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 required efficiency; finally, the cell may not have the desired receptor at all. Some time ago, it occurred to researchers that immune cells should be modified, providing them with exactly the receptor that is needed. This is how the CAR T-lymphocyte method appeared, where CAR stands for chimaeric antigen receptor – that is, T-lymphocytes with a chimeric antigen receptor (antigen is understood as 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 antigenic molecules and recognize them well. Then CAR T cells are injected back into the patient.
Usually, CAR T-lymphocytes are tuned to cancer cells, constructing such receptors for them that would recognize only cancer antigen molecules 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 tune against aged cells, which accumulate and provoke various chronic diseases. And in 2019 in Nature an article was published in which CAR T cells were involved in the heart. After a heart attack, damaged areas in the heart heal, but new muscle cells do not appear (the heart cannot regenerate), so connective tissue takes their place – in other words, scarring of the heart occurs. The connective tissue does not conduct electrical impulses and does not contract, in addition, it is not too elastic, so that the scar interferes with the work of the heart. It is desirable that the connective tissue appears just as much, as much is needed, but it tends to grow, so that after an attack the heart muscle works worse than before, not only because some of the muscle cells have died, but also because of the connective tissue.
The fibroblast connective tissue cells in an active state carry the FAP protein (fibroblast activating protein – a protein that activates fibroblasts). CAR T cells can be configured to recognize FAP and destroy active fibroblasts so that scarring is not too severe. However, the problem is that CAR T cells will work for several months, and during this time they will generally destroy all active fibroblasts – and after all, the damage in the heart should still heal.
In a recent article in Science it is said that modified T-lymphocytes will not work very long if they are modified directly in the body. The experiments were carried out with mice injected with nanoparticles with mRNA inside (approximately the same method is used in RNA vaccines). Lipid nanoparticles serve as messengers that deliver to T lymphocytes mRNA encoding a receptor for FAP protein recognition on fibroblasts. So that the parcels 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.
Why won’t such CAR T cells last long? Because mRNA does not live long, and after a short time it will be destroyed, and T cells will stop synthesizing a receptor for FAP recognition. In mice after a day or two, 15–22% of CAR T-lymphocytes were found in the blood, after which their number began to fall and after a week they completely disappeared.
To test how effective such a method is for the heart, the mice were injected with drugs that made the heart muscle work hard. After signs of fibrosis (that is, proliferation of connective tissue) appeared in the heart, the animals were injected with modifying nanoparticles. And indeed, less connective tissue was produced in the heart: the hearts of mice with CAR T cells looked almost the same as in normal healthy mice, and it worked significantly better than in mice in which the lymphocytes were not modified.
That is, T-lymphocytes can, if anything, be modified right on the spot, without getting them out of the body – and the method of such a modification, as mentioned, has already been tested in humans thanks to mRNA vaccines. And you don’t have to be limited to the heart: T cells can be targeted to other tissues and organs that require short-term immune intervention. On the other hand, if we talk about the heart, then here it is necessary to check how the CAR T-lymphocyte method is suitable for severe lesions of the heart muscle with large-scale scarring.
Based on materials The Scientist
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