Targeting cardiac fibrosis with engineered T cells
Targeting cardiac fibrosis with engineered T cells
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DOI：
10.1038/s41586-019-1546-z
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发表时间：
2019-09-19
期刊：
影响因子：
64.8
通讯作者：
Epstein, Jonathan A.
中科院分区：
文献类型：
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作者：
Aghajanian, Haig;Kimura, Toru;Epstein, Jonathan A.
纤维化几乎见于每一种形式的心肌疾病(1)。在损伤后，心脏中的心脏成纤维细胞开始通过沉积多余的细胞外基质来重塑心肌，导致组织的僵硬增加和顺应性降低。过度的心脏纤维化是各种形式的心脏病和心力衰竭进展的重要因素(2)。然而，针对纤维化的临床干预和治疗仍然有限(3)。在这里，我们展示了重定向T细胞免疫治疗的有效性，以特异性地针对小鼠的病理性心肌纤维化。我们发现，表达异种抗原的心脏成纤维细胞可以通过过继转移抗原特异性CD8(+)T细胞有效地靶向和消融。通过对健康人和疾病人心脏成纤维细胞基因特征的表达分析，我们确定了心脏成纤维细胞的内源性靶点-成纤维细胞激活蛋白。过继转移表达抗成纤维细胞活化蛋白嵌合抗原受体的T细胞可显著减少小鼠心脏纤维化并恢复损伤后的功能。这些结果为开发治疗心脏病的免疫治疗药物提供了原则上的证据。
Fibrosis is observed in nearly every form of myocardial disease(1). Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess extracellular matrix, resulting in increased stiffness and reduced compliance of the tissue. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure(2). However, clinical interventions and therapies that target fibrosis remain limited(3). Here we demonstrate the efficacy of redirected T cell immunotherapy to specifically target pathological cardiac fibrosis in mice. We find that cardiac fibroblasts that express a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8(+) T cells. Through expression analysis of the gene signatures of cardiac fibroblasts obtained from healthy and diseased human hearts, we identify an endogenous target of cardiac fibroblasts-fibroblast activation protein. Adoptive transfer of T cells that express a chimeric antigen receptor against fibroblast activation protein results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide proof-of-principle for the development of immunotherapeutic drugs for the treatment of cardiac disease.