The Dual Nature of Specific Immunological Activity of Tumor-derived gp96 Preparations

Chandawarkar, Rajiv Y.; Wagh, Mihir S.; Srivastava, Pramod K.

doi:10.1084/jem.189.9.1437

Cited by 122 publications

(93 citation statements)

References 21 publications

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“…4A, a dose-dependent adjuvant effect was observed for gp96 in the ELISPOT assay, with the peak activity at 10 g, but gp96 alone had no CTL response. Higher amounts (50 g) of gp96 were detrimental to the adjuvant effect, presumably due to the fact that excess gp96 might be immunosuppressive and decreased the capability of mice to generate an immune T cell response, which was also consistent with a previous report (31). BSA, as a negative control, was unable to provide any adjuvant effect.…”

Section: Adjuvant Effects Of Gp96 and Its Terminal Fragmentssupporting

confidence: 79%

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

Zhou

Han

et al. 2005

The Journal of Immunology

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Previously, we reported that a 7-mer HLA-A11-restricted peptide (YVNTNMG) of hepatitis B virus (HBV) core Ag (HBcAg88–94) was associated with heat shock protein (HSP) gp96 in liver tissues of patients with HBV-induced hepatocellular carcinoma (HCC). This peptide is highly homologous to a human HLA-A11-restricted 9-mer peptide (YVNVNMGLK) and to a mouse H-2-Kd-restricted 9-mer peptide (SYVNTNMGL). To further characterize its immunogenicity, BALB/c mice were vaccinated with the HBV 7-mer peptide. It was found that a specific CTL response was induced by the 7-mer peptide, although the response was ∼50% of that induced by the mouse H-2-Kd-restricted 9-mer peptide, as detected by ELISPOT, tetramer, and 51Cr release assays. To evaluate the adjuvant effect of HSP gp96, mice were coimmunized with gp96 and the 9-mer peptide, and a significant adjuvant effect was observed with gp96. To further determine whether the immune effect of gp96 was dependent on peptide binding, the N- and C-terminal fragments of gp96, which are believed to contain the putative peptide-binding domain, were cloned and expressed in Escherichia coli. CTL assays indicated that only the N-terminal fragment, but not the C-terminal fragment, was able to produce the adjuvant effect. These results clearly demonstrated the potential of using gp96 or its N-terminal fragment as a possible adjuvant to augment CTL response against HBV infection and HCC.

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Section: Adjuvant Effects Of Gp96 and Its Terminal Fragmentssupporting

confidence: 79%

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

Zhou

Han

et al. 2005

The Journal of Immunology

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“…The extent of elevated gp96 expression in liver tissues was significantly correlated with the disease progression of HBV infection, but high level expression of gp96 did not induce an immunoresponse against HBV infection as expected [13]. Other studies involving gp96 as adjuvant have also indicated that highdose gp96 administration can down-regulate inflammatory events and anti-tumor effect [14,15]. This result has been attributed to the activation of Treg or myeloid suppressor cells.…”

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confidence: 69%

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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“…[22][23][24][25] When administered exogenously to APCs, the peptides transported by HSPs are very efficiently presented by MHC class I molecules. Peptides complexed to HSPs in vitro, [26][27][28] as well as HSP-peptide complexes purified from cells expressing viral proteins 29,30 or tumor cells, [31][32][33][34][35] induce specific CTL responses. Finally, recombinant HSP-antigen fusion proteins 36,37 were able to elicit CD4 þ -independent CD8 þ cytotoxic T-lymphocyte (CTL) responses.…”

Section: Introductionmentioning

confidence: 99%

Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines

Shen

et al. 2004

Gene Ther

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DNA vaccines are an appealing strategy for inducing cytotoxic T-lymphocyte and antibody responses against tumor cells as well as infectious agents. Dendritic cells (DCs) play a critical role in inducing immune responses, but their potential is not fully utilized in the DNA vaccine setting since they take up only a minor fraction of the injected DNA. Here we describe a novel DNA vaccination strategy based on the targeting of a modified tumor-associated antigen, the human papilloma virus (HPV) type 16 E7 protein, to DCs by a heat-shock protein (HSP) to enhance antigen presentation and immune responses. Specifically, a chimerical HPV-E7 and HSP70 fusion gene preceded with a leader sequence was constructed. When mice were immunized with this construct, the DNA is taken up by various types of cells, which then produce and secrete an HPV-E7-HSP70 fusion protein that is targeted to DCs by the HSP70 portion of the chimerical molecule for antigen presentation. In studies to test the efficacy of this strategy, we demonstrated that DNA vaccination with this secretory HPV-E7-HSP70 construct strongly enhanced an antigen-specific CD8 þ T-cell response as well as a specific B-cell response in mice. Furthermore, this immunization approach not only protected mice against lethal challenge with an HPV E7-expressing tumor line (TC-1), but also showed a therapeutic effect against established tumors. The results of this study indicate that secretory HSPs can be broadly used to target tumorassociated antigens to DCs to enhance antigen-specific immune responses. Gene Therapy (2004) 11, 924-932.

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The Dual Nature of Specific Immunological Activity of Tumor-derived gp96 Preparations

Cited by 122 publications

References 21 publications

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

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

Treg suppress CTL responses upon immunization with HSP gp96

Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines

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