Decrease in blood pressure and regression of cardiovascular complications by angiotensin II vaccine in mice.
Decrease in blood pressure and regression of cardiovascular complications by angiotensin II vaccine in mice.
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DOI：
10.1371/journal.pone.0060493
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Morishita R
中科院分区：
文献类型：
--
作者：
Nakagami F;Koriyama H;Nakagami H;Osako MK;Shimamura M;Kyutoku M;Miyake T;Katsuya T;Rakugi H;Morishita R
最近开发的疫苗除了治疗传染病外，还可以治疗癌症、类风湿性关节炎和阿尔茨海默病等各种疾病。然而，在临床使用之前，针对自身抗原的疫苗必须被证明是有效和安全的，在诱导B细胞产生足够的体液免疫反应的同时，避免T细胞对自身的反应。尽管针对血管紧张素II(Ang II)的疫苗对啮齿动物和人类有效，但对疫苗的免疫激活和安全性知之甚少。在这项研究中，我们评估了血管紧张素II多肽疫苗在小鼠身上的有效性和安全性。Ang II与锁孔帽状血蓝蛋白(KLH)结合后，可诱导抗Ang II抗体的产生，阻断Ang II信号转导通路。然而，血管紧张素II本身并不激活T细胞，通过免疫小鼠T细胞的增殖和淋巴因子产生来评估，而KLH激活T细胞。在注射血管紧张素Ⅱ的模型中，未免疫的小鼠表现出高血压，而免疫的小鼠(血管紧张素Ⅱ-KLH)表现出显著的收缩压下降，并伴随着心肌肥大和纤维化的显著减轻。重要的是，即使在大量注射Ang II后，抗Ang II抗体效价也没有上升，这表明Ang II本身促进了抗体的产生，很可能是由于T细胞的较少激活。此外，免疫小鼠未见炎症细胞聚集，因为内源性Ang II不会激活Ang II-KLH免疫后的T细胞。综上所述，这些数据表明，针对Ang II的疫苗可能有效地降低高血压和预防心血管并发症，而没有严重的副作用。
Vaccines have been recently developed to treat various diseases such as cancer, rheumatoid arthritis and Alzheimer’s disease in addition to infectious diseases. However, before use in the clinical setting, vaccines targeting self-antigens must be demonstrated to be effective and safe, evoking an adequate humoral immune response from B cells while avoiding T cell activation in response to self. Although the vaccine targeting angiotensin II (Ang II) is efficient in rodents and humans, little is known regarding the immunological activation and safety of the vaccine. In this study, we evaluated the efficiency and safety of an Ang II peptide vaccine in mice. Immunization with Ang II conjugated to keyhole limpet hemocyanin (KLH) successfully induced the production of anti-Ang II antibody, which blocked Ang II signaling in human aortic smooth muscle cells. However, Ang II itself did not activate T cells, as assessed by the proliferation and lymphokine production of T cells in immunized mice, whereas KLH activated T cells. In an Ang II-infused model, the non-immunized mice showed high blood pressure (BP), whereas the immunized mice (Ang II-KLH) showed a significant decrease in systolic BP, accompanied by significant reductions in cardiac hypertrophy and fibrosis. Importantly, anti-Ang II antibody titer was not elevated even after the administration of large amounts of Ang II, indicating that Ang II itself boosted antibody production, most likely due to less activation of T cells. In addition, no accumulation of inflammatory cells was observed in immunized mice, because endogenous Ang II would not activate T cells after immunization with Ang II-KLH. Taken together, these data indicate that vaccines targeting Ang II might be effective to decrease high BP and prevent cardiovascular complications without severe side effects.