Antigen delivery with poly(propylacrylic acid) conjugation enhances MHC-1 presentation and T-cell activation.
Antigen delivery with poly(propylacrylic acid) conjugation enhances MHC-1 presentation and T-cell activation.
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DOI：
10.1021/bc800317a
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发表时间：
2009-02
影响因子：
4.7
通讯作者：
Stayton, Patrick S.
中科院分区：
文献类型：
--
作者：
Flanary, Suzanne;Hoffman, Allan S.;Stayton, Patrick S.
虽然许多传染病通过疫苗策略得到控制，但重要的局限性继续促使开发更好的抗原递送系统。这项研究的重点是使用pH敏感的聚合物载体的基础上聚（丙基丙烯酸）（PPAA），以解决需要更有效的CD 8细胞毒性T细胞（CTL）的反应。用卵清蛋白作为蛋白抗原的MHC-1/CD 8 CTL细胞模型系统用于测试PPAA是否可以增强卵清蛋白向MHC-1展示途径的递送。通过二硫键交换将卵清蛋白与聚（丙基丙烯酸-co-吡啶基二硫丙烯酸酯）（PPAA-PDSA）偶联，以制备可逆偶联物，该偶联物可被抗原呈递细胞胞质溶胶中的谷胱甘肽氧化还原系统还原。PPAA-PDSA卵清蛋白缀合物显示母体聚合物的pH敏感性膜破坏性质，如通过它们的溶血活性（在内体pH值为6-6.5时急剧活性）所确定的。与游离卵清蛋白相比，聚合物-卵清蛋白缀合物在MHC-1呈递和卵清蛋白特异性CTL活化方面表现出强的22倍增加。用不显示膜破坏活性的卵清蛋白和聚（甲基丙烯酸）（PMAA）的对照缀合物未观察到CTL活化，表明聚合物的膜去稳定化性质导致增加的MHC-1展示和CTL活化。进一步的机制研究定量了放射性标记缀合物稳定细胞内定位的时间过程。与卵清蛋白或PMAA-卵清蛋白的小于10%相比，52%的初始内化的PPAA-缀合的卵清蛋白在4小时后保留在细胞中。这些结果显示PPAA-抗原缀合物的增强的胞质递送和MHC-1呈递，表明它们保证将来表征为CD 8增强的疫苗递送系统。
While many infectious diseases are controlled by vaccine strategies, important limitations continue to motivate the development of better antigen delivery systems. This study focuses on the use of a pH-sensitive polymeric carrier based on poly(propylacrylic acid) (PPAA) to address the need for more potent CD8 cytotoxic T-cell (CTL) responses. An MHC-1/CD8 CTL cell model system with ovalbumin as the protein antigen was used to test whether PPAA could enhance the delivery of ovalbumin into the MHC-1 display pathway. Ovalbumin was conjugated to poly(propylacrylic acid-co-pyridyldisulfide acrylate) (PPAA-PDSA) by disulfide exchange to make reversible conjugates that could be reduced by the glutathione redox system in the cytosol of antigen presenting cells. The PPAA-PDSA ovalbumin conjugates displayed the pH-sensitive membrane disruptive properties of the parent polymer as determined by their hemolysis activities (sharply active at the endosomal pH values of 6–6.5). The polymer-ovalbumin conjugates exhibited strong 22-fold increases in the MHC-1 presentation and ovalbumin-specific CTL activation compared to free ovalbumin. No CTL activation was observed with control conjugates of ovalbumin and poly(methylacrylic acid) (PMAA) that do not display membrane disruptive activies, suggesting it is the membrane destabilizing properties of the polymer that result in increased MHC-1 display and CTL activation. Further mechanistic studies quantitated the time course of stable intracellular localization of radiolabeled conjugates. 52% of initially internalized PPAA-conjugated ovalbumin remained in the cells after 4 hrs, compared to less than 10% of ovalbumin or PMAA-ovalbumin. These results showing enhanced cytosolic delivery and MHC-1 presentation for the PPAA-antigen conjugates suggest that they warrant future characterization as a CD8-enhancing vaccine delivery system.
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影响因子：
2.4
作者：
Albarran, B;To, R;Stayton, PS
通讯作者：
Stayton, PS
影响因子：
82.9
作者：
Folgori, A;Capone, S;Nicosia, A
通讯作者：
Nicosia, A
DOI：
10.1016/j.jconrel.2005.02.027
发表时间：
2005-07-20
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Kwon YJ;Standley SM;Goh SL;Fréchet JM
通讯作者：
Fréchet JM
DOI：
10.1073/pnas.94.22.12059
发表时间：
1997-10-28
影响因子：
11.1
作者：
Goletz, TJ;Klimpel, KR;Berzofsky, JA
通讯作者：
Berzofsky, JA
影响因子：
10.8
作者：
Bulmus, V;Woodward, M;Hoffman, A
通讯作者：
Hoffman, A