Intrinsic immunogenicity of rapidly-degradable polymers evolves during degradation.
Intrinsic immunogenicity of rapidly-degradable polymers evolves during degradation.
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DOI：
10.1016/j.actbio.2015.12.026
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发表时间：
2016-03-01
影响因子：
9.7
通讯作者：
Jewell CM
中科院分区：
文献类型：
--
作者：
Andorko JI;Hess KL;Pineault KG;Jewell CM
最近的研究表明，许多生物材料疫苗载体能够激活免疫刺激途径，即使在没有其他免疫信号的情况下。生物降解过程中聚合物性质的变化如何影响这种固有的免疫原性还没有得到很好的研究，但这些信息可能有助于合理设计可降解的疫苗载体，帮助直接免疫应答。我们使用可降解的聚（β-氨基酯）（PBAE）来探索作为聚合物降解程度和聚合物形式（例如，可溶性颗粒）。PBAE颗粒通过静电相互作用凝聚以模拟常见的疫苗方法，其强烈激活树突细胞，驱动抗原呈递，并在抗原存在下增强T细胞增殖。聚合物分子量强烈影响这些效应，在短降解时间内具有最大刺激-对应于高分子量-并且随着降解的继续而减弱。相反，游离聚合物是免疫惰性的。在小鼠中，PBAE颗粒增加淋巴结中细胞的数量和活化状态。机制研究表明，随着聚合物降解过程中颗粒的物理化学性质和浓度发生变化，免疫原性也会不断变化。这项工作证实了可降解的合成聚合物的免疫学特性可以随着时间的推移而演变，并创造了在新疫苗中利用这一特性的机会。
Recent studies reveal many biomaterial vaccine carriers are able to activate immunostimulatory pathways, even in the absence of other immune signals. How the changing properties of polymers during biodegradation impact this intrinsic immunogenicity is not well studied, yet this information could contribute to rational design of degradable vaccine carriers that help direct immune response. We use degradable poly(beta-amino esters) (PBAEs) to explore intrinsic immunogenicity as a function of the degree of polymer degradation and polymer form (e.g., soluble, particles). PBAE particles condensed by electrostatic interaction to mimic a common vaccine approach strongly activate dendritic cells, drive antigen presentation, and enhance T cell proliferation in the presence of antigen. Polymer molecular weight strongly influences these effects, with maximum stimulation at short degradation times – corresponding to high molecular weight – and waning levels as degradation continues. In contrast, free polymer is immunologically inert. In mice, PBAE particles increase the numbers and activation state of cells in lymph nodes. Mechanistic studies reveal that this evolving immunogenicity occurs as the physicochemical properties and concentration of particles change during polymer degradation. This work confirms the immunological profile of degradable, synthetic polymers can evolve over time and creates an opportunity to leverage this feature in new vaccines.