Generation of Murine CTL by a Hepatitis B Virus-Specific Peptide and Evaluation of the Adjuvant Effect of Heat Shock Protein Glycoprotein 96 and Its Terminal Fragments

Li, Hongtao; Zhou, Meng; Han, Jian; Zhu, Xiaodong; Dong, Tao; Gao, George F.; Tien, Po

doi:10.4049/jimmunol.174.1.195

Cited by 76 publications

(68 citation statements)

References 47 publications

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“…Immunization with P15 and an adjuvant elicited a substantial quantity of specific cytotoxic CD8 ϩ T lymphocytes that could be used to assess the function of cellular immunity in protection and clearance of SARS-CoV. Using the N-terminal fragment N334 of GP96 with IFA seems to be especially wellsuited for this purpose (49). This immune method can also be practiced easily and effectively in testing immunogenicity of potential CTL epitopes.…”

Section: Discussionmentioning

confidence: 99%

“…To determine the in vivo immunogenic potential of peptide P15, we immunized HLA-A2.1/K b transgenic mice with peptide P15, using IFA and the N-terminal fragment N334 (22-355aa) of murine GP96 as an adjuvant (49). After three rounds of weekly in vivo stimulation, splenocytes from primed mice were tested for IFN-␥ production and chimeric HLA-A*0201 tetramer staining.…”

Section: In Vivo Induction Of Peptide-specific Ctls In Hla-a21/k B -mentioning

confidence: 99%

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Screening and Identification of Severe Acute Respiratory Syndrome-Associated Coronavirus-Specific CTL Epitopes

Zhou

De-sheng

et al. 2006

The Journal of Immunology

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107

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Severe acute respiratory syndrome (SARS) is a highly contagious and life-threatening disease that emerged in China in November 2002. A novel SARS-associated coronavirus was identified as its principal etiologic agent; however, the immunopathogenesis of SARS and the role of special CTLs in virus clearance are still largely uncharacterized. In this study, potential HLA-A*0201-restricted spike (S) and nucleocapsid protein-derived peptides were selected from an online database and screened for potential CTL epitopes by in vitro refolding and T2 cell-stabilization assays. The antigenicity of nine peptides which could refold with HLA-A*0201 molecules was assessed with an IFN-γ ELISPOT assay to determine the capacity to stimulate CTLs from PBMCs of HLA-A2+ SARS-recovered donors. A novel HLA-A*0201-restricted decameric epitope P15 (S411–420, KLPDDFMGCV) derived from the S protein was identified and found to localize within the angiotensin-converting enzyme 2 receptor-binding region of the S1 domain. P15 could significantly enhance the expression of HLA-A*0201 molecules on the T2 cell surface, stimulate IFN-γ-producing CTLs from the PBMCs of former SARS patients, and induce specific CTLs from P15-immunized HLA-A2.1 transgenic mice in vivo. Furthermore, significant P15-specific CTLs were induced from HLA-A2.1-transgenic mice immunized by a DNA vaccine encoding the S protein; suggesting that P15 was a naturally processed epitope. Thus, P15 may be a novel SARS-associated coronavirus-specific CTL epitope and a potential target for characterization of virus control mechanisms and evaluation of candidate SARS vaccines.

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Section: Discussionmentioning

confidence: 99%

Section: In Vivo Induction Of Peptide-specific Ctls In Hla-a21/k B -mentioning

confidence: 99%

Screening and Identification of Severe Acute Respiratory Syndrome-Associated Coronavirus-Specific CTL Epitopes

Zhou

De-sheng

et al. 2006

The Journal of Immunology

Self Cite

107

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“…49 Even, the reports on the adjuvant activity of C-terminal domain of gp96 are controversial, depending on the antigen. 50,51 The data showed that the construct containing the C-terminal of gp96 fused with Her2/neu, but not the co-administration of the two separated constructs, decreased CD4+CD25+foxp3+ regulatory T cells at the tumor site and enhanced CTL activity as well as IFN-γ secretion. Therefore, the C-terminal of gp96 can be used as molecular adjuvant along with other tumor/ bacterial/viral antigens for improving vaccine potency.…”

Section: Dna-based Vaccinesmentioning

confidence: 99%

“…58 Lipophosphoglycan 3 (LPG3), the Leishmania homologous with Gp96, is involved in assembly of LPG as the most abundant might induce an innate immune response to produce an immunological environment optimal for adequate peptide quantities to be cross-presented. 75 …”

Section: Protein/peptide-based Vaccinementioning

confidence: 99%

“…The results demonstrated the potential of using gp96 or its N-terminal fragment of gp96, but not the C-terminal fragment of gp96, as a possible adjuvant to enhance CTL response against hepatitis B virus infection (HBV) infection and hepatocellular carcinoma (HCC). 75 Increasing amounts of the immunizing peptide resulted in dose-dependent increases in the CTL response when gp96 or its N-terminal fragment was used as the adjuvant, indicating that their adjuvant effects were peptide concentration dependent. One explanation is that the increased amount of peptide may form more HSP-peptide complex to obtain sufficient cross-presentation.…”

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confidence: 99%

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Bolhassani

Rafati

2013

Human Vaccines & Immunotherapeutics

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Treg suppress CTL responses upon immunization with HSP gp96

Liu

Qiu

et al. 2009

Eur J Immunol

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HSP gp96-based vaccines have been trialled in rodent models and, more recently, in humans. Better understanding of gp96's immunomodulatory role will help with the design of more effective strategies for treatment of cancer and infectious diseases. In this study, we monitored the activities of T cells and activation of Treg in BABL/c mice after immunization using different doses of gp96 as adjuvant. We found that co-injection of gp96 simultaneously stimulated both CTL and Treg activity. Activation of CTL at low dose was far more pronounced than Treg activation. Treg population and suppression increased with gp96 dose, eventually abrogating the T-cell response induced by immunization. Lowdose cyclophosphamide treatment could restore the T-cell responses lost after high-dose gp96 adjuvant injection by suppression of Treg activation. We further examined the effect of different doses of gp96 or N355 peptide administration on tumor rejection. Our results provide new insights into the mechanisms of gp96-mediated balance between regulatory and responder T cells, which may facilitate future development of an effective gp96-based therapeutic vaccine.Key words: CTL . gp96 . Hepatitis B virus . Treg Introduction HSP gp96, a counterpart of the cytosolic HSP90 family residing in the endoplasmic reticulum, plays important roles in the activation of innate and adaptive immunity. This molecule has the unique ability to associate with antigenic peptides from tumor, virus and intracellular bacteria. Peptides bound by gp96 are taken up by APC through cell surface receptor CD91 and can be presented by both MHC class I and MHC class II molecules [1][2][3]. In mouse models, gp96-peptide complexes have been shown to prime and induce MHC class I-restricted CTL responses by crosspresentation of peptides to MHC class I molecules. Additionally, gp96 may act as co-stimulator and activator of CD4 1 and CD8 1T cells [4], increasing cell proliferation and secretion of cytokines. The gp96 protein also induces innate immune responses. Interaction of gp96 with APC (e.g. dendritic cells) leads to maturation or enhanced function of dendritic cells [5]. Recently gp96 was demonstrated to function in the expression of both intracellular and cell surface TLR [6]. In rodent models, autologous tumor-derived gp96-peptide complexes are highly effective in the elimination of tumor burden [7,8]. Immunization of mice with gp96 complexed with specific CTL epitopes derived from various viruses has been shown to elicit virus-specific CTL or protective immunity [1,9,10]. Since gp96 has been demonstrated to act as a powerful adjuvant, clinical trials of gp96-based therapeutic vaccines have been initiated for treatment of cancer [8,11].Previous study in our lab found that gp96 and its N-terminal fragment, N355, have the ability to augment CTL responses against to hepatitis B virus (HBV). However, higher amounts of Ã These authors contributed equally to this work. 3110gp96 were detrimental to the adjuvant effect and decreased the capability of mice to generate an i...

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Generation of Murine CTL by a Hepatitis B Virus-Specific Peptide and Evaluation of the Adjuvant Effect of Heat Shock Protein Glycoprotein 96 and Its Terminal Fragments

Cited by 76 publications

References 47 publications

Screening and Identification of Severe Acute Respiratory Syndrome-Associated Coronavirus-Specific CTL Epitopes

Screening and Identification of Severe Acute Respiratory Syndrome-Associated Coronavirus-Specific CTL Epitopes

Mini-chaperones

Treg suppress CTL responses upon immunization with HSP gp96

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