Liaw Yi-Wei, Lin Chi-Yu, Lai Yu-Sheng, Yang Tzu-Chung, Wang Chau-Jong, Whang-Peng Jacqueline, Liu Leroy F, Lin Chia-Po, Nieh Shin, Lu Shao-Chun, Hwang Jaulang
Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan; Department of Biochemistry, Medical College, Taipei Medical University, Taipei, Taiwan.
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; Department of Biochemistry, Medical College, Taipei Medical University, Taipei, Taiwan.
PLoS One. 2014 Dec 8;9(12):e111529. doi: 10.1371/journal.pone.0111529. eCollection 2014.
Low HDL-C levels are associated with atherosclerosis and non-alcoholic steatohepatitis, and increased levels may reduce the risk of these diseases. Inhibition of cholesteryl ester transfer protein (CETP) activity is considered a promising strategy for increasing HDL-C levels. Since CETP is a self-antigen with low immunogenicity, we developed a novel CETP vaccine (Fc-CETP6) to overcome the low immunogenicity of CETP and for long-term inhibition of CETP activity. The vaccine consists of a rabbit IgG Fc domain for antigen delivery to antigen-presenting cells fused to a linear array of 6 repeats of a CETP epitope to efficiently activate B cells. Rabbits were fed a high fat/cholesterol (HFC) diet to induce atherosclerosis and NASH, and immunized with Fc-CETP6 vaccine. The Fc-CETP6 vaccine successfully elicited anti-CETP antibodies and lowered plasma CETP activity. The levels of plasma HDL-C and ApoA-I were higher, and plasma ox-LDL lower, in the Fc-CETP6-immunized rabbits as compared to the unimmunized HFC diet-fed rabbits. Pathological analyses revealed less lipid accumulation and inflammation in the aorta and liver of the Fc-CETP6-immunized rabbits. These results show that the Fc-CETP6 vaccine efficiently elicited antibodies against CETP and reduced susceptibility to both atherosclerosis and steatohepatitis induced by the HFC diet. Our findings suggest that the Fc-CETP6 vaccine may improve atherosclerosis and NASH and has high potential for clinical use.
低高密度脂蛋白胆固醇（HDL-C）水平与动脉粥样硬化和非酒精性脂肪性肝炎相关，而HDL-C水平升高可能降低这些疾病的风险。抑制胆固醇酯转运蛋白（CETP）活性被认为是提高HDL-C水平的一种有前景的策略。由于CETP是一种免疫原性较低的自身抗原，我们开发了一种新型的CETP疫苗（Fc-CETP6），以克服CETP免疫原性低的问题，并长期抑制CETP活性。该疫苗由一个用于将抗原递呈给抗原呈递细胞的兔IgG Fc结构域组成，该结构域与CETP表位的6个重复序列的线性阵列融合，以有效激活B细胞。给兔子喂食高脂肪/高胆固醇（HFC）饮食以诱导动脉粥样硬化和非酒精性脂肪性肝炎，并使用Fc-CETP6疫苗进行免疫。Fc-CETP6疫苗成功诱导出抗CETP抗体并降低了血浆CETP活性。与未免疫的HFC饮食喂养的兔子相比，Fc-CETP6免疫的兔子血浆HDL-C和载脂蛋白A-I水平更高，而血浆氧化低密度脂蛋白（ox-LDL）水平更低。病理分析显示，Fc-CETP6免疫的兔子的主动脉和肝脏中的脂质积累和炎症较少。这些结果表明，Fc-CETP6疫苗有效地诱导了针对CETP的抗体，并降低了由HFC饮食诱导的动脉粥样硬化和脂肪性肝炎的易感性。我们的研究结果表明，Fc-CETP6疫苗可能改善动脉粥样硬化和非酒精性脂肪性肝炎，具有很高的临床应用潜力。
