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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 immunocompromised hosts. As a strategy for stimulating immunity against EBV for the treatment of EBV-associated tumors, we have genetically engineered dendritic cells (DC) to express EBV antigens, such as latent membrane protein 2B (LMP2B), using recombinant adenovirus vectors. CD8+ T lymphocytes from HLA-A2.1+, EBV-seropositive healthy donors were cultured with autologous DC infected with recombinant adenovirus vector AdEGFP, encoding an enhanced green fluorescent protein (EGFP), or AdLMP2B at a multiplicity of infection of 250. After 48 h, >95% of the DC were positive for EGFP expression as assessed by fluorescence-activated cell sorting analysis, indicating efficient gene transfer. AdLMP2-transduced DC were used to stimulate CD8+ T cells. Responder CD8+ T cells were tested for gamma interferon (IFN-gamma ) release by enzyme-linked spot (ELISPOT) assay and cytotoxic activity. Prior to in vitro stimulation, the frequencies of T-cells directed against two HLA-A2-presented LMP2 peptides (LMP2 329-337 and LMP2 426-434) were very low as assessed 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 against the LMP2 329-337 peptide, from 0.003 to 0.3 (P < 0.001). Moreover, specific cytolytic activity was observed against the autologous EBV B-lymphoblastoid cell lines after 21 days of stimulation of T-cell responders with AdLMP2-transduced DC (P < 0.01). In summary, autologous mature DC genetically modified with an adenovirus encoding EBV antigens stimulate the generation of EBV-specific CD8+ effector T cells in vitro, supporting the potential application of EBV-based adenovirus vector vaccination for the immunotherapy of the EBV-associated malignancies.

* Corresponding author. Mailing address: University of Pittsburgh School of Medicine, Department of Surgery, W1555 Biomedical Science 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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