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Development of DNA vaccine against intracellular protozoa bored on ubiquitin-proteasome system

Research Project

Project/Area Number 15390136
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Parasitology (including Sanitary zoology)
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

HIMENO Kunisuke  Kyushu University, Faculty of Microbiology and immunology, Professor, 大学院・医学研究院, 教授 (50112339)

Co-Investigator(Kenkyū-buntansha) HISAEDA Hajime  Kyushu University, Faculty of Microbiology and immunology, Associate Professor, 大学院・医学研究院, 助教授 (50243689)
HAMANO Shinjiro  Kyushu University, Faculty of Microbiology and immunology, Assistant, 大学院・医学研究院, 助手 (70294915)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥15,200,000 (Direct Cost: ¥15,200,000)
Fiscal Year 2005: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2004: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2003: ¥7,000,000 (Direct Cost: ¥7,000,000)
Keywordsintracellular protozoa / DNA vaccine / gene gun / ubiquitin / ubiquitin-proteasome / CD8^+ T cell / proteasome KO mice / proteasome inhibitor / 細胞内寄生原虫 / ユビキチンプロテアソーム系 / トキソプラズマ / SAG-1 / ユビキチン融合遺伝子 / PA28ノックアウトマウス
Research Abstract

The intracellular protozoan Toxoplasma gondii (T.gondii) is a major opportunistic pathogen in the immunocompromized patient population worldwide. Among the vaccine candidates, the SAG1 protein is the best characterized. This 30-kDa protein is the major surface antigen of T.gondii tachyzoites, is highly conserved in T.gondii strains, inducing high antibody levels in humans, and is recognized by all the serum samples from infected subjects. CD8^+ T cells play an essential role in the protection against a highly virulent RH strain of T.gondii. Some CD8^+ CTL epitopes included in the SAG1 had been defined. However, most vaccine trials including DNA vaccine have resulted in failure agaist the high virulent RH strain except against the cultured and attenuated strain. In the present study, we constructed the vaccine vector encoding ubiquitinated SAG1 which is expected to be processed by "ubiquitin-proteasome pathway" and then be led to MHC class I molecules, resulting in the activation of SAG1-specific CD8^+ T cells.
Mice immunized with the chimeric DNA developed potent protective immunity against Toxoplasma mediated by SAG1-specific CD8^+ T cells, while mice immunized with SAG1 gene alone did not. The enhanced immunity was dependent on the ubiquitination of SAG1 that enabled it to be efficiently processed by the proteasome pathway resulting in efficient induction of specific CD8^+T cells. The immunity was dependent on immunoproteasome LMP7 but independent on PA28a/b, a proteasome activator.

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (50 results)

All 2006 2005 2004 2003 Other

All Journal Article (44 results) Publications (6 results)

  • [Journal Article] The ubiquitin-proteasome system plays essential roles in presenting an 8-mer CTL epitope expressed in APC to corresponding CD8^+T cells.2006

    • Author(s)
      Duan X.et al.
    • Journal Title

      Int. Immunol. 18・5

      Pages: 679-687

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The involvement of immunoproteasomes in induction of MHC class I-restricted immunity targeting Toxoplasma SAG1.2006

    • Author(s)
      Ishii K. et al.
    • Journal Title

      Microbes and Infection 8・4

      Pages: 1045-1053

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The ubiquitin-proteasome system plays essential roles in presenting an 8-mer CTL epitope expressed in APC to corresponding CD8^+ T cells.2006

    • Author(s)
      Duan X.et al.
    • Journal Title

      Int.Immunol. May;18(5)

      Pages: 679-687

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The involvement of immunoproteasomes in induction of MHC class I-restricted immunity targeting Toxoplasma SAG1.2006

    • Author(s)
      Ishii K. et al.
    • Journal Title

      Microbes and Infection Apr;8(4)

      Pages: 1045-1053

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The ubiquitin-proteasome system plays an essential role in presenting an 8-mer CTL epitope expressed in APC to corresponding CD8^+T cells.2006

    • Author(s)
      Duan X.et al.
    • Journal Title

      Int.Immunol. (in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] The involvement of immunoproteasomes in induction of MHC class I-restricted immunity targeting Toxoplasma SAG1.2006

    • Author(s)
      Ishii K. et al.
    • Journal Title

      Microbes and Infection (in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Resistance to GITR signaling in antigen specific CD4^+CD25^+ regulatory T cells during Plasmodium yoelii infection.2005

    • Author(s)
      Hisaeda H. et al.
    • Journal Title

      Eur. J. Immunol. 35

      Pages: 3516-3524

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A novel DNA vaccine based on the ubiquitin-proteasome pathway targeting 'self' antigens expressed in melanoma/melanocyte.2005

    • Author(s)
      Zhang M. et al.
    • Journal Title

      Gene Ther. 12

      Pages: 1049-1057

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Malaria : immune evasion by parasites.2005

    • Author(s)
      Hisaeda H. et al.
    • Journal Title

      Int. J. Biochem. Cell Biol. 37

      Pages: 700-706

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Resistance to GITR signaling in antigen specific CD4^+CD25^+ regulatory T cells during Plasmodium yoelii infection.2005

    • Author(s)
      Hisaeda H. et al.
    • Journal Title

      Eur.J.Immunol. 35

      Pages: 3516-3524

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] A novel DNA vaccine based on the ubiquitin-proteasome pathway targeting ‘self' antigens expressed in melanoma/melanocyte.2005

    • Author(s)
      Zhang M. et al.
    • Journal Title

      Gene Ther. 12

      Pages: 1049-1057

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Malaria : immune evasion by parasites.2005

    • Author(s)
      Hisaeda H. et al.
    • Journal Title

      Int.J.Biochem. Cell Biol. 37

      Pages: 700-706

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A novel DNA vaccine based on the ubiquitin-proteasome pathway targeting 'self' antigens expressed in melanoma/melanocyte2005

    • Author(s)
      Zhang M. et al.
    • Journal Title

      Gene Ther. 12

      Pages: 1049-1057

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Malaria : immune evasion by parasites.2005

    • Author(s)
      Hisaeda H. et al.
    • Journal Title

      Int.J.Biochem.Cell Biol. 37

      Pages: 700-706

    • Related Report
      2005 Annual Research Report
  • [Journal Article] A novel DNA vaccine based on the ubiquitin-proteasome pathway targeting ‘self'antigens expressed in melanoma/melanocyte.2005

    • Author(s)
      Zhang M. et al.
    • Journal Title

      Gene Therapy (In press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Malaria : immune evasion by parasites.2005

    • Author(s)
      Hisaeda H. et al.
    • Journal Title

      Int J Biochem Cell Biol. 37・4

      Pages: 700-706

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Toll-Like Receptor 4 Mediates the Antitumor Host Response Induced by a 55-Kilodalton Protein Isolated from Aeginetia indica L., a Parasitic Plant.2004

    • Author(s)
      Okamoto M. et al.
    • Journal Title

      Clin Diagn Lab Immunol. 11・3

      Pages: 483-495

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Formalin-fixed tumor cells effectively induce antitumor immunity both in prophylactic and therapeutic conditions.2004

    • Author(s)
      Obata C. et al.
    • Journal Title

      J Dermkatol Sci. 34・3

      Pages: 209-219

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cathepsin L is crucial for Thl-type immune response during Leishmania major infection.2004

    • Author(s)
      Onishi K. et al.
    • Journal Title

      Microbes and Infection 6・5

      Pages: 468-474

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Hyperproduction of proinflammatory cryokines by WSX-1-deficient NKT cells in concenavalin A-induced hapatitis.2004

    • Author(s)
      Yamanaka A. et al.
    • Journal Title

      J Immunol. 172・6

      Pages: 3590-3596

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ubiquitin-fusion degradation pathway plays an indispensable role in anked DNA vaccination with a chimeric gene encoding a syngeneic cytotoxic Tlymphocyte epitope of melancocyte and green fluorescent potein.2004

    • Author(s)
      Zhang M. et al.
    • Journal Title

      Immunol. 112・4

      Pages: 567-574

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] IL-18 gene therapy develops Th1-type immune responses in Leishmania major-infected BALB/c mice : is the effect mediated by the CpG signaling TLR9?2004

    • Author(s)
      Li Y.et al.
    • Journal Title

      Gene Therapy 11・11

      Pages: 941-948

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] Escape of malaria parasites from host immunity requires CD4^+CD25^+regulatory T cells.2004

    • Author(s)
      Hisaeda H. et al.
    • Journal Title

      Nature Medicine 10・1

      Pages: 29-30

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Toll-Like Receptor 4 Mediates the Antitumor Host Response Induced by a 55-Kilodalton Protein Isolated from Aeginetia indica L., a Parasitic Plant.2004

    • Author(s)
      Okamoto M. et al.
    • Journal Title

      Clin Diagn Lab Immunol. May;11(3)

      Pages: 483-495

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Formalin-fixed tumor cells effectively induce antitumor immunity both in prophylactic and therapeutic conditions.2004

    • Author(s)
      Obata C. et al.
    • Journal Title

      J Dermatol Sci. May;34(3)

      Pages: 209-219

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cathepsin L is crucial for Th1-type immune response during Leishmania major infection.2004

    • Author(s)
      Onishi K. et al.
    • Journal Title

      Microbes and Infection Apr;6(5)

      Pages: 468-474

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Hyperproduction of proinflammatory cytokines by WSX-1-deficient NKT cells in concanavalin A-induced hepatitis.2004

    • Author(s)
      Yamanaka A. et al.
    • Journal Title

      J Immunol. Mat15;172(6)

      Pages: 3590-3596

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ubiquitin-fusion degradation pathway plays an indispensable role in naked DNA vaccination with a chimeric gene encoding a syngeneic cytotoxic T lymphocyte epitope of melanocyte and green fluorescent protein.2004

    • Author(s)
      Zhang M. et al.
    • Journal Title

      Immunology Aug;112(4)

      Pages: 567-574

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] IL-18 gene therapy develops Th1-type immune responses in Leishmania major-infected BALB/c mice : is the effect mediated by the CpG signaling TLR9?2004

    • Author(s)
      Li Y.et al.
    • Journal Title

      Gene Therapy Jun;11(11)

      Pages: 941-948

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Escape of malaria parasites from host immunity requires CD4^+CD25^+ regulatory T cells.2004

    • Author(s)
      Hisaeda H. et al.
    • Journal Title

      Nature Medicine 10(1)

      Pages: 29-30

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Formalin-fixed tumor cells effectively induce antitumor immunity both in prophylactic and therapeutic conditions.2004

    • Author(s)
      Obata C. et al.
    • Journal Title

      J Dermatol Sci. 34・3

      Pages: 209-219

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cathepsin L is crucial for Th1-type immune response during Leishmania major infection.2004

    • Author(s)
      Onishi K. et al.
    • Journal Title

      Microbes and Infection 172・6

      Pages: 468-474

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Hyperproduction of proinflammatory cytokines by WSX-1-deficient NKT cells in concanavalin A-induced hepatitis.2004

    • Author(s)
      Yamanaka A. et al.
    • Journal Title

      J Immunol. 172・6

      Pages: 3590-3596

    • Related Report
      2004 Annual Research Report
  • [Journal Article] WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation pro-inflammatory cytokine production.2003

    • Author(s)
      Hamano S. et al.
    • Journal Title

      Immunity 19・5

      Pages: 657-667

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses.2003

    • Author(s)
      Seki YI. et al.
    • Journal Title

      Nat. Med. 9・8

      Pages: 1047-1054

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Insights into the roles of cathepsins in antigen processing and presentation revealed by specific inhibitors.2003

    • Author(s)
      Katunuma N. et al.
    • Journal Title

      Biol. Chem. 384

      Pages: 883-890

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Malaria vaccines tha inhibit parasite spread by mosquito vectors.2003

    • Author(s)
      Hisaeda H. et al.
    • Journal Title

      Recent Research Developments in Immunology 5

      Pages: 34-38

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Gene gun-based co-immunijzation of merozoite surface protein-1 cDNA with IL-12 expression plasmid confers protection against lethal Plasmodium yoelii in A/J mice.2003

    • Author(s)
      Sakai T. et al.
    • Journal Title

      Vaccine 21

      Pages: 1432-1444

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Gene gun-based in vivo gene transfer. Application to DNA vaccination.2003

    • Author(s)
      Sakai T. et al.
    • Journal Title

      Methods Mol Biol. 215

      Pages: 181-191

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation pro-inflammatory cytokine production.2003

    • Author(s)
      Hamano S. et al.
    • Journal Title

      Immunity 19(5)

      Pages: 657-667

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses.2003

    • Author(s)
      Seki YI. et al.
    • Journal Title

      Nat Med. 9(8)

      Pages: 1047-1054

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Insights into the roles of cathepsins in antigen processing and presentation revealed by specific inhibitors.2003

    • Author(s)
      Katunuma N. et al.
    • Journal Title

      Biol.Chem. 384

      Pages: 883-890

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Malaria vaccines that inhibit parasite spread by mosquito vectors.2003

    • Author(s)
      Hisaeda H. et al.
    • Journal Title

      Recent Research Developments in Immunology 5

      Pages: 159-166

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Gene gun-based co-immunization of merozoite surface protein-1 cDNA with IL-12 expression plasmid confers protection against lethal Plasmodium yoelii in A/J mice.2003

    • Author(s)
      Sakai T. et al.
    • Journal Title

      Vaccine 21(13-14)

      Pages: 1432-1444

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Publications] M.Zhang, K.Himeno et al.: "Melanoma immunotherapy by a DNA vaccine based on the ubiquitin-proteasome pathway."Gene Therapy. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Y.Li, K.Himeno et al.: "IL-18 gene therapy develops Th1-type immune responses in Leishmania major-infected BALB/c mice : is the effect mediated by the CpG signaling TLR9?"Gene Therapy. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] K.Onishi, K.Himeno et al.: "Cathepsin L is crucial for Th1-type immune response during Leishmania major infection."Microbes and Infection. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] H.Hisaeda, K.Himeno et al.: "Escape of malaria parasites from host immunity requires CD4^+CD25^+regulatory T cells."Nature Medicine. 10・1. 29-30 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] S.Hamano, K.Himeno et al.: "WSX-1 is required for resistance to Trypanosoma cruzi infection by reulation pro-inflammatory cytokine production."Immunity. 19・5. 257-667 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] YI.Seki, K.Himeno et al.: "SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses."Mature Medicine. 9・8. 1047-1054 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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