美国宾夕法尼亚大学医学院Jonathan A. Epstein研究组，发现可利用工程化T细胞靶向治疗心肌纤维化。相关论文2019年9月11日在线发表在《自然》上。

研究人员证明重定向T细胞免疫疗法特异性靶向小鼠病理性心脏纤维化的功效。研究人员发现表达异种抗原的心脏成纤维细胞可以通过抗原特异性CD8 阳性T细胞的过继转移有效地靶向和消除。通过对从健康和患病的人类心脏获得的心脏成纤维细胞的基因特征的表达分析，研究人员鉴定了心脏成纤维细胞-成纤维细胞活化蛋白的内源靶标。表达针对成纤维细胞活化蛋白的嵌合抗原受体的T细胞的过继转移导致小鼠心脏损伤后心脏纤维化和功能恢复的显著减少。这些结果为开发用于治疗心脏病的免疫治疗药物提供了原理性证明。

据悉，在几乎所有形式的心肌疾病中均可观察到纤维化。受伤后，心脏中的心脏成纤维细胞通过沉积过量的细胞外基质开始重塑心肌，导致刚度的增加和组织顺应性的降低。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。然而，针对纤维化的临床干预和治疗仍然有限。

附：英文原文

Title:Targeting cardiac fibrosis with engineered T cells

Author:Haig Aghajanian, Toru Kimura, Joel G. Rurik, Aidan S. Hancock, Michael S. Leibowitz, Li Li, John Scholler, James Monslow, Albert Lo, Wei Han, Tao Wang, Kenneth Bedi, Michael P. Morley, Ricardo A. Linares Saldana, Nikhita A. Bolar, Kendra McDaid, Charles-Antoine Assenmacher, Cheryl L. Smith, Dagmar Wirth, Carl H. June, Kenneth B. Margulies, Rajan Jain, Ellen Puré, Steven M. Albelda & Jonathan A. Epstein

Issue&Volume: 2019-09-11

Abstract:

Fibrosis is observed in nearly every form of myocardial disease. 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. However, clinical interventions and therapies that target fibrosis remain limited3. 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.

DOI: 10.1038/s41586-019-1546-z

Source:https://www.nature.com/articles/s41586-019-1546-z