Engineered T-cells as a Target for Fibrosis in Myocardial Disease

Simran Kaur ‘20

cardiac
Figure 1. Cardiac connective tissue is composed of fibroblasts, which produce extracellular matrix (ECM) upon activation or injury. Accumulation of excess ECM results in cardiac fibrosis and possible cardiac failure.  

Fibrosis, the excessive deposition of extracellular matrix by fibroblasts into cardiac tissue, is a significant process in the development of cardiac disease and subsequent cardiac failure, but there are not many clinical treatments that can effectively target it. Cardiac fibroblasts express an antigen that can be targeted by the transplantation of antigen-specific CD8+ T-cells because CD8+ T-cells are involved in the inflammatory response in cardiac fibrosis. Researchers in this study used T-cell immunotherapy in order to specifically target and eradicate cardiac fibrosis in mice. 

Mice were generated to express the xenogeneic antigen ovalbumin peptide (OVA), the primary antigen on cardiac fibroblasts involved in the activation of fibrosis, by using tamoxifen-recombinase specifically targeted to the periostin (Postn) locus. The Postn locus has been known to be expressed by injury-activated cardiac fibroblasts. In order to produce injury and subsequent fibrosis in cardiac tissue, the mice were administered angiotensin II and phenylephrine for a duration of 28 days through an osmotic minipump. The combination of these two drugs is known to cause significant cardiac fibrosis and dysfunction because of its direct negative effects on fibroblasts and myocytes. In addition, Tamoxifen was regularly administered via intraperitoneal injection to ensure the expression of OVA on the fibroblasts. In order to specifically target CD8+ T-cells, a transplant of CD8+ T-cells that express a receptor against the OVA peptide (OT-I T-cells) was performed a week after the initiation of the experiment. 

The mice were euthanized, and coronal sections of cardiac tissue were taken to determine the level of fibrosis. Sirius-red staining of samples taken from both the control and experimental groups showed that the mice that received the OT-I T-cells suffered from a significantly less amount of cardiac fibrosis in comparison to the cohort of control mice. In addition, cardiac hypertrophy in the experimental mice was also lower, shown by the heart to bodyweight ratio. The results of this study show that the adoptive transfer of T-cells that specifically target antigen receptors can decrease cardiac fibrosis and help restore cardiac function following injury. Future studies would be beneficial to reinforce the principle of using immunotherapeutic drugs in the treatment of cardiac diseases. 

 

References:

  1. H. Aghajanian, et al., Targeting Cardiac Fibrosis with Engineered T cells. Nature, (2019). doi: 10.1038/s41586-019-1546-z.
  2. Image retrieved from: https://commons.wikimedia.org/wiki/File:Muscle_Tissue_Cardiac_Muscle_(42013029032).jpg

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