Fredriksen Agnete Brunsvik, Bogen Bjarne
Institute of Immunology, University of Oslo, Oslo, Norway.
Blood. 2007 Sep 15;110(6):1797-805. doi: 10.1182/blood-2006-06-032938. Epub 2007 May 31.
V regions of monoclonal Ig express an exquisite B-cell tumor-specific antigen called idiotype (Id). Id is a weak antigen and it is important to improve immunogenicity of Id vaccines. Chemokine receptors are expressed on antigen-presenting cells (APCs) and are promising targets for Id vaccines. Here we compare monomeric and dimeric forms of MIP-1alpha and RANTES that target Id to APCs in a mouse B lymphoma (A20) and a multiple myeloma model (MOPC315). MIP-1alpha was more potent than RANTES. The dimeric proteins were more potent than monomeric equivalents in short-term assays. When delivered in vivo by intramuscular injection of plasmids followed by electroporation, dimeric proteins efficiently primed APCs in draining lymph nodes for activation and proliferation of Id-specific CD4(+) T cells. Good anti-Id antibody responses were obtained, and mice immunized only once were 60% to 80% protected in both tumor models. CD8(+) T cells contributed to the protection. Antibody responses and tumor protection were reduced when the human Ig hinge = C(H)3 dimerization motif was replaced with syngeneic mouse counterparts, indicating that tumor-protective responses were dependent on xenogeneic sequences. The results suggest that bivalency and foreign sequences combine to increase the efficiency of chemokine-Id DNA vaccines.
单克隆Ig的V区表达一种称为独特型（Id）的精细B细胞肿瘤特异性抗原。Id是一种弱抗原，提高Id疫苗的免疫原性很重要。趋化因子受体在抗原呈递细胞（APC）上表达，是Id疫苗的有前景的靶点。在此，我们在小鼠B淋巴瘤（A20）和多发性骨髓瘤模型（MOPC315）中比较了将Id靶向APC的MIP-1α和RANTES的单体和二聚体形式。MIP-1α比RANTES更有效。在短期试验中，二聚体蛋白比单体等效物更有效。通过肌肉注射质粒后进行电穿孔在体内递送时，二聚体蛋白有效地启动引流淋巴结中的APC，以激活和增殖Id特异性CD4(+) T细胞。获得了良好的抗Id抗体反应，并且仅免疫一次的小鼠在两种肿瘤模型中受到60%至80%的保护。CD8(+) T细胞有助于保护作用。当人Ig铰链 = C(H)3二聚化基序被同基因小鼠对应物取代时，抗体反应和肿瘤保护作用降低，表明肿瘤保护反应依赖于异种序列。结果表明，双价性和外源序列相结合可提高趋化因子-Id DNA疫苗的效率。
