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Anne-Marie T. Ciupitu^*, Max Petersson^*, Carey L. O'Donnell, Kevin Williams, Satish Jindal^||, Rolf Kiessling^*,¶, and 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

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.

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: raymond.welsh{at}banyan.ummed.edu

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.

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