Polyplexes assembled from self-peptides and regulatory nucleic acids blunt toll-like receptor signaling to combat autoimmunity.
Polyplexes assembled from self-peptides and regulatory nucleic acids blunt toll-like receptor signaling to combat autoimmunity.
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DOI：
10.1016/j.biomaterials.2016.11.052
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发表时间：
2017-02
期刊：
影响因子：
14
通讯作者：
Jewell CM
中科院分区：
文献类型：
--
作者：
Hess KL;Andorko JI;Tostanoski LH;Jewell CM
当免疫系统错误地将自身分子识别为外来分子时，就会发生自身免疫性疾病。在多发性硬化症（MS）的情况下，髓鞘质受到攻击。有趣的是，新的研究揭示了 Toll 样受体 (TLR)，这种通常参与针对病原体产生免疫反应的途径，在人类和动物模型中驱动自身免疫性疾病方面发挥着重要作用。我们推断，由髓磷脂自身抗原和调节性 TLR 拮抗剂形成的复合物可能会限制髓磷脂特异性 T 细胞分化过程中的 TLR 信号传导，通过使 T 细胞远离炎症表型来诱导耐受。通过用阳离子氨基酸修饰髓磷脂肽来形成复合物，以产生能够缩合基于阴离子核酸的 TLR 拮抗剂的肽。这些免疫复合物消除了通常用于浓缩复合物的合成聚合物，并且不依赖于基因表达；然而，这些复合物模仿了传统聚合复合物的关键特征，例如可调负载和共同递送。使用这些材料和经典的复合物分析技术，我们展示了两种免疫信号的浓缩、免受酶降解的保护以及可调节的物理化学特性。我们发现多聚复合物可减少 TLR 信号传导，并且在原代 DC 和 T 细胞共培养中可减少髓磷脂驱动的炎症。在多发性硬化症小鼠模型中，这些致耐受性复合物可改善疾病的进展、严重程度和发病率。
Autoimmune diseases occur when the immune system incorrectly recognize self-molecules as foreign; in the case of multiple sclerosis (MS), myelin is attacked. Intriguingly, new studies reveal toll-like receptors (TLR), pathways usually involved in generating immune response again pathogens, play a significant role in driving autoimmune disease in both humans and animal models. We reasoned polyplexes formed from myelin self-antigen and regulatory TLR antagonists might limit TLR signaling during differentiation of myelin-specific T cells, inducing tolerance by biasing T cells away from inflammatory phenotypes. Complexes were formed by modifying myelin peptide with cationic amino acids to create peptides able to condense the anionic nucleic-acid based TLR antagonist. These immunological polyplexes eliminate synthetic polymers commonly used to condense polyplexes and do not rely on gene expression; however, the complexes mimic key features of traditional polyplexes such as tunable loading and co-delivery. Using these materials and classic polyplex analysis techniques, we demonstrate condensation of both immune signals, protection from enzymatic degradation, and tunable physicochemical properties. We show polyplexes reduce TLR-signaling, and in primary DC and T cell co-culture, reduce myelin-driven inflammation. During mouse models of MS, these tolerogenic polyplexes improve the progression, severity, and incidence of disease.
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影响因子：
9.7
作者：
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通讯作者：
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影响因子：
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作者：
Clemente-Casares, Xavier;Blanco, Jesus;Santamaria, Pere
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