The first victory over lupus erythematosus
Maxim Rousseau, Polit.roo
For the first time, scientists managed to completely rid experimental mice of a disease known as systemic lupus erythematosus. This was done with the help of one of the varieties of gene therapy – the use of chimeric antigenic receptors.
Lupus is an autoimmune disease, the cells of the immune system in patients become hyperactive and lose the ability to distinguish between pathogens and healthy body tissues. As a result, they cause inflammation and damage to joints, skin and internal organs. According to the American Lupus Foundation, about five million people suffer from it in the world.
The purpose of creating chimeric antigen receptors is to teach the T-cells of the immune system to fight certain types of cells that are associated with a particular disease. The target may be, for example, cells of certain types of tumors, and in the case of lupus, B-lymphocytes become it. His own T-lymphocytes are extracted from the patient's body and subjected to genetic modification, during which a specially constructed gene of a certain protein – the cell surface receptor - is transmitted to them. This is the chimeric antigenic receptor. This protein is able to selectively bind to antigens – proteins of target cells. Thus, T-lymphocytes, having returned to the patient's body, are already trained to recognize and destroy these cells.
Therapy using chimeric antigenic receptors (CAR-T therapy) originated in the 1990s and the main direction of its expected application has always been considered the treatment of oncological diseases. Recently, two methods of CAR-T therapy designed to combat acute lymphoblastic leukemia and B-cell lymphoma have been approved for clinical use in the USA. But experts in autoimmune diseases have been following the development of this technique with interest for a long time and have been thinking about using it in their field.
In 2016, the first success in this direction was achieved. At the University of Pennsylvania, with the help of chimeric antigen receptors, it was possible to rid mice of a rare autoimmune disease – pemphigus vulgaris (pemphigus vulgaris), which affects the skin and mucous membranes. But when treating systemic lupus erythematosus, difficulties arose. Doctors have had the genetically engineered antibody rituximab at their disposal since 1997, targeting the CD20 protein present on the cell membranes of B-lymphocytes. It is used for certain types of lymphomas, chronic lymphocytic leukemia, as well as autoimmune diseases: rheumatoid arthritis and multiple sclerosis. But rituximab was ineffective in the treatment of systemic lupus erythematosus.
There was even an assumption that B-lymphocytes are not important for the fight against lupus. But immunologist Mark Shlomchik from the University of Pittsburgh and his colleagues found that the point here is that rituximab antibodies, after attaching to B-lymphocytes, need the help of other cells of the immune system – macrophages to destroy them, and with lupus, the activity of these cells can be blocked. Therefore, a means of getting rid of B-cells was needed that did not need their help.
Immunologist Marko Radic from the University of Tennessee and his colleagues decided to resort to the creation of chimeric antigenic receptors. They used in their experiment specially created lines of laboratory mice in which systemic lupus erythematosus was reproduced. T-cells were taken from these mice and endowed with a chimeric receptor targeting the CD19 B-cell antigen. In order to destroy unmodified T cells in the body of mice, they were exposed to radiation. Then T cells with a chimeric receptor were injected into their body.
In 26 out of 41 mice that received modified T cells, all B lymphocytes with CD19 antigen were successfully destroyed. The symptoms of systemic lupus erythematosus on the spleen, skin, kidneys and other organs of these mice completely disappeared. After the experiment, most mice lived for more than a year, which is quite a long time for these animals. All the mice from the control group lived no more than 10 months, and many of them died much earlier. The results of the experiment are summarized in an article published by the journal Science Transal Medicine (Kansal et al., Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus).
Rheumatologist Jennifer Anolik, head of the lupus department at the University of Rochester Medical Center in New York, called this study a "critical milestone" and its results "very convincing." However, she recalls that there are still many questions to be clarified, in particular, it is not yet clear why T-lymphocytes with chimeric receptors turned out to be useless in 15 mice.
CAR-T therapy is a very radical remedy, because to save the patient, it completely destroys his B-lymphocytes, and his body loses the ability to produce antibodies to other antigens. Therefore, patients who have undergone treatment should then receive donor antibodies regularly until the end of their lives. But researchers believe that its use to combat lupus is justified no less than in cases with lymphoma and leukemia, because in some patients lupus develops no less aggressively than cancer, and in such cases severe damage to kidney tissue can lead to the death of the patient.
Portal "Eternal youth" http://vechnayamolodost.ru