Molecular Dynamics of Multivalent Soluble Antigen Arrays Support a Two-Signal Co-delivery Mechanism in the Treatment of Experimental Autoimmune Encephalomyelitis
Molecular Dynamics of Multivalent Soluble Antigen Arrays Support a Two-Signal Co-delivery Mechanism in the Treatment of Experimental Autoimmune Encephalomyelitis
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DOI：
10.1021/acs.molpharmaceut.5b00825
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发表时间：
2016-02-01
影响因子：
4.9
通讯作者：
Berkland, Cory
中科院分区：
文献类型：
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作者：
Hartwell, Brittany L.;Hall, Aaron Smalter;Berkland, Cory
许多目前用于自身免疫性疾病如多发性硬化症（MS）的疗法导致全面免疫抑制，从而导致疗效不足，不良副作用的风险增加。多价可溶性抗原阵列，在柔性聚合物骨架上呈现自身抗原和次级抑制信号的纳米材料，被假设为将免疫应答转向选择性自身抗原耐受以抑制自身免疫性疾病。自身抗原和二级信号的双信号共递送被认为对于针对实验性自身免疫性脑脊髓炎（MS的小鼠模型）的治疗功效是必要的。动态光散射和计算机分子动力学模拟补充了这些研究，以阐明双信号的作用共递送在确定治疗潜力中。物理化学特性，如颗粒大小和分子间相互作用和链缠结的分子亲和力可能促进两个信号的共转运，以产生疗效。这些发现阐明了可溶性抗原阵列发挥其治疗作用的潜在机制，并有助于指导未来多价抗原特异性免疫疗法的发展。
Many current therapies for autoimmune diseases such as multiple sclerosis (MS) result in global immunosuppression, rendering insufficient efficacy with increased risk of adverse side effects. Multivalent soluble antigen arrays, nanomaterials presenting both autoantigen and secondary inhibitory signals on a flexible polymer backbone, are hypothesized to shift the immune response toward selective autoantigenic tolerance to repress autoimmune disease. Two-signal co-delivery of both autoantigen and secondary signal were deemed necessary for therapeutic efficacy against experimental autoimmune encephalomyelitis, a murine model of MS. Dynamic light scattering and in silico molecular dynamics simulations complemented these studies to illuminate the role of two signal co-delivery in determining therapeutic potential. Physicochemical characteristics such as particle size and molecular affinity for intermolecular interactions and chain entanglement likely facilitated cotransport of two signals to produce efficacy. These findings elucidate potential mechanisms whereby soluble antigen arrays enact their therapeutic effect and help to guide the development of future multivalent antigen-specific immunotherapies.