Chimeric T-lymphocytes versus "wrong" B-lymphocytes
Biologists have come closer to treating the causes of autoimmune diseases
Alexander Ershov, N+1
Immunologists from the University of Pennsylvania have come closer to treating the cause of autoimmune diseases by targeting B-lymphocytes that respond abnormally to their own antigens. The results of the first tests of the technology on mice and on cell cultures are published in Science (Ellebrecht et al., Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease.
Autoimmune diseases occur when the immune system begins to recognize its own antigens as someone else's. This leads to the death of cells carrying these antigens, to systemic inflammation and other unpleasant consequences, up to a fatal outcome. Existing methods of treating autoimmune diseases are based on general and nonspecific suppression of immunity, but as a result of such therapy, the work of not only the "wrong" cells stops, but also the entire immune system. And usually this leads to the body's vulnerability to infectious diseases – even those that are normally not terrible for a person.
Scientists have been working with a rare but severe autoimmune disease called pemphigus vulgaris. During the development of this disease, a special population of B-lifocytes attacks one of the proteins of the cell matrix, desmoglein (in this case, desmoglein-3). As a result, the structure of the tissue is disrupted, blisters appear on the skin and mucous membranes, which can even lead to the inability to eat.
To eliminate the cause of the disease, scientists turned to the technology of creating cells with chimeric receptors (CAR), which is now actively beginning to be used for the treatment of oncological diseases. The method (which we have recently written about in detail) involves the introduction of a genetic construct into the patient's own immune cells, T cells, which provides the synthesis of a chimeric receptor. With the help of such a receptor, T cells can select the desired target from all clonal populations of B-lymphocytes. The specificity of the chimeric receptor is provided by the variable part selected by scientists, and the destruction signal is provided by the constant part of the T-cell receptor with coreceptors. In this case, the scientists provided T cells with a receptor with several fragments of desmoglein-3. Such modified T cells could bind only to those B cells that produce antibodies to desmoglein.
The scheme of cancer therapy with CAR and autoimmune diseases with CAAR (from the press release of the Perelman School of Medicine New Therapy Treats Autoimmune Disease Without Harming Normal Immunity).
It turned out that this technology works successfully not only on cell culture (T-cells destroyed only pathological B-lymphocytes), but also on mice that were artificially injected with B-lymphocytes against desmoglein. Without therapy, such mice, like humans, had blisters in the oral cavity, but injection of T cells prevented this process.
It is not yet clear how safe the new therapy is – whether the modified T cells will attack any other cell populations besides anti-desmoglein B-lymphocytes. It is also unknown whether the new therapy will be able to cure the symptoms of pemphigus, and not only prevent their occurrence. As a next step, the scientists plan to test the method on dogs. Unlike mice, they have their own version of pemphigus vulgaris, which means they should be better suited as model animals for its study.
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04.07.2016