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Conjugation of Transforming Growth Factor Beta to Antigen-Loaded Poly(lactide-co-glycolide) Nanoparticles Enhances Efficiency of Antigen-Specific Tolerance
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-11-17 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00624 Liam M. Casey 1 , Ryan M. Pearson 2, 3 , Kevin R. Hughes 2 , Jeffrey M. H. Liu 2 , Justin A. Rose 1 , Madeleine G. North 2 , Leon Z. Wang 2 , Mei Lei 2 , Stephen D. Miller 4, 5 , Lonnie D. Shea 1, 2
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-11-17 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00624 Liam M. Casey 1 , Ryan M. Pearson 2, 3 , Kevin R. Hughes 2 , Jeffrey M. H. Liu 2 , Justin A. Rose 1 , Madeleine G. North 2 , Leon Z. Wang 2 , Mei Lei 2 , Stephen D. Miller 4, 5 , Lonnie D. Shea 1, 2
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Current strategies for treating autoimmunity involve the administration of broad-acting immunosuppressive agents that impair healthy immunity. Intravenous (i.v.) administration of poly(lactide-co-glycolide) nanoparticles (NPs) containing disease-relevant antigens (Ag-NPs) have demonstrated antigen (Ag)-specific immune tolerance in models of autoimmunity. However, subcutaneous (s.c.) delivery of Ag-NPs has not been effective. This investigation tested the hypothesis that codelivery of the immunomodulatory cytokine, transforming growth factor beta 1 (TGF-β), on Ag-NPs would modulate the immune response to Ag-NPs and improve the efficiency of tolerance induction. TGF-β was coupled to the surface of Ag-NPs such that the loadings of Ag and TGF-β were independently tunable. The particles demonstrated bioactive delivery of Ag and TGF-β in vitro by reducing the inflammatory phenotype of bone marrow-derived dendritic cells and inducing regulatory T cells in a coculture system. Using an in vivo mouse model for multiple sclerosis, experimental autoimmune encephalomyelitis, TGF-β codelivery on Ag-NPs resulted in improved efficacy at lower doses by i.v. administration and significantly reduced disease severity by s.c. administration. This study demonstrates that the codelivery of immunomodulatory cytokines on Ag-NPs may enhance the efficacy of Ag-specific tolerance therapies by programming Ag presenting cells for more efficient tolerance induction.
中文翻译：
转化生长因子β与负载抗原的聚（丙交酯-乙交酯）纳米粒子的缀合提高了抗原特异性耐受性的效率
当前用于治疗自身免疫的策略包括给予损害健康免疫力的广泛作用的免疫抑制剂。静脉内（iv）聚施用（丙交酯-共包含疾病相关抗原（Ag-NPs）的纳米粒子（NP）已在自身免疫模型中证明了抗原（Ag）特异性免疫耐受。然而，Ag-NP的皮下（sc）递送并不有效。这项研究检验了以下假设，即在Ag-NP上的免疫调节细胞因子的代码传递，即转化生长因子β1（TGF-β）会调节对Ag-NP的免疫反应，并提高耐受诱导的效率。将TGF-β偶联至Ag-NP的表面，使得Ag和TGF-β的负载可独立调节。通过减少骨髓来源的树突状细胞的炎性表型并在共培养系统中诱导调节性T细胞，该颗粒在体外证明了Ag和TGF-β的生物活性传递。使用体内用于多发性硬化的小鼠模型，实验性自身免疫性脑脊髓炎，Ag-NPs上的TGF-β编码转运通过静脉给药可降低剂量，并通过sc给药显着降低疾病严重性。这项研究表明，通过对Ag呈递细胞进行编程以更有效地诱导耐受性，免疫调节细胞因子在Ag-NPs上的代码传递可以增强Ag特异性耐受治疗的功效。
更新日期：2017-11-17
中文翻译：
转化生长因子β与负载抗原的聚（丙交酯-乙交酯）纳米粒子的缀合提高了抗原特异性耐受性的效率
当前用于治疗自身免疫的策略包括给予损害健康免疫力的广泛作用的免疫抑制剂。静脉内（iv）聚施用（丙交酯-共包含疾病相关抗原（Ag-NPs）的纳米粒子（NP）已在自身免疫模型中证明了抗原（Ag）特异性免疫耐受。然而，Ag-NP的皮下（sc）递送并不有效。这项研究检验了以下假设，即在Ag-NP上的免疫调节细胞因子的代码传递，即转化生长因子β1（TGF-β）会调节对Ag-NP的免疫反应，并提高耐受诱导的效率。将TGF-β偶联至Ag-NP的表面，使得Ag和TGF-β的负载可独立调节。通过减少骨髓来源的树突状细胞的炎性表型并在共培养系统中诱导调节性T细胞，该颗粒在体外证明了Ag和TGF-β的生物活性传递。使用体内用于多发性硬化的小鼠模型，实验性自身免疫性脑脊髓炎，Ag-NPs上的TGF-β编码转运通过静脉给药可降低剂量，并通过sc给药显着降低疾病严重性。这项研究表明，通过对Ag呈递细胞进行编程以更有效地诱导耐受性，免疫调节细胞因子在Ag-NPs上的代码传递可以增强Ag特异性耐受治疗的功效。
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