Enrichment of Ly6C^hi monocytes by multiple GM-CSF injections with HBV vaccine contributes to viral clearance in a HBV mouse model

Abstract

Adjuvants are considered a necessary component for HBV therapeutic vaccines but few are licensed in clinical practice due to concerns about safety or efficiency. In our recent study, we established that a combination protocol of 3-day pretreatments with GM-CSF before a vaccination (3 × GM-CSF+VACCINE) into the same injection site could break immune tolerance and cause over 90% reduction of HBsAg level in the HBsAg transgenic mouse model. Herein, we further investigated the therapeutic potential of the combination in AAV8–1.3HBV-infected mice. After 4 vaccinations, both serum HBeAg and HBsAg were cleared and there was a 95% reduction of HBV-positive hepatocytes, in addition to the presence of large number of infiltrating CD8+ T cells in the livers. Mechanistically, the HBV-specific T-cell responses were elicited via a 3 × GM-CSF+VACCINE-induced conversion of CCR2-dependent CD11b+ Ly6Chi monocytes into CD11b+CD11c+ DCs. Experimental depletion of Ly6Chi monocytes resulted in a defective HBV-specific immune response thereby abrogating HBV eradication. This vaccination strategy could lead to development of an effective therapeutic protocol against chronic HBV in infected patients.

CCR5 deficiency enhances hepatic innate immune cell recruitment and inflammation in a murine model of acute hepatitis B infection

“…In contrast to the present study, previous murine experiments have demonstrated that treatment with an adjuvant (e.g. TLR9 ligands) was essential for recruitment of large populations of proinflammatory monocytes into the liver in the context of HBV infection . Following administration of TLR9 ligands, Huang et al .…”

“…Zhao et al . found similar results following administration of GM‐CSF during DNA vaccination in a murine model of chronic HBV . Interestingly, the requirement for adjuvant administration to drive proinflammatory monocyte recruitment into the liver was not observed in Ccr5 ‐deficient mice.…”

“…TLR9 ligands) was essential for recruitment of large populations of proinflammatory monocytes into the liver in the context of HBV infection. 17,18 Following administration of TLR9 ligands, Huang et al demonstrated that CD11b + proinflammatory monocytes establish local inflammatory pockets within the liver called iMATES (intrahepatic myeloid-cell aggregates for T-cell population expansion. 18 These iMATES facilitated T-cell priming and development of functional anti-HBV T-cell responses, suggesting that the increased hepatic CD11b + proinflammatory monocytes observed in the current experiments may help shape subsequent cellular immune responses in KO mice.…”

“…Zhao et al found similar results following administration of GM-CSF during DNA vaccination in a murine model of chronic HBV. 17 Interestingly, the requirement for adjuvant administration to drive proinflammatory monocyte recruitment into the liver was not observed in Ccr5-deficient mice. Further study is warranted with a longer duration of follow-up time to determine whether these proinflammatory monocytes establish iMATES and influence anti-HBV T-cell responses later in HBV infection in the absence of CCR5 signaling.…”

Lymphocyte Antigen 6 Complex, Locus C+ Monocytes and Kupffer Cells Orchestrate Liver Immune Responses Against Hepatitis B Virus in Mice

“…This is consistent with the current observation that compared with the control group, the e/c‐null group recruited fewer TNF‐α–producing Ly6C + monocytes and displayed a delayed viral clearance. Second, in an adeno‐associated virus–transduced HBV model, viral clearance by multiple granulocyte‐macrophage colony‐stimulating factor injections is associated with elevated Ly6C + monocytes in peripheral blood mononuclear cells …”