Dendritic Cells Transduced with an Adenovirus Vector Encoding Epstein-Barr Virus Latent Membrane Protein 2B: a New Modality for Vaccination

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Journal of Virology, December 1999, p. 10416-10425, Vol. 73, No. 12
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Dendritic Cells Transduced with an Adenovirus Vector Encoding Epstein-Barr Virus Latent Membrane Protein 2B: a New Modality for Vaccination

E. Ranieri,¹ W. Herr,¹ A. Gambotto,² W. Olson,¹ D. Rowe,³ P. D. Robbins,² L. Salvucci Kierstead,¹ S. C. Watkins,⁴ L. Gesualdo,¹ and W. J. Storkus¹^,²^,^*

Departments of Surgery¹ and Molecular Genetics and Biochemistry,² University of Pittsburgh School of Medicine, and Center of Biologic Imaging, University of Pittsburgh Medical Center,⁴ Pittsburgh, Pennsylvania 15261, and Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213³

Received 23 June 1999/Accepted 24 August 1999

Epstein-Barr virus (EBV) is a herpesvirus commonly associated with several malignancies, particularly in immunocompromisedhosts. As a strategy for stimulating immunity against EBV forthe treatment of EBV-associated tumors, we have genetically engineereddendritic cells (DC) to express EBV antigens, such as latent membraneprotein 2B (LMP2B), using recombinant adenovirus vectors. CD8⁺ T lymphocytes from HLA-A2.1⁺, EBV-seropositive healthy donors were cultured with autologousDC infected with recombinant adenovirus vector AdEGFP, encodingan enhanced green fluorescent protein (EGFP), or AdLMP2B at amultiplicity of infection of 250. After 48 h, >95% of the DC werepositive for EGFP expression as assessed by fluorescence-activatedcell sorting analysis, indicating efficient gene transfer. AdLMP2-transducedDC were used to stimulate CD8⁺ T cells. Responder CD8⁺ T cells were tested for gamma interferon (IFN- $gamma$ ) release by enzyme-linkedspot (ELISPOT) assay and cytotoxic activity. Prior to in vitrostimulation, the frequencies of T-cells directed against two HLA-A2-presentedLMP2 peptides (LMP2 329-337 and LMP2 426-434) were very low asassessed by IFN- $gamma$ spot formation (T-cell frequency, <0.003%).IFN- $gamma$ ELISPOT assays performed at day 14 showed a significant(2-log) increase of the day 0 frequency of T cells reactive againstthe LMP2 329-337 peptide, from 0.003 to 0.3 (P < 0.001). Moreover,specific cytolytic activity was observed against the autologousEBV B-lymphoblastoid cell lines after 21 days of stimulation ofT-cell responders with AdLMP2-transduced DC (P < 0.01). In summary,autologous mature DC genetically modified with an adenovirus encodingEBV antigens stimulate the generation of EBV-specific CD8⁺ effector T cells in vitro, supporting the potential applicationof EBV-based adenovirus vector vaccination for the immunotherapyof the EBV-associatedmalignancies.

^* Corresponding author. Mailing address: University of Pittsburgh School of Medicine, Department of Surgery, W1555 BiomedicalScience Tower, 200 Lothrop St., Pittsburgh, PA 15261. Phone: (412)624-6453. Fax: (412) 624-1172. E-mail: storkuswj{at}msx.upmc.edu.

Journal of Virology, December 1999, p. 10416-10425, Vol. 73, No. 12
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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