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* Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Molecular Microbiology and Immunology, and
Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231;
¶ Department of Anatomy, Chung-Ang University College of Medicine, Seoul, Korea; and
|| Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599
Administration of DNA vaccines via gene gun has emerged as an important form of Ag-specific immunotherapy. The MHC CIITA is a master regulator of MHC class II expression and also induces expression of class I molecules. We reasoned that the gene gun administration of CIITA DNA with DNA vaccines employing different strategies to improve MHC I and II processing could enhance DNA vaccine potency. We observed that DC-1 cells transfected with CIITA DNA lead to higher expression of MHC I and II molecules, leading to enhanced Ag presentation through the MHC I/II pathways. Furthermore, our data suggested that coadministration of DNA-encoding calreticulin (CRT) linked to human papillomavirus (HPV) 16 E6 Ag (CRT/E6) with CIITA DNA leads to enhanced E6-specific CD8+ T cell immune responses in vaccinated mice. In addition, coadministration of the combination of CRT/E6 DNA with CIITA DNA and DNA encoding the invariant chain (Ii) linked to the pan HLA-DR-reactive epitope (Ii-PADRE) further enhanced E6-specific CD8+ T cell immune responses in vaccinated mice. Treatment with the combination vaccine was also shown to enhance the antitumor effects and to prolong survival in TC-1 tumor-bearing mice. Vaccination with the combination vaccine also led to enhanced E6-specific CD8+ memory T cells and to long-term protection against TC-1 tumors and prolonged survival in vaccinated mice. Thus, our findings suggest that the combination of CIITA DNA with CRT/E6 and Ii-PADRE DNA vaccines represents a potentially effective means to combat tumors in the clinical setting.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Flight Attendant Medical Research Institute and National Cancer Institute Specialized Programs of Research Excellence in Cervical Cancer Grants P50 CA098252 and 1 R01 CA114425-01.
2 Address correspondence and reprint requests to Dr. T.-C. Wu, Departments of Pathology and Oncology, School of Medicine, Johns Hopkins University, CRBII Room 309, 1550 Orleans Street, Baltimore, MD 21231. E-mail address: wutc{at}jhmi.edu
3 Abbreviations used in this paper: DC, dendritic cell; CRT, calreticulin; HPV, human papillomavirus; Ii, invariant chain; Ii-PADRE, Ii pan HLA-DR-reactive epitope; PADRE, pan HLA-DR-reactive epitope.
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