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Blood, 1 February 2004, Vol. 103, No. 3, pp. 811-819.
Prepublished online as a Blood First Edition Paper on October 9, 2003; DOI 10.1182/blood-2003-02-0524.
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GENE THERAPY
Highly efficient expression of transgenic proteins by naked DNA-transfected dendritic cells through terminal differentiation
Adriana T. Larregina,
Adrian E. Morelli,
Olga Tkacheva,
Geza Erdos,
Cara Donahue,
Simon C. Watkins,
Angus W. Thomson, and
Louis D. Falo, Jr
From the Department of Dermatology, the Thomas E. Starzl Transplantation Institute and Department of Surgery, and the Department of Cell Biology and Physiology and Center for Biological Imaging, University of Pittsburgh School of Medicine, PA.
Dendritic cells (DCs) play a key role in the induction and control of immunity. Genetic engineering of DCs is a promising approach for the development of a broad range of immunomodulatory strategies, for purposes ranging from genetic immunization to tolerance induction. The development of DC-based immunotherapies is limited by the inability to efficiently transfect DCs using naked DNA. Here we demonstrate that after plasmid DNA delivery, the transgene expression level controlled by the human immediate-early cytomegalovirus promoter (hIE-CMVp) is higher in mature DCs than in immature DCs and is further increased after terminal differentiation of DCs by agonist anti-CD40 monoclonal antibody (mAb) or after DC interaction with CD4+ T cells. CD40 signaling of DCs resulted in nuclear translocation of the transcription factors nuclear factor- B (NF-B), activator of protein-1 (AP-1), and cyclic adenosine monophosphate (cAMP)–responsive element, necessary for the activation of hIE-CMVp. Transgene expression by DCs diminished after the inhibition of these transcription factors or the blockade of adhesion molecules involved in the DC–T-cell synapse. Importantly, CD40 signaling of DCs results in the highly efficient expression and presentation of transgenic antigens and the induction of "in vivo" cytotoxic T-cell (CTL) responses specific for transgenic antigen peptides, demonstrating the functional potential of genetically engineered DCs.
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