Yu Weili, Hu Tao
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences , Beijing 100190, China.
University of Chinese Academy of Sciences , Beijing 100190, China.
Mol Pharm. 2016 Nov 7;13(11):3626-3635. doi: 10.1021/acs.molpharmaceut.6b00138. Epub 2016 Oct 18.
Protein-based vaccines are of potential to deal with the severe situations posed by Mycobacterium tuberculosis (Mtb). Due to inherently poor immunogenicity of Mtb protein antigens, a potent immunostimulatory adjuvant is needed to enhance the cellular and humoral immune response to Mtb protein antigens. Inulin and chitosan (Cs) are polysaccharide adjuvants that can be used to achieve such an objective. The inulin-Cs conjugate (inulin-Cs) acted as a potent adjuvant through a synergistic interaction of inulin and Cs. CFP10 and TB10.4 are two important virulent protein antigens of Mtb. The CFP10-TB10.4 fusion protein (CT) was constructed and used as the protein antigen. In the present study, an adjuvant delivery system (inulin-Cs-CT) was developed by covalent conjugation of CT with inulin-Cs. Conjugation with inulin-Cs significantly increased the hydrodynamic volume of CT and did not alter the structure of CT. High levels of Th1-type cytokines (IFN-γ, TNF-α, and IL-2) and Th2-type cytokine (IL-4) were secreted by provocation of inulin-Cs-CT. Inulin-Cs-CT elicited high CT-specific antibody titers, mostly in the form of IgG1 and IgG2b. Pharmacokinetics revealed that conjugation with inulin-Cs could prolong the serum exposure of CT to the immune system. Pharmacodynamics suggested that conjugation with inulin-Cs led to an efficient production of CT-specific IgG. Thus, conjugation of inulin-Cs can serve as a potent adjuvant delivery system to improve the immunogenicity of the Mtb protein antigens.
基于蛋白质的疫苗有潜力应对由结核分枝杆菌（Mtb）引发的严峻形势。由于Mtb蛋白质抗原固有的免疫原性较差，因此需要一种有效的免疫刺激佐剂来增强对Mtb蛋白质抗原的细胞免疫和体液免疫反应。菊粉和壳聚糖（Cs）是可用于实现这一目标的多糖佐剂。菊粉-壳聚糖共轭物（菊粉-Cs）通过菊粉和Cs的协同相互作用作为一种有效的佐剂。CFP10和TB10.4是Mtb的两种重要的毒力蛋白抗原。构建了CFP10-TB10.4融合蛋白（CT）并将其用作蛋白质抗原。在本研究中，通过CT与菊粉-Cs的共价共轭开发了一种佐剂递送系统（菊粉-Cs-CT）。与菊粉-Cs共轭显著增加了CT的流体动力学体积，并且没有改变CT的结构。通过刺激菊粉-Cs-CT分泌了高水平的Th1型细胞因子（IFN-γ、TNF-α和IL-2）和Th2型细胞因子（IL-4）。菊粉-Cs-CT引发了高CT特异性抗体滴度，主要以IgG1和IgG2b的形式存在。药代动力学表明，与菊粉-Cs共轭可以延长CT在免疫系统中的血清暴露时间。药效学表明，与菊粉-Cs共轭导致CT特异性IgG的有效产生。因此，菊粉-Cs共轭可以作为一种有效的佐剂递送系统来提高Mtb蛋白质抗原的免疫原性。
