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Institute of Immunology, University of Oslo and Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
Ligation of CD40 induces maturation of dendritic cells (DC) and could be a useful target for vaccines. In this study, we have constructed two types of Ab-based vaccine constructs that target mouse CD40. One type is a recombinant Ab with V regions specific for CD40 and has defined T cell epitopes inserted into its C region. The other type is a homodimer, each chain of which is composed of a targeting unit (single-chain fragment variable targeting CD40), a dimerization motif, and an antigenic unit. Such proteins bound CD40, stimulated maturation of DC, and enhanced primary and memory T cell responses. When delivered i.m. as naked DNA followed by electroporation, the vaccines induced T cell responses against MHC class II-restricted epitopes, Ab responses, and protection in two tumor models (myeloma and lymphoma). Two factors apparently contributed to these results: 1) agonistic ligation of CD40 and induction of DC maturation, and 2) delivery of Ag to APC and presentation on MHC class II molecules. These results highlight the importance of agonistic targeting of Ag to CD40 for induction of long-lasting and protective immune responses.
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 funded by the Research Council of Norway, Norwegian Cancer Society, and Multiple Myeloma Research Foundation.
2 K.W.S. and A.B.F. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Agnete B. Fredriksen, Institute of Immunology, University of Oslo and Rikshospitalet-Radiumhospitalet Medical Center, N-0027 Oslo, Norway; E-mail address: a.b.fredriksen{at}medisin.uio.no or Dr. Bjarne Bogen, Institute of Immunology, University of Oslo and Rikshospitalet-Radiumhospitalet Medical Center, N-0027 Oslo, Norway; E-mail address: bjarne.bogen{at}medisin.uio.no
4 Abbreviations used in this paper: DC, dendritic cell; h
3, human 3; NIP, 4-hydroxy-3-iodo-5-nitrophenylacetic acid; scFv, single-chain fragment variable; [3H]Thd, [3H]thymidine; wt, wild type.
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