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Enhancement of DNA vaccine potency through linkage of antigen gene to ER chaperone molecules, ER-60, tapasin, and calnexin

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Journal of Biomedical Science

Abstract

DNA vaccines have emerged as an attractive approach for generating antigen-specific immunotherapy. Strategies that enhance antigen presentation may potentially be used to enhance DNA vaccine potency. Previous experiments showed that chimeric DNA vaccines utilizing endoplasmic reticulum (ER) chaperone molecules, such as Calreticulin (CRT), linked to an antigen were capable of generating antigen-specific CD8+ T cell immune responses in vaccinated mice. In this study, we tested DNA vaccines encoding the ER chaperone molecules ER-60, tapasin (Tap), or calnexin (Cal), linked to human papillomavirus type 16 (HPV-16) E7 for their abilities to generate E7-specific T cell-mediated immune responses and antitumor effects in vaccinated mice. Our results demonstrated that vaccination with DNA encoding any of these chaperone molecules linked to E7 led to a significant increase in the frequency of E7-specific CD8+ T cell precursors and generated stronger antitumor effects against an E7-expressing tumor in vaccinated mice compared to vaccination with wild-type E7 DNA. Our data suggest that DNA vaccines employing these ER chaperone molecules linked to antigen may enhance antigen-specific CD8+ T cell immune responses, resulting in a significantly more potent DNA vaccine.

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References

  • J.J. Donnelly J.B. Ulmer J.W. Shiver M.A. Liu (1997) ArticleTitleDNA vaccines. Annu. Rev. Immunol. 15 617–648 Occurrence Handle10.1146/annurev.immunol.15.1.617 Occurrence Handle1:CAS:528:DyaK2sXisVCmtLs%3D Occurrence Handle9143702

    Article  CAS  PubMed  Google Scholar 

  • S. Gurunathan D.M. Klinman R.A. Seder (2000) ArticleTitleDNA vaccines: immunology, application, and optimization Annu. Rev. Immunol. 18 927–974 Occurrence Handle10.1146/annurev.immunol.18.1.927 Occurrence Handle1:CAS:528:DC%2BD3cXjs1Gmt7w%3D Occurrence Handle10837079

    Article  CAS  PubMed  Google Scholar 

  • W.W. Leitner H. Ying N.P. Restifo (1999) ArticleTitleDNA RNA-based vaccines: principles, progress and prospects Vaccine 18 765–777 Occurrence Handle10.1016/S0264-410X(99)00271-6 Occurrence Handle1:CAS:528:DC%2BD3cXivF2quw%3D%3D Occurrence Handle10580187

    Article  CAS  PubMed  Google Scholar 

  • H.L. Robinson (1997) ArticleTitleNucleic acid vaccines: an overview Vaccine 15 785–787 Occurrence Handle10.1016/S0264-410X(96)00249-6 Occurrence Handle1:CAS:528:DyaK2sXksleku7Y%3D Occurrence Handle9234513

    Article  CAS  PubMed  Google Scholar 

  • D.M Pardoll A.M Beckerleg (1995) ArticleTitleExposing the immunology of naked DNA vaccines. Immunity 3 165–169 Occurrence Handle10.1016/1074-7613(95)90085-3 Occurrence Handle1:CAS:528:DyaK2MXnsl2gtbc%3D Occurrence Handle7648389

    Article  CAS  PubMed  Google Scholar 

  • F. Rodriguez L.L. An S. Harkins J. Zhang M. Yokoyama G. Widera J.T. Fuller C. Kincade I.L. Campbell J.L. Whitton (1998) ArticleTitleDNA immunization with minigenes low frequency of memory cytotoxic T lymphocytes and inefficient antiviral protection are rectified by ubiquitination J. Virol. 72 5174–5181 Occurrence Handle1:CAS:528:DyaK1cXjtVehsrk%3D Occurrence Handle9573289

    CAS  PubMed  Google Scholar 

  • T.W. Tobery R.F. Siliciano (1997) ArticleTitleTargeting of HIV-1 antigens for rapid intracellular degradation enhances cytotoxic T lymphocyte (CTL) recognition and the induction of de novo CTL responses in vivo after immunization. J. Exp Med. 909–920 185

    Google Scholar 

  • J.S. Boyle J.L Brady A.M. Lew (1998) ArticleTitleEnhanced responses to a DNA vaccine encoding a fusion antigen that is directed to sites of immune induction. Nature 408–411 392

    Google Scholar 

  • W.F. Cheng C.F. Hung C.Y. Chai K.F. Hsu L. He M. Ling T.C. Wu (2001) ArticleTitleTumor-specific immunity and antiangiogenesis generated by a DNA vaccine encoding calreticulin linked to a tumor antigen. J. Clin Invest. 669–678 108

    Google Scholar 

  • C.-F. Hung K.-F. Hsu W.-F. Cheng C.-Y. Chai L. He M. Ling T.-C. Wu (2001) ArticleTitleEnhancement of DNA vaccine potency by linkage of antigen gene to a gene encoding the extracellular domain of Flt3-ligand Cancer Res. 1080–1088 61

    Google Scholar 

  • A. Biragyn K. Tani M.C. Grimm S. Weeks L.W. Kwak (1999) ArticleTitleGenetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity [see comments] Nat. Biotechnol. 253–258 17

    Google Scholar 

  • C.-F. Hung W.-F. Cheng K.-F. Hsu C.-Y. Chai L. He M. Ling T.-C. Wu (2001) ArticleTitleCancer immunotherapy using a DNA vaccine encoding the translocation domain of a bacterial toxin linked to a tumor antigen Cancer Res. 3698–3703 61

    Google Scholar 

  • CA King MB Spellerberg D Zhu J Rice SS Sahota AR Thompsett TJ Hamblin J. Radl FK Stevenson (1998) ArticleTitleDNA vaccines with single-chain Fv fused to fragment C of tetanus toxin induce protective immunity against lymphoma and myeloma [see comments] Nat. Med. 4 1281–1286 Occurrence Handle10.1038/3266 Occurrence Handle1:CAS:528:DyaK1cXntlalsbs%3D Occurrence Handle9809552

    Article  CAS  PubMed  Google Scholar 

  • YH Chow BL Chiang YL Lee WK Chi WC Lin YT Chen MH Tao (1998) ArticleTitleDevelopment of Th1 and Th2 populations and the nature of immune responses to hepatitis B virus DNA vaccines can be modulated by codelivery of various cytokine genes J. Immunol. 160 1320–1329 Occurrence Handle1:CAS:528:DyaK1cXns1Ogtw%3D%3D Occurrence Handle9570550

    CAS  PubMed  Google Scholar 

  • WR Weiss KJ Ishii RC Hedstrom M Sedegah M Ichino K Barnhart DM Klinman SL Hoffman (1998) ArticleTitleA plasmid encoding murine granulocyte-macrophage colony-stimulating factor increases protection conferred by a malaria DNA vaccine J. Immunol. 161 2325–2332 Occurrence Handle1:CAS:528:DyaK1cXlslagtrg%3D Occurrence Handle9725227

    CAS  PubMed  Google Scholar 

  • M Corr H Tighe D Lee J Dudler M Trieu DC Brinson DA Carson (1997) ArticleTitleCostimulation provided by DNA immunization enhances antitumor immunity J. Immunol. 159 4999–5004 Occurrence Handle1:CAS:528:DyaK2sXntlKlurg%3D Occurrence Handle9366427

    CAS  PubMed  Google Scholar 

  • DM Klinman G Yamshchikov Y Ishigatsubo (1997) ArticleTitleContribution of CpG motifs to the immunogenicity of DNA vaccines J. Immunol. 158 3635–3639 Occurrence Handle1:CAS:528:DyaK2sXisFCitb4%3D Occurrence Handle9103425

    CAS  PubMed  Google Scholar 

  • C Condon SC Watkins CM Celluzzi K Thompson LD Falo (1996) ArticleTitleDNA-based immunization by in vivo transfection of dendritic cells Nat. Med. 2 1122–1128 Occurrence Handle10.1038/nm1096-1122 Occurrence Handle1:CAS:528:DyaK28Xmt1Wmsr4%3D Occurrence Handle8837611

    Article  CAS  PubMed  Google Scholar 

  • A Porgador KR Irvine A Iwasaki B.H. Barber N.P. Restifo R.N. Germain (1998) ArticleTitlePredominant role for directly transfected dendritic cells in antigen presentation to CD8+ T cells after gene gun immunization J. Exp. Med. 188 1075–1082 Occurrence Handle10.1084/jem.188.6.1075 Occurrence Handle1:CAS:528:DyaK1cXmsVKit7g%3D Occurrence Handle9743526

    Article  CAS  PubMed  Google Scholar 

  • C.F. Hung T.C. Wu (2003) ArticleTitleImproving DNA vaccine potency via modification of professional antigen presenting cells Curr. Opin. Mol. Ther. 5 20–24 Occurrence Handle1:CAS:528:DC%2BD3sXivFelurY%3D Occurrence Handle12669466

    CAS  PubMed  Google Scholar 

  • P.J. Lehner J. Trowsdale (1998) ArticleTitleAntigen presentation: coming out gracefully. Curr. Biol. R605–R608 8

    Google Scholar 

  • Y. Wang D. Chen M.J. Androlewicz (1999) ArticleTitleThe role of endoplasmic reticulum-associated protein degradation in MHC class I antigen processing Immunol. Rev. 172 67–72 Occurrence Handle1:CAS:528:DC%2BD3cXkvVajtw%3D%3D Occurrence Handle10631937

    CAS  PubMed  Google Scholar 

  • P.J. Lehner M.J. Surman P. Cresswell (1998) ArticleTitleSoluble tapasin restores MHC Class 1 expression and function in the tapasin-negative cell line 220. Immunity 8 221–231 Occurrence Handle1:CAS:528:DyaK1cXhsVChtrs%3D

    CAS  Google Scholar 

  • S. Li K.M. Paulsson H.-O. Sjögrn P. Wang (1999) ArticleTitlePeptide-bound major histocompatibility complex class I molecules associate with tapasin before dissociation from transporter associated with antigen processing J. Biol. Chem. 274 8649–8654 Occurrence Handle1:CAS:528:DyaK1MXitFyrsbc%3D Occurrence Handle10085102

    CAS  PubMed  Google Scholar 

  • B. Ortmann J. Copeman P. Lehner B. Sadasivan J. Herberg A.G. Grandea S.R. Riddell R. Tampe T. Spies J. Trowsdale (1997) ArticleTitleA critical role for tapasin in the assembly and function of multimeric MHC Class 1–TAP complexes Science 277 1306–1309 Occurrence Handle1:CAS:528:DyaK2sXlslant7w%3D Occurrence Handle9271576

    CAS  PubMed  Google Scholar 

  • C.A. Peh N. Laham S.R. Burrows Y. Zhu J. McCluskey (2000) ArticleTitleDistinct functions of tapasin revealed by polymorphism in MHC class I peptide loading J. Immunol. 64 292–299

    Google Scholar 

  • P. Spee J. Subjeck J. Neefjes (1999) ArticleTitleIdentification of novel peptide binding proteins in the endoplasmic reticulum: ERp72, calnexin, and grp170 Biochemistry 38 10559–10566 Occurrence Handle1:CAS:528:DyaK1MXksVOlt7Y%3D Occurrence Handle10441153

    CAS  PubMed  Google Scholar 

  • D.B. Williams (1995) ArticleTitleCalnexin: a molecular chaperone with a taste for carbohydrate Biochem. Cell Biol. 73 123–132 Occurrence Handle1:CAS:528:DyaK2MXnsVSmu70%3D Occurrence Handle7576485

    CAS  PubMed  Google Scholar 

  • J.A. Lindquist O.N. Jensen M. Mann G. Hämmerling (1998) ArticleTitleER-60, a chaperone with thiol-dependent reductase activity involved in MHC class 1 assembly EMBO J. 17 2186–2195 Occurrence Handle1:CAS:528:DyaK1cXivFOmsLY%3D Occurrence Handle9545232

    CAS  PubMed  Google Scholar 

  • E.A. Hughes P. Cresswell (1998) ArticleTitleThe thiol oxidoreductase ERp57 is a component of the MHC class 1 peptide-loading complex Curr. Biol. 8 709–712 Occurrence Handle1:CAS:528:DyaK1cXjslegsrY%3D Occurrence Handle9637923

    CAS  PubMed  Google Scholar 

  • J.D. Oliver H.L. Roderick D.H. Llewellyn S. High (1999) ArticleTitleERp57 functions as a subunit of specific complexes formed with the ER lectins calreticulin and calnexin Mol. Biol. Cell 10 2573–2582 Occurrence Handle1:CAS:528:DyaK1MXlsVyru7w%3D Occurrence Handle10436013

    CAS  PubMed  Google Scholar 

  • L.H. Ellenson T.C. Wu (2004) ArticleTitleFocus on endometrial and cervical cancer Cancer Cell 5 533–538 Occurrence Handle1:CAS:528:DC%2BD2cXltlGgs7Y%3D Occurrence Handle15193256

    CAS  PubMed  Google Scholar 

  • C.-H. Chen T.-L. Wang C.-F. Hung Y. Yang R.A. Young D.M. Pardoll T.-C. Wu (2000) ArticleTitleEnhancement of DNA vaccine potency by linkage of antigen gene to an HSP70 gene Cancer Res. 60 1035–1042 Occurrence Handle1:CAS:528:DC%2BD3cXhs1ShsL0%3D Occurrence Handle10706121

    CAS  PubMed  Google Scholar 

  • K.-Y. Lin F.G. Guarnieri K.F. Staveley-O’Carroll H.I. Levitsky T. August D.M. Pardoll T.-C. Wu (1996) ArticleTitleTreatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen Cancer Res. 56 21–26 Occurrence Handle1:CAS:528:DyaK28Xit1CjtA%3D%3D Occurrence Handle8548765

    CAS  PubMed  Google Scholar 

  • M.C. Feltkamp H.L. Smits M.P. Vierboom R.P. Minnaar B.M. de Jough J.W. Drijfhout J. ter Schegget C.J. Melief W.M. Kast (1993) ArticleTitleVaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16-transformed cells Eur. J. Immunol. 23 2242–2249 Occurrence Handle1:CAS:528:DyaK2cXivVynsw%3D%3D Occurrence Handle7690326

    CAS  PubMed  Google Scholar 

  • R.W. Tindle G.J. Fernando J.C. Sterling I.H. Frazer (1991) ArticleTitleA ‘public’ T-helper epitope of the E7 transforming protein of human papillomavirus 16 provides cognate help for several E7 B-cell epitopes from cervical cancer-associated human papillomavirus genotypes Proc. Natl. Acad. Sci. USA 88 5887–5891 Occurrence Handle1:CAS:528:DyaK3MXmt12rur0%3D Occurrence Handle1712110

    CAS  PubMed  Google Scholar 

  • C.J. Melief W.M. Kast (1995) ArticleTitleT-cell immunotherapy of tumors by adoptive transfer of cytotoxic T lymphocytes and by vaccination with minimal essential epitopes Immunol. Rev. 145 167–177 Occurrence Handle1:CAS:528:DyaK2MXnsVemurk%3D Occurrence Handle7590825

    CAS  PubMed  Google Scholar 

  • N.P. Restifo I. Bacik K.R. Irvine J.W. Yewdell B.J. McCabe R.W. Anderson L.C. Eisenlohr S.A. Rosenberg J.R. Bennink (1995) ArticleTitleAntigen processing in vivo and the elicitation of primary CTL responses J. Immunol. 154 4414–4422 Occurrence Handle1:CAS:528:DyaK2MXltF2gtb4%3D Occurrence Handle7722298

    CAS  PubMed  Google Scholar 

  • H. Ji T.-L. Wang C.-H. Chen C.-F. Hung S. Pai K.-Y. Lin R.J. Kurman D.M. Pardoll T.-C. Wu (1999) ArticleTitleTargeting HPV-16 E7 to the endosomal/lysosomal compartment enhances the antitumor immunity of DNA vaccines against murine HPV-16 E7-expressing tumors Human Gene Ther. 10 2727–2740 Occurrence Handle1:CAS:528:DyaK1MXnsFSitbg%3D

    CAS  Google Scholar 

  • W.W. Nichols B.J. Ledwith S.V. Manam P.J. Troilo (1995) ArticleTitlePotential DNA vaccine integration into host cell genome Ann. NY Acad. Sci. 772 30–39 Occurrence Handle1:CAS:528:DyaK28Xit1Gmt7s%3D Occurrence Handle8546411

    CAS  PubMed  Google Scholar 

  • D.V. Heck C.L. Yee P.M. Howley K. Munger (1992) ArticleTitleEfficiency of binding the retinoblastoma protein correlates with the transforming capacity of the E7 oncoproteins of the human papillomaviruses Proc. Natl. Acad. Sci. USA 89 4442–4446 Occurrence Handle1:CAS:528:DyaK38Xkt1eitbY%3D Occurrence Handle1316608

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung UniversityChang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan

    Cheng-Tao Lin, Ting-Chang Chang, Angel Chao & Yung-Kuei Soong

  2. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Elizabeth Dzeng, Chien-Fu Hung & Chyong-Huey Lai

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  1. Cheng-Tao Lin
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  2. Ting-Chang Chang
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  3. Angel Chao
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  4. Elizabeth Dzeng
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  5. Yung-Kuei Soong
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  6. Chien-Fu Hung
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  7. Chyong-Huey Lai
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Correspondence to Chien-Fu Hung.

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Lin, CT., Chang, TC., Chao, A. et al. Enhancement of DNA vaccine potency through linkage of antigen gene to ER chaperone molecules, ER-60, tapasin, and calnexin. J Biomed Sci 12, 279–287 (2005). https://doi.org/10.1007/s11373-005-0334-y

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  • DOI: https://doi.org/10.1007/s11373-005-0334-y

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