A nasal double DNA adjuvant system induces atheroprotective IgM antibodies via dendritic cell-B-1a B cell interactions
A nasal double DNA adjuvant system induces atheroprotective IgM antibodies via dendritic cell-B-1a B cell interactions
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DOI：
10.1016/j.vaccine.2022.01.027
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发表时间：
2022-02-06
期刊：
影响因子：
5.5
通讯作者：
Ono，Yoshiaki
中科院分区：
文献类型：
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作者：
Yoshimatsu，Hideki;Kataoka，Kosuke;Ono，Yoshiaki
我们之前已经证明，树突状细胞（DC）靶向鼻腔双DNA佐剂系统，由表达Flt3配体（pFL）和CpG寡脱氧核苷酸1826 （CpG ODN）的DNA质粒组成，引发对粘膜和系统室中各种抗原的特异性免疫反应。本研究以磷酸胆碱（PC）偶联锁孔帽皮血青素（PC- klh）为抗原，研究了鼻双DNA佐剂系统是否诱导载脂蛋白e缺陷（ApoEKO）小鼠动脉粥样硬化保护性免疫。此外，我们评估了诱导抗pc特异性免疫反应的分子和细胞机制。与单独给予PC-KLH的小鼠相比，PC-KLH加pFL和CpG ODN的鼻腔免疫增强了血浆、腹膜液和鼻洗液中pc特异性IgM的诱导。重要的是，这些抗体与PC分子具有高度特异性的结合，并且与抗t15独特型具有剂量依赖性的结合（AB1-2）。在最后一次免疫12周后，带有PC-KLH的鼻腔双DNA佐剂系统导致apoeko小鼠主动脉弓动脉粥样硬化的减少。因此，我们接下来评估了诱导这些抗体的免疫细胞学机制。结合PC-KLH的鼻腔双DNA辅助系统不仅显著增加了脾脏、腹腔（PEC）和鼻咽部相关淋巴组织（NALT）中CD11c+ dc的频率，而且显著增加了CD11c+ dc对增殖诱导配体和b细胞活化因子的表达。此外，双DNA佐剂系统诱导脾脏、PEC和NALT中B-1 B细胞数量显著增加，CD5+B220+(B-1a) B细胞上跨膜激活剂和钙调节剂以及亲环蛋白配体相互作用物的表达增加。这些结果表明，含有PC-KLH的鼻腔双DNA佐剂系统通过dc与B-1a B细胞的相互作用，在粘膜和全身淋巴组织中诱导t15样抗体，抑制动脉粥样硬化的进展。
We previously demonstrated that the dendritic cell (DC)-targeting nasal double DNA adjuvant system, which consists of a DNA plasmid expressing Flt3 ligand (pFL) and CpG oligodeoxynucleotide 1826 (CpG ODN), elicits specific immune responses to various antigens in the mucosal and systemic compartments. Here, we investigated, using phosphorylcholine (PC)-conjugated keyhole limpet hemocyanin (PC-KLH) as an antigen, whether the nasal double DNA adjuvant system induces protective immunity to atherosclerosis in apolipoprotein E-deficient (ApoEKO) mice. Further, we assessed the molecular and cellular mechanisms in the induction of anti-PC-specific immune responses.Nasal immunization with PC-KLH plus pFL and CpG ODN enhanced induction of PC-specific IgM in plasma, peritoneal fluids, and nasal washes when compared with mice administered PC-KLH alone. Of importance, these antibodies exhibited highly specific binding to the PC molecule, and dose-dependent binding to anti-T15 idiotype (AB1-2). Twelve weeks after the last immunization, the nasal double DNA adjuvant system with PC-KLH resulted in a reduction of atherogenesis in the aortic arch ofApoEKO mice. Therefore, we next assessed immunocytological mechanism to induce these antibodies. The nasal double DNA adjuvant system with PC-KLH resulted not only in significantly increased frequencies of CD11c+DCs in the spleen, peritoneal cavity (PEC), and nasopharyngeal-associated lymphoid tissues (NALT), but also significantly increased expression of a proliferation-inducing ligand and B-cell-activating factor by CD11c+DCs. In addition, the double DNA adjuvant system induced significantly increased numbers of B-1 B cells in the spleen, PEC, and NALT, and increased expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor on CD5+B220+(B-1a) B cells. These findings demonstrated that the nasal double DNA adjuvant system with PC-KLH resulted in the induction of T15-like antibodies in the mucosal and systemic lymphoid tissues through interaction between DCs and B-1a B cells, and inhibited the progression of atherogenesis.