Abstract：
Adjuvants and immunomodulators that effectively drive a Th17-skewed immune response are not part of the standard vaccine toolkit. Vaccine adjuvants and delivery technologies that can induce Th17 or Th1/17 immunity and protection against bacterial pathogens, such as tuberculosis (TB), are urgently needed. Th17-polarized immune response can be induced using agonists that bind and activate C-type lectin receptors (CLRs) such as macrophage inducible C-type lectin (Mincle). A simple but effective strategy was developed for codelivering Mincle agonists with the recombinant Mycobacterium tuberculosis fusion antigen, M72, using tunable silica nanoparticles (SNP). Anionic bare SNP, hydrophobic phenyl-functionalized SNP (P-SNP), and cationic amine-functionalized SNP (A-SNP) of different sizes were coated with three synthetic Mincle agonists, UM-1024, UM-1052, and UM-1098, and evaluated for adjuvant activity in vitro and in vivo. The antigen and adjuvant were coadsorbed onto SNP via electrostatic and hydrophobic interactions, facilitating multivalent display and delivery to antigen presenting cells. The cationic A-SNP showed the highest coloading efficiency for the antigen and adjuvant. In addition, the UM-1098-adsorbed A-SNP formulation demonstrated slow-release kinetics in vitro, excellent stability over 12 months of storage, and strong IL-6 induction from human peripheral blood mononuclear cells. Co-adsorption of UM-1098 and M72 on A-SNP significantly improved antigen-specific humoral and Th17-polarized immune responses in vivo in BALB/c mice relative to the controls. Taken together, A-SNP is a promising platform for codelivery and proper presentation of adjuvants and antigens and provides the basis for their further development as a vaccine delivery platform for immunization against TB or other diseases for which Th17 immunity contributes to protection.
摘要：
有效驱动Th17偏斜免疫应答的佐剂和免疫调节剂不是标准疫苗工具包的一部分。可以诱导Th17或Th1/17免疫和保护细菌病原体的疫苗佐剂和递送技术，如结核病（TB），迫切需要。可以使用结合并激活C型凝集素受体(CLR)的激动剂如巨噬细胞诱导的C型凝集素(Mincle)来诱导Thl7极化的免疫应答。开发了一种简单但有效的策略，用于将Mincle激动剂与重组结核分枝杆菌融合抗原共同递送，M72，采用可调谐二氧化硅纳米颗粒（SNP）。阴离子裸SNP，疏水苯基官能化SNP（P-SNP），用三种合成的Mincle激动剂包被不同大小的阳离子胺官能化SNP（A-SNP），UM-1024、UM-1052和UM-1098，并在体外和体内评估佐剂活性。抗原和佐剂通过静电和疏水相互作用共吸附到SNP上，促进多价展示和递送至抗原呈递细胞。阳离子A-SNP对抗原和佐剂显示最高的着色效率。此外,UM-1098吸附的A-SNP制剂在体外表现出缓慢释放动力学，优异的稳定性超过12个月的储存，和人外周血单核细胞强烈的IL-6诱导。与对照相比,UM-1098和M72在A-SNP上的共吸附显著改善了BALB/c小鼠体内的抗原特异性体液和Th17极化免疫应答。一起来看,A-SNP是用于共同递送和正确呈递佐剂和抗原的有前途的平台,并且为它们作为用于针对TB或Thl7免疫有助于保护的其他疾病的免疫的疫苗递送平台的进一步开发提供了基础。
