Author:
Zhang Jimin,Geng Shuang,Jia Hongyu,Zhao Gan,Zhao Weidong,Yu Jie,Yang Feifei,Zhu Haoxiang,Cai Huan,Yang Lishan,Zhang Shuren,Zhou Xian,Li Chaofan,Yu Fang,Jin Xiang,Zhang Shijie,Wang Xianzheng,Yang Yida,Wang Bin
Abstract
ABSTRACTObjectiveSeroclearance of hepatitis B surface antigen (HBsAg) remains a challenge to the functional cure of HBV infection due to an HBV-specific immune tolerance that prevents virus eradication.MethodsIn this clinical study, chronic hepatitis B patients treated with the standard nucleotide analog (NA) Adefovir Dipivoxil (ADV) or treated with ADV and IFN-α were immunized with granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with Human HBV Vaccine.ResultsThis THRIL-GM-Vac approach (THRee Injections of Low-dose GM-CSF followed by one dose of the HBV Vaccine) has achieved at least a 10-fold reduction of HBsAg level in 10 out of 23 (43.5%) patients tested. Moreover, two out of the ten patients eventually reached seroclearance. Thus THRIL-GM-Vac could break HBV-specific tolerance and boost HBsAg-specific cellular immunity. Consequently, the THRIL-GM-Vac approach could provide effective therapy for patients bearing medium-to-low levels of HBsAg.ConclusionOur findings carry the clinical significance of showing a novel way to break immunotolerance that can tackle the persistent infection manifested as generated by chronic HBV burden in chronic hepatitis B (CHB) patients.Significance of this studyWhat is already known about the subject?Chronic hepatitis B virus (CHB) patients can be controlled with antiviral therapies while rarely cured or functionally cured. In addition to the standard anti-viral treatment, immunotherapeutic approaches may break the HBV established immunotolerance and, in turn, mount effective activation or reactivation of host anti-HBV immunity and can be achieved in HBV-related animal models. However, achieving such a functional cure in CHB patients has been challenging.What are the new findings?We demonstrated in this study that some levels of HBsAg seroclearance in CHB patients were treated with a 3-day treatment of GM-CSF followed by one HBV vaccine for six treatments within one year in addition to the standard of anti-viral treatment.Notably, dynamics of HBsAg declined in responders were correlated with dynamics of HBsAg-specific Treg cells and reciprocally associated with the dynamical changes of HBsAg-specific IFN-γ +CD4+ (Th1) and IFN-γ +CD8+(Tc1) T cells over the course.How might it impact on clinical practice in the foreseeable future?It demonstrates in CHB patients that breaking Treg-immunotolerance can significantly be correlated with reducing the level of HBsAg in the ‘responders’ by immunotherapy.Such correlation can be used to predict outcomes of the efficacy of an immunotherapeutic treatment prior to completing its treatments.The evidence of HBsAg seroclearance in CHB patients by the presented immunotherapeutic approach will also shed light on improving such approach or similar strategies and further benefit those unmet medical needs.
Publisher
Cold Spring Harbor Laboratory