CD47 Enhances In Vivo Functionality of Artificial Antigen-Presenting Cells.
CD47 Enhances In Vivo Functionality of Artificial Antigen-Presenting Cells.
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DOI：
10.1158/1078-0432.ccr-14-2696
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发表时间：
2015-05-01
期刊：
影响因子：
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通讯作者：
Schütz C
中科院分区：
文献类型：
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作者：
Bruns H;Bessell C;Varela JC;Haupt C;Fang J;Pasemann S;Mackensen A;Oelke M;Schneck JP;Schütz C
人工抗原呈递细胞（aAPC）已成功地用于在体外以及体内刺激抗原特异性T细胞应答。虽然aAPC在体外与自体树突状细胞相比是有利的，但它们在体内的作用可能通过巨噬细胞的快速清除而减弱。因此，为了防止巨噬细胞摄取aAPC并使其清除率最小化，从而增加体内功能，我们研究了“不要吃我”三信号aAPC与经典的两信号aAPC相比的效率。为了产生“不要吃我”aAPC，将⑶ 47另外固定到经典aAPC（aAPC ⑶ 47+）上。在体外人原代T细胞和巨噬细胞共培养物中分析aAPC和aAPC ⑶ 47+。在NOD/SCID T细胞增殖和B16-SIY黑素瘤模型中比较体内效率。该研究表明，与人巨噬细胞共培养的aAPC ⑶ 47+显示出吞噬作用的⑶ 47浓度依赖性抑制，而它们产生和扩增抗原特异性T细胞的能力不受影响。此外，当与aAPC产生的T细胞相比时，aAPC ⑶ 47+产生的T细胞显示出等同的杀伤能力和多功能性。此外，体内研究证明aAPC ⑶ 47+相对于正常aAPC的增强的刺激能力和肿瘤抑制，以及不同器官中的不同生物分布。我们的数据首次表明，用CD 47功能化的aAPC在体外保持其刺激能力，并证明增强的体内效率。因此，这种下一代aAPC CD 47+具有独特的潜力来增强aAPC技术在未来免疫治疗方法中的应用。
Artificial Antigen-Presenting Cells, aAPC, have successfully been used to stimulate antigen-specific T cell responses in vitro as well as in vivo. While aAPC compare favorable to autologous dendritic cells in vitro, their effect in vivo might be diminished through rapid clearance by macrophages. Therefore, to prevent uptake and minimize clearance of aAPC by macrophages, and thereby increasing in vivo functionality, we investigated the efficiency of “don’t eat me” three-signal aAPC compared to classical two-signal aAPC. To generate “don’t eat me” aAPC, CD47 was additionally immobilized onto classical aAPC (aAPCCD47+). aAPC and aAPCCD47+ were analyzed in in vitro human primary T cell and macrophage co-cultures. In vivo efficiency was compared in a NOD/SCID T cell proliferation and a B16-SIY melanoma model. This study demonstrates that aAPCCD47+ in co-culture with human macrophages show a CD47 concentration dependent inhibition of phagocytosis, while their ability to generate and expand antigen-specific T cells was not affected. Furthermore, aAPCCD47+ generated T cells displayed equivalent killing abilities and polyfunctionality when compared to aAPC generated T cells. In addition, in vivo studies demonstrated an enhanced stimulatory capacity and tumor inhibition of aAPCCD47+ over normal aAPC in conjunction with diverging bio-distribution in different organs. Our data for the first time show that aAPC functionalized with CD47 maintain their stimulatory capacity in vitro and demonstrate enhanced in vivo efficiency. Thus this next generation aAPCCD47+ have a unique potential to enhance the application of the aAPC technology for future immunotherapy approaches.