Glue for a broken heart
Modified immune cells treat the consequences of a heart attack
Kirill Stasevich, Science and Life (nkj.ru ) based on the materials of The Scientist
Immune cells recognize pathogens and diseased cells with the help of receptors: surface proteins that are able to bind to certain molecules belonging to viruses, bacteria, malignant cells, etc. But these immune receptors do not always work with the proper efficiency; finally, the cell may not have the right receptor at all. Some time ago, it occurred to researchers that immune cells should be modified by providing them with exactly the right receptor. This is how the CAR method of T-lymphocytes appeared, where CAR means chimaeric antigen receptor – that is, T-lymphocytes with a chimeric receptor for an antigen (an antigen is a molecule that the immune system must recognize and respond to). T cells are taken from an individual and their receptors are modified so that they recognize specific antigen molecules and recognize them well. Then CAR T-lymphocytes are injected back to the patient.
Usually, CAR T lymphocytes are tuned to cancer cells by constructing receptors for them that would recognize only cancer molecules-antigens that are absent on healthy cells. But in general, this method can be adapted for other purposes. Two years ago we wrote about how CAR T-lymphocytes are tuned against aged cells, which, accumulating, provoke various chronic diseases. And in 2019, an article was published in Nature in which CAR T cells were engaged in the heart. After a heart attack, the damaged areas in the heart heal, but no new muscle cells appear (the heart cannot regenerate), so connective tissue takes their place – in other words, scarring of the heart occurs. Connective tissue does not conduct electrical impulses and does not contract, in addition, it is not too elastic, so that the scar prevents the heart from working. It is desirable that connective tissue appears exactly as much as it needs, but it tends to grow, so that after an attack, the heart muscle works worse than before, not only because part of the muscle cells died, but also because of the connective tissue.
Connective tissue fibroblast cells in the active state carry the FAP protein (fibroblast activating protein – a protein that activates fibroblasts). CAR T cells can be configured so that they recognize FAP and destroy active fibroblasts – then scarring will not be too strong. However, the problem is that CAR T cells will work for several months, and during this time they will destroy all active fibroblasts altogether - and after all, the damage in the heart should still heal.
In a recent article in Science (Gao & Chen, T cells to fix a broken heart) it is said that modified T lymphocytes will not work for very long if they are modified directly in the body. Experiments were conducted with mice injected with nanoparticles with mRNA inside (approximately the same method is used in RNA vaccines). Lipid nanoparticles (LNPs) serve as parcels that deliver mRNA encoding a receptor for recognition of the FAP protein on fibroblasts to T-lymphocytes. In order for the parcels to arrive exactly at the address, they are coated on the outside with antibodies to the CD5 protein – it sits on the surface of T-lymphocytes.
A drawing from an article in Science.
Why will such CAR T cells work for a short time? Because mRNA does not live for a long time, and after a short time it will collapse, and T cells will stop synthesizing the receptor for FAP recognition. In mice, after a day or two, 15-22% of CAR T-lymphocytes were detected in the blood, after which their number began to fall and after a week they completely disappeared.
To test how effective this method is against the heart, mice were injected with drugs that forced the heart muscle to work hard. After signs of fibrosis appeared in the heart (that is, the growth of connective tissue), modifying nanoparticles were injected into the animals. And there was indeed less connective tissue in the heart: the heart of mice with CAR T-lymphocytes looked almost the same as in normal healthy mice, and it worked noticeably better than in mice whose lymphocytes were not modified.
That is, T-lymphocytes can be modified on the spot, if necessary, without getting them out of the body – and the method of such modification, as it was said, has already been tested in humans thanks to mRNA vaccines. And it is not necessary to be limited to the heart: T-cells can be targeted at some other tissues and organs where short-term immune intervention is required. On the other hand, if we talk about the heart, then it is necessary to check whether the method of CAR T-lymphocytes is suitable for severe lesions of the heart muscle with large-scale scarring.
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