Vaccination-based immunotherapy to target profibrotic cells in liver and lung
Vaccination-based immunotherapy to target profibrotic cells in liver and lung
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基于疫苗的免疫疗法针对肝和肺中的促纤维化细胞
DOI：
10.1016/j.stem.2022.08.012
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发表时间：
2022
期刊：
影响因子：
23.9
通讯作者：
So
中科院分区：
文献类型：
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作者：
obecki M;Chen J;Krzywinska E;Nagarajan S;Fan Z;Nelius E;Monne Rodriguez JM;Seehusen F;Hussein A;Moschini G;Hajam EY;Kiran R;Gotthardt D;Debbache J;Badoual C;Sato T;Isagawa T;Takeda N;Tanchot C;Tartour E;Weber A;Werner S;Loffing J;So
纤维化是几乎所有形式的慢性疾病的最终途径，无论其发病机制如何。在慢性损伤时，活化的纤维化成纤维细胞存款过量的细胞外基质，并且严重的组织纤维化可发生在几乎任何器官中。然而，靶向纤维化细胞，同时保留健康组织中的稳态成纤维细胞的抗纤维化疗法是有限的。我们测试了是否对内源性蛋白质，强烈表达在纤维化细胞，但高度限制在静止的成纤维细胞的特异性免疫，可以引发抗原特异性细胞毒性T细胞反应，以改善器官fibrosis.In silicopepitope预测显示，激活基因Adam12和Gli1在profibrotic细胞和由此产生的“自我肽”可以利用T细胞疫苗消融纤维化细胞。我们证明了疫苗接种方法对建立CD8+T细胞应答的有效性，该应答减少了小鼠肝脏和肺中的成纤维细胞和纤维化。这些结果为基于疫苗的免疫疗法治疗纤维化提供了原理证明。
Fibrosis is the final path of nearly every form of chronic disease, regardless of the pathogenesis. Upon chronic injury, activated, fibrogenic fibroblasts deposit excess extracellular matrix, and severe tissue fibrosis can occur in virtually any organ. However, antifibrotic therapies that target fibrogenic cells, while sparing homeostatic fibroblasts in healthy tissues, are limited. We tested whether specific immunization against endogenous proteins, strongly expressed in fibrogenic cells but highly restricted in quiescent fibroblasts, can elicit an antigen-specific cytotoxic T cell response to ameliorate organ fibrosis.In silicoepitope prediction revealed that activation of the genesAdam12andGli1in profibrotic cells and the resulting "self-peptides" can be exploited for T cell vaccines to ablate fibrogenic cells. We demonstrate the efficacy of a vaccination approach to mount CD8+T cell responses that reduce fibroblasts and fibrosis in the liver and lungs in mice. These results provide proof of principle for vaccination-based immunotherapies to treat fibrosis.