanzees at the National Institutes of Health (NIH) demonstrated a significant difference in ALT levels during acute hepatitis of different viral etiologies, with a hierarchy in the extent of liver damage according to the infecting virus: the highest level was in HDV superinfection, followed by infection with a precore HBV mutant, HBV/HDV coinfection, and, lastly, wild-type HBV infection. Our study demonstrates that both the virus and host are important in disease pathogenesis and offers new insights into their roles. We found that distinct cytokine profiles were associated with disease severity and clinical outcome. In particular, resolution of classic acute hepatitis B (AHB) correlated with a predominant Th1 response, whereas HBV/HDV coinfection showed a predominant proinflammatory response. Severe AHB and HDV superinfection showed a restricted cytokine profile and no evidence of Th1 response. The lack of cytokines associated with adaptive T-cell responses toward the precore HBV mutant and HDV superinfection argues in favor of a direct cytopathic effect of these viruses.

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“…In general, cytotoxic mechanisms for HBV-specific CD4+ and CD8+ T cells and noncytotoxic mechanisms for IFN-γ and TNF-α, which are produced by natural killer (NK) cells, are detectable in acute hepatitis B patients [ 17 , 18 ]. Activated NK cells can activate CD4+ and CD8+ T cells, DCs and NK T cells [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Cytokines and Chemokines Involved in Hepatitis B Surface Antigen Loss in Human Immunodeficiency Virus/Hepatitis B Virus Coinfected Patients

Urata

Watanabe

Hirashima

et al. 2021

JCM

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It has been reported that hepatic flare (HF), attributable to the development of immune reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfected patients, occurs frequently after the start of anti-retroviral therapy (ART). We have observed several cases of hepatitis B surface antigen (HBsAg) loss after IRIS. However, the factors leading to HBsAg clearance remain unknown. We measured CD4+ and CD8+ T cells, cytokines and chemokines in 16 patients coinfected HIV-1 and HBV with IRIS, and analyzed the factors leading to HBsAg clearance after IRIS. There was no significant difference in the CD4+ and CD8+ T cell counts between the HBsAg clearance and non-clearance groups, while the serum concentrations of almost all cytokines and chemokines in the HBsAg clearance group were higher than in the HBsAg non-clearance group at any time of observation. In particular, IP-10 at the ALT peak, GM-CSF and IL-12 one month after the ALT peak and TNF-α and GM-CSF after the ALT concentrations fell to within normal limits, were significantly higher in the HBsAg clearance group. It seems that HBsAg loss after IRIS requires continued immune responses against HBV, involving Th1 cytokines.

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Cytokine and chemokine signatures associated with hepatitis B surface antigen loss in hepatitis B patients

Cited by 34 publications

References 34 publications

Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B

Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B

Distinct Cytokine Profiles Correlate with Disease Severity and Outcome in Longitudinal Studies of Acute Hepatitis B Virus and Hepatitis D Virus Infection in Chimpanzees

Cytokines and Chemokines Involved in Hepatitis B Surface Antigen Loss in Human Immunodeficiency Virus/Hepatitis B Virus Coinfected Patients

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