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Nature. 2019 Sep;573(7774):430-433. doi: 10.1038/s41586-019-1546-z. Epub 2019 Sep 11.

Targeting cardiac fibrosis with engineered T cells.

Author information

1
Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
2
Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3
Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
6
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
7
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
8
Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
9
Echocardiography Laboratory, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
10
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
11
Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, Germany.
12
Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. epsteinj@upenn.edu.
13
Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. epsteinj@upenn.edu.
14
Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. epsteinj@upenn.edu.
15
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. epsteinj@upenn.edu.

Abstract

Fibrosis is observed in nearly every form of myocardial disease1. 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 failure2. 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.

Comment in

PMID:
31511695
PMCID:
PMC6752964
[Available on 2020-03-11]
DOI:
10.1038/s41586-019-1546-z

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