Heat shock proteins (hsp's) isolated from murine cancer cells can elicit protective immunity and specific cytotoxic T lymphocytes (CTLs) by channeling tumor-derived peptides bound to hsp's to the major histocompatibility class I antigen presentation pathway. Here we have investigated if hsp70 can be used in a novel peptide vaccine for the induction of protective antiviral immunity and memory CTLs. A CTL epitope from the well-defined lymphocytic choriomeningitis virus (LCMV) system was mixed with recombinant hsp70 in vitro under conditions that optimize peptide binding to hsp70. Mice were immunized with the hsp70–peptide mixture and challenged with LCMV. Virus titers were reduced 10–100-fold in these mice compared to control mice. Immunization with the hsp70–peptide mixture resulted in the development of CTL memory cells that could be reactivated during LCMV infection, and that in a 51Cr-release assay could lyse cells pulsed with the same peptide, but not cells pulsed with another LCMV peptide. These results show that hsp70 can be used with CTL epitopes to induce efficient protective antiviral immunity and the generation of peptide-specific CTLs. The results also demonstrate the usefulness of hsp70 as an alternative to adjuvants and DNA vectors for the delivery of CTL epitopes to antigen-presenting cells.
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2 March 1998
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March 02 1998
Immunization with a Lymphocytic Choriomeningitis Virus Peptide Mixed with Heat Shock Protein 70 Results in Protective Antiviral Immunity and Specific Cytotoxic T Lymphocytes
Anne-Marie T. Ciupitu,
Anne-Marie T. Ciupitu
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
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Max Petersson,
Max Petersson
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
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Carey L. O'Donnell,
Carey L. O'Donnell
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
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Kevin Williams,
Kevin Williams
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
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Satish Jindal,
Satish Jindal
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
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Rolf Kiessling,
Rolf Kiessling
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
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Raymond M. Welsh
Raymond M. Welsh
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
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Anne-Marie T. Ciupitu
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
Max Petersson
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
Carey L. O'Donnell
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
Kevin Williams
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
Satish Jindal
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
Rolf Kiessling
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
Raymond M. Welsh
From the *Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden S-171 77; the ‡Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; §Biogen, Inc., Cambridge, Massachusetts 02142; ‖NeoGenesis, Inc., Cambridge, Massachusetts 02142; and the ¶Department of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden S-171 77
Jehad Charo is thanked for critical discussions.
This study was supported by a grant for Rolf Kiessling from the Swedish Medical Research Council. Anne-Marie T. Ciupitu is supported by a fellowship from the Swedish Cancer Society. The work of Raymond Welsh is supported by U.S. Public Health Service National Institutes of Health research grants AI-17672, AR-35506, and CA-34461.
Address correspondence to Raymond M. Welsh, Department of Pathology, University of Massachusetts Medical Center, 55 Lake Ave. North, Worcester, MA 01655-0125. Phone: 508-856-5819; Fax: 508-856-5780; E-mail: [email protected]
1
Abbreviations used in this paper: GP, glycoprotein; hsp, heat shock protein; LCMV, lymphocytic choriomeningitis virus; rhsp 70, recombinant human hsp70; VSV, vesicular stomatitis virus.
Received:
July 16 1997
Revision Received:
December 08 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 187 (5): 685–691.
Article history
Received:
July 16 1997
Revision Received:
December 08 1997
Citation
Anne-Marie T. Ciupitu, Max Petersson, Carey L. O'Donnell, Kevin Williams, Satish Jindal, Rolf Kiessling, Raymond M. Welsh; Immunization with a Lymphocytic Choriomeningitis Virus Peptide Mixed with Heat Shock Protein 70 Results in Protective Antiviral Immunity and Specific Cytotoxic T Lymphocytes . J Exp Med 2 March 1998; 187 (5): 685–691. doi: https://doi.org/10.1084/jem.187.5.685
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