Heat shock protein gp96 enhances humoral and T cell responses, decreases Treg frequency and potentiates the anti-HBV activity in BALB/c and transgenic mice

Wang, Saifeng; Qiu, Lipeng; Liu, Guangze; Li, Yang; Zhang, Xiaojun; Jin, Wensong; Gao, George F.; Kong, Xianping; Meng, Songdong

doi:10.1016/j.vaccine.2011.05.008

Cited by 32 publications

(26 citation statements)

References 35 publications

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“…The HBV transgenic mice were generated with a viral DNA construct, pHBV1.3, containing 1.3 copies of the HBV genome (D genotype). All transgenic mice tested positive for serum HBV surface antigen (HBsAg) and virus DNA, as well as the HBV core proteins (HBcAg) in hepatocytes in their livers (28). Animals received humane care, and the study of mice was in strict accordance with the regulation of the Institute of Microbiology, Chinese Academy of Sciences of Research Ethics Committee.…”

Section: Methodsmentioning

confidence: 99%

“…HBV transgenic BALB/c mice were then used to determine if HBV replication directly affects miR-122 levels in vivo. The HBV transgenic mice are generally immunotolerant to HBV because no liver necroinflammation is observed in these mice (28), which excludes the possible effect of hepatic inflammation on miR-122 levels. The HBV transgenic mice were found to have lower liver miR-122 levels than BALB/c mice (1.0 versus 0.675 Ϯ 0.06; P Ͻ 0.05) (Fig.…”

Section: Suppression Of Mir-122 By Hbv Replicationmentioning

confidence: 99%

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Hepatitis B Virus mRNA-Mediated miR-122 Inhibition Upregulates PTTG1-Binding Protein, Which Promotes Hepatocellular Carcinoma Tumor Growth and Cell Invasion

Wang

et al. 2013

J Virol

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134

143

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M icroRNAs (miRNAs) are a large family of small (ϳ21-nucleotide [nt]) noncoding RNAs that interact with complementary target sites in their target mRNAs to induce translational repression, deadenylation, and degradation (1). However, the reciprocal effect of target mRNA on miRNA activity is largely unknown. is the most abundant liverspecific miRNA, accounting for approximately 70% of the total miRNA population in the adult liver (2). It has been found to play key roles in liver development and hepatic function (3, 4), hepatocyte growth, neoplastic transformation and tumorigenicity (5-8), lipid metabolism (9, 10), and regulation of hepatitis B virus (HBV) and hepatitis C virus (HCV) replication (11-13).HBV is a small (ϳ3.2 kb), enveloped, partially doublestranded DNA virus. The HBV genome contains four overlapping open reading frames (ORFs). The RNA transcripts are polyadenylated; capped; 3.5, 2.4, 2.1, and 0.7 kb in length; and named the pre-C/C or pregenomic RNA (pgRNA), pre-S, S, and X mRNAs, respectively. These mRNAs encode several overlapping viral proteins, including the polymerase, core, HBe, pre-S1, S2, S, and X proteins (14). There are approximately 350 million chronic HBV carriers worldwide, and chronic HBV infection is the major etiological factor in hepatocellular carcinoma (HCC) (15, 16). The relative risk for the development of HCC in chronic hepatitis B (CHB) patients is estimated to be 25 to 100 times higher than that in those without infection (15,17,18).Several possible pathways and molecular mechanisms have been reported for the involvement of HBV infection in malignant transformation of liver cells, including both direct and indirect mechanisms that likely act synergistically. Direct effects by viral factors include HBV DNA integration into the hepatocyte genome (which acts via cis-or trans-activation of nearby genes or enhances host chromosomal instability), the antiapoptotic and procarcinogenic functions of the HBx and truncated pre-S2/S viral proteins, and HBV mutants and genotypes (14,15,19,20). The indirect effects of chronic viral infection on malignant transformation include persistent inflammation and liver cirrhosis (which may significantly contribute to the transformation of hepatocytes and promote hepatocarcinogenesis through an integrated multistep process [21,22]), aberrant DNA methylation of specific cellular genes (23), and host susceptibility (24). However, the molecular mechanisms underlying HBV-induced carcinogenesis remain elusive and await further investigation (14, 15).Our previous study showed that loss of miR-122 induced by HBV infection enhances HBV replication through cyclin G1-modulated p53 activity, thereby possibly contributing to viral persistence (25). Moreover, miR-122 repression is only found in HCC arising in HBV-infected livers but not in HCV-infected liv-

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Section: Methodsmentioning

confidence: 99%

Section: Suppression Of Mir-122 By Hbv Replicationmentioning

confidence: 99%

Hepatitis B Virus mRNA-Mediated miR-122 Inhibition Upregulates PTTG1-Binding Protein, Which Promotes Hepatocellular Carcinoma Tumor Growth and Cell Invasion

Wang

et al. 2013

J Virol

Self Cite

134

143

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“…We and others have routinely tested the cross-presentation of HSP-chaperoned peptides and provision of co-stimulation by APCs in vitro (12–16,32,37–41). Recent observations that HSPs can prime diverse T cell and B cell responses (4,15,25–28) suggest that immune responses can be skewed by the responding APC, as shown in other settings (23). This appears to be dependent on the sum total of co-stimulation and efficiency of peptide cross-presentation by APCs.…”

Section: Discussionmentioning

confidence: 91%

“…This study is important for development of novel HSP-based vaccines for immunotherapy of cancer and infectious disease and in improvement of on-going clinical trials. Finally, these studies will shed light on the observations that HSPs are capable of priming Th1 (2,4,5,20,22), Th2 (25,26), Th17 (15) and Treg (27–28) responses under different immunization conditions.…”

Section: Introductionmentioning

confidence: 98%

Identification of the Cellular Sentinels for Native Immunogenic Heat Shock Proteins In Vivo

Messmer

Pasmowitz

Kropp

et al. 2013

The Journal of Immunology

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Select members of the heat shock proteins (HSPs) family, such as gp96, elicit immune responses specific to their chaperoned peptides. While immunological effects of HSPs on antigen presenting cell (APCs) described to date have largely been demonstrated with cell lines or primary cells in culture, their collective responses in vitro have been consistent with priming immune responses. Here we examine the physiologically relevant APCs in mice that are targeted following vaccination with native, murine HSP and characterize those cells. Gp96 accesses the subcapsular region of the draining lymph node and is internalized predominantly by CD11b+ cells in this locale. Cells acquiring gp96 can transfer protective anti-tumor immunity to naïve mice by actively cross-presenting gp96-chaperoned peptides and providing co-stimulation. Our studies illustrate how HSPs act to alert the immune system of cellular damage and will be of paramount importance in immunotherapy of patients with cancer and infectious disease.

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“…A formulation comprising recombinant HBV and a CpG oligonucleotide (1018 ISS) has been shown to induce a robust humoral and cell mediated immunity against HBV 15 . Heat shock protein gp96 enhanced immune responses and potentiates the anti-HBV activity in BALB/c and transgenic mice 16 .…”

Section: Introductionmentioning

confidence: 99%

Mushroom lectin overcomes hepatitis B virus tolerance via TLR6 signaling

Liu

et al. 2017

Sci Rep

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Currently, chronic hepatitis B virus (HBV) infection remains a serious public health problem in the world. Recombinant HBV vaccine, as a preventive strategy against HBV infection, generates high antibody level, but it is not effective to activate innate and cellular immunity for chronic HBV infection therapy. Lectins from mushroom are natural and active proteins which have been shown important biological functions. However, little is known about the immunological mechanism engaged by mushroom lectins. Here we report that, lectin from Pleurotus ostreatus (POL) stimulated innate response by activating Toll-like receptor 6 signal pathway of dendritic cells. Subsequently POL enhanced HBV specific antibody level and follicular helper T cells response which overcame HBV tolerance in transgenic mice. This study suggests a novel mechanism for POL acting on immune response and a therapeutic approach to break HBV tolerance.

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Heat shock protein gp96 enhances humoral and T cell responses, decreases Treg frequency and potentiates the anti-HBV activity in BALB/c and transgenic mice

Cited by 32 publications

References 35 publications

Hepatitis B Virus mRNA-Mediated miR-122 Inhibition Upregulates PTTG1-Binding Protein, Which Promotes Hepatocellular Carcinoma Tumor Growth and Cell Invasion

Hepatitis B Virus mRNA-Mediated miR-122 Inhibition Upregulates PTTG1-Binding Protein, Which Promotes Hepatocellular Carcinoma Tumor Growth and Cell Invasion

Identification of the Cellular Sentinels for Native Immunogenic Heat Shock Proteins In Vivo

Mushroom lectin overcomes hepatitis B virus tolerance via TLR6 signaling

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