A Proposed Mechanism for the Induction of Cytotoxic T Lymphocyte Production by Heat Shock Fusion Proteins

Cho, Bryan K.; Palliser, Deborah; Guillen, Eduardo; Wiśniewski, Jan; Young, Richard A.; Chen, Jianzhu; Eisen, Herman N.

doi:10.1016/s1074-7613(00)80179-x

Cited by 124 publications

(92 citation statements)

References 39 publications

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“…7). These results are consistent with previous reports showing that HSP fusion proteins can induce potent immune responses both in mice and humans [24][25][26], further validating the general approach of using HSP fusion proteins in inducing anti-tumor responses.…”

Section: Discussionsupporting

confidence: 92%

Heat shock fusion protein induces both specific and nonspecific anti‐tumor immunity

Zhang

et al. 2006

Eur J Immunol

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Mucin 1 (MUC1) is a tumor antigen, and the most important epitopes that can induce cytotoxic T lymphocytes (CTL) reside in the variable-number tandem repeats (VNTR). Heat shock protein (HSP) complexes isolated from tumors have been shown to induce specific anti-tumor immunity. HSP alone can also induce nonspecific immunity. To explore the possibility to utilize the specific anti-tumor immunity induced by MUC1 VNTR and the nonspecific immunity induced by HSP, we constructed a recombinant protein (HSP65-MUC1) by fusing Bacillus Calmette-GuØrin-derived HSP65 with the MUC1 VNTR peptide and tested its ability to induce anti-tumor activities in a tumor challenge model. The growth of MUC1-expressing tumors was significantly inhibited in mice immunized with HSP65-MUC1, both before and after tumor challenge. A much larger percentage of immunized mice survived the tumor challenge than nonimmunized mice. Correlating with the anti-tumor activity, HSP65-MUC1 was shown to induce MUC1-specific CTL as well as nonspecific anti-tumor immunity. In the human system, HSP65-MUC1-loaded human DC induced the generation of autologous MUC1-specific CTL in vitro. These results suggest that exogenously applied HSP65-MUC1 may be used to treat MUC1 tumors by inducing the epitope-specific CTL as well as nonspecific anti-tumor responses mediated by the HSP part of the fusion protein.

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Section: Discussionsupporting

confidence: 92%

Heat shock fusion protein induces both specific and nonspecific anti‐tumor immunity

Zhang

et al. 2006

Eur J Immunol

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“…Briefly, the Ag cassette containing the SIY-peptide, a sequence previously shown to induce strong anti-SIY responses (28), was introduced into the bacterial genome by homologous recombination as previously described (29). Mice were infected by i.v.…”

Section: Recombinant Lm (Rlm)-siy and Infectionmentioning

confidence: 99%

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo

Kim

Priatel

Teh

et al. 2006

The Journal of Immunology

139

130

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Naive T cells require costimulation for robust Ag-driven differentiation and survival. Members of the TNFR family have been shown to provide costimulatory signals conferring survival at distinct phases of the T cell response. In this study, we show that CD4 and CD8 T cells depend on TNFR type 2 (p75) for survival during clonal expansion, allowing larger accumulation of effector cells and conferring protection from apoptosis for a robust memory pool in vivo. We demonstrate using the MHC class I-restricted 2C TCR and MHC class II-restricted AND TCR transgenic systems that TNFR2 regulates the threshold for clonal expansion of CD4 and CD8 T cell subsets in response to cognate Ag. Using a novel recombinant Listeria monocytogenes (rLM) expressing a secreted form of the 2C agonist peptide (SIY) to investigate the role of TNFR2 for T cell immunity in vivo, we found that TNFR2 controls the survival and accumulation of effector cells during the primary response. TNFR2−/− CD8 T cells exhibit loss of protection from apoptosis that is correlated with diminished survivin and Bcl-2 expression. Null mutant mice were more susceptible to rLM-SIY challenge at high doses of primary infection, correlating with impaired LM-specific T cell response in the absence of TNFR2-mediated costimulation. Moreover, the resulting memory pools specific for SIY and listeriolysin O epitopes derived from rLM-SIY were diminished in TNFR2−/− mice. Thus, examination of Ag-driven T cell responses revealed a hitherto unknown costimulatory function for TNFR2 in regulating T cell survival during the differentiation program elicited by intracellular pathogen in vivo.

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“…However, among EBV latent-cycle proteins, CD4 + T responses to LMP2A epitopes are much less frequent than EBNA1 and LMP1 (18). Previous studies have demonstrated that MtHsp70 accompanied antigens can induce potential antigen-specific CD8 + T cells with cytolytic and cytokine-secreting functions through CD4 + T cell independent modes (21,23,(39)(40)(41)(42). In this study, we conjugated a conserved LMP2A HLA-A2.1 restricted epitope LMP2A 356-364 to MtHsp70, which not only induces LMP2A 356-364 specific immune recognition in vitro, but also elicits LMP2A specific CTL in vivo.…”

Section: Discussionmentioning

confidence: 99%

Immunotherapy of Epstein-Barr Virus Associated Malignancies Using Mycobacterial HSP70 and LMP2A356–364 Epitope Fusion Protein

et al. 2009

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Epstein-Barr virus infection is strongly associated with a number of malignancies. The EBV latent membrane protein 2A has been implicated as one of the most attractive candidates for immunotherapy of related malignancies. In previous studies, the T cell epitopes of LMP2A have been identified systematically. However, the epitope-based vaccine generally meets inefficient immunogenicity when used in vivo directly, which could be overcome by combination with appropriate adjuvants. Heat shock protein is a natural chaperon, which is able to activate the classical major histocompatibility complex class I antigen-processing pathway (cross-presentation). In this study, a minigene encoding LMP2A 356-364 (FLYALALLL) was genetically fused to the carboxy-terminal of mycobacterial heat shock protein 70. The epitope fusion protein was expressed and purified, and the cross-presentation of

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A Proposed Mechanism for the Induction of Cytotoxic T Lymphocyte Production by Heat Shock Fusion Proteins

Cited by 124 publications

References 39 publications

Heat shock fusion protein induces both specific and nonspecific anti‐tumor immunity

Heat shock fusion protein induces both specific and nonspecific anti‐tumor immunity

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo

Immunotherapy of Epstein-Barr Virus Associated Malignancies Using Mycobacterial HSP70 and LMP2A356–364 Epitope Fusion Protein

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