Diebold S S, Cotten M, Koch N, Zenke M
Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany.
Gene Ther. 2001 Mar;8(6):487-93. doi: 10.1038/sj.gt.3301433.
Dendritic cells (DC) present immunogenic epitopes of antigens in the context of MHC class I and class II molecules in association with costimulatory molecules, and efficiently activate both cytotoxic T cells and T helper cells. Gene modified DC expressing antigen encoding cDNA represent a particularly attractive approach for the immunotherapy of disease. We previously described a gene delivery system for DC based on receptor-mediated endocytosis of ligand/polyethylenimine (PEI) DNA transfer complexes that target cell surface receptors which are abundantly expressed on DC. Employing this gene delivery system, DC were generated that express chicken ovalbumin (OVA) cDNA as a model antigen and introduce antigen into the MHC class I presentation pathway. We demonstrate here that modification of OVA cDNA as transferrin receptor (TfR) or invariant chain (Ii) fusions effectively generate MHC class II specific immune responses in addition to MHC class I responses. TfR-OVA contains the membrane anchoring region of transferrin receptor and represents a membrane-bound form of OVA for access to the MHC class II compartment. Ii-OVA fusions directly target the MHC class II processing pathway. Thus, modification of antigen encoding cDNA represents a convenient and effective means to direct antigens to MHC class II presentation and thus to generate T cell help.
树突状细胞（DC）在主要组织相容性复合体（MHC）I类和II类分子的背景下，与共刺激分子一起呈递抗原的免疫原性表位，并有效激活细胞毒性T细胞和辅助性T细胞。表达编码cDNA抗原的基因修饰DC是一种特别有吸引力的疾病免疫治疗方法。我们之前描述了一种基于受体介导的配体/聚乙烯亚胺（PEI）DNA转移复合物内吞作用的DC基因递送系统，该复合物靶向DC上大量表达的细胞表面受体。利用这种基因递送系统，产生了表达鸡卵清蛋白（OVA）cDNA作为模型抗原的DC，并将抗原引入MHC I类呈递途径。我们在此证明，将OVA cDNA修饰为转铁蛋白受体（TfR）或恒定链（Ii）融合物，除了产生MHC I类反应外，还能有效产生MHC II类特异性免疫反应。TfR-OVA包含转铁蛋白受体的膜锚定区域，代表一种膜结合形式的OVA，可进入MHC II类区室。Ii-OVA融合物直接靶向MHC II类加工途径。因此，修饰编码抗原的cDNA是一种将抗原导向MHC II类呈递从而产生T细胞辅助的便捷有效方法。
