Schjetne Karoline W, Fredriksen Agnete B, Bogen Bjarne
Institute of Immunology, University of Oslo and Rikshospitalet-Radiumhospitalet Medical Center, N-0027 Oslo, Norway.
J Immunol. 2007 Apr 1;178(7):4169-76. doi: 10.4049/jimmunol.178.7.4169.
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.
CD40的连接可诱导树突状细胞（DC）成熟，可能是疫苗的一个有用靶点。在本研究中，我们构建了两种靶向小鼠CD40的基于抗体的疫苗构建体。一种类型是具有针对CD40的V区的重组抗体，并在其C区插入了确定的T细胞表位。另一种类型是同二聚体，其每条链由一个靶向单元（靶向CD40的单链可变片段）、一个二聚化基序和一个抗原单元组成。这类蛋白质结合CD40，刺激DC成熟，并增强初始和记忆性T细胞反应。当作为裸DNA经肌肉注射后进行电穿孔给药时，这些疫苗在两种肿瘤模型（骨髓瘤和淋巴瘤）中诱导了针对MHC II类限制性表位的T细胞反应、抗体反应和保护作用。显然有两个因素促成了这些结果：1）CD40的激动性连接和DC成熟的诱导，以及2）将抗原递呈给抗原提呈细胞并在MHC II类分子上呈递。这些结果突出了将抗原激动性靶向CD40对于诱导持久和保护性免疫反应的重要性。
