Treating autoimmune diseases has the "one-of-a-world key".

Zhang Bo (left) experiments with team members.In recent years, CAR-T, as a revolutionary new cellular immunotherapy method, has been used in tumor treatment by genetic engineering technology to install the navigation system CAR and activate T cells, which can accurately and efficiently identify tumor cells and then kill tumor cells in a long-lasting way through immune action.
But unlike tumors, autoimmune diseases such as rheumatoid arthritis have a variety of B cells that secrete multiple autoantibodies, have specific surface antigen receptors, whether CAR-T is effective and selective, specific attacks on their own reactive B cells have not been reported.
statistics, there are nearly 20 million patients with rheumatoid arthritis, severe spina bifiditis and psoriasis in China. Although this kind of autoimmune disease is not fatal, it brings long-term pain and physiological distortion to the patient, which seriously affects the patient's quality of life.
In view of this, The Team Zhang Wei, a professor at Concord Hospital in Beijing, and Zhou Demin, a professor at Peking University School of Pharmacy, have jointly and innovatively developed a controlled, universal-type chimic antigen-insular T-cell (CAR-T) technology based on their own antigen peptides, and applied it to the treatment of autoimmune diseases.
study was published in the Rheumatology Yearbook and Cell Chemistry Biology.well known that CAR-T limits its widespread use due to the complexity of the preparation process, high technical barriers, and the inability to flexibly control and terminate activation leading to cytokine storms. How to construct a universal and regulatable CAR-T technology has become an important research direction of immunotherapy.
to this problem, the two team members conducted repeated discussions and painstaking experimental research, which lasted nearly 4 years, and finally first reported the use of their own antigen-specific CAR-T to treat autoimmune diseases.
team pioneered the construction of car-T cells with specific antigens that can be targeted to kill B cells. To solve the problem that traditionally a CAR-T can kill only one type of cell with the same receptor, the team has developed a universal CAR-T based on the connecting arm molecule.
" universal CAR-T is an inert CAR-T that identifies isothione fluorin (FITC) molecules, connecting arm molecules with FITC and specific antigen peptide molecules, connecting CAR-T via FITC at one end and B cells via antigen antibody-specific binding at the other end. Zhang said that the design is equivalent to "only open a lock" "a key" upgrade to a "one-size-all key", simply according to the type of antibody of the patient B cells to replace the antigen end of the connecting arm molecules, you can customize the target to kill different types of B cells.
, will the model stand the test? To this end, the team validated the effectiveness of the technique through hybrid tumor cell models and found that the more connecting arm molecules were added, the stronger the effect of killing hybrid tumor B cells, showing a strict arm dose dependence effect.
, the team demonstrated that the technique could be applied to immune cell groups that secrete specific antibodies and effectively kill immune cells through mouse models and in-body experiments that collagen induced arthritis.In order to explore the clinical transformation potential of this program, Zhang Wei's team isolated the B cell population of rheumatoid arthritis patients, and combined the generic CAR-T with antigen mesotides according to the patient's autoantibodies type, customized to kill the different autoreactive B cells of secretion-specific surface antibodies, and realized the concept verification of CAR-T's targeting and customized treatment of autoimmune diseases.
To further improve the safety of the technology and avoid cytokine storms caused by the continuous activation of CAR-T, the team upgraded the connecting arm molecules to introduce a light-controlled fracture group that accurately regulates the role of CAR-T by means of a "switch" that can fuse the above-mentioned "one-size-all key" at any time.
"We designed the light-controlled connecting arm molecule FITC-O-Folate, i.e. FITC and folic acid groups are connected together by photosensitive structures, the connecting arm breaks in light, and car-T is separated from the target cell. According to Zhou Demin, the activation of CAR-T depends strictly on the connecting arm molecule and presents a dose-dependent kill effect, while the closure of CAR-T does not depend on the metabolism of the connecting arm molecule, allowing precise shutdown at any time.
addition, the study further found that by subsequently adding new arm molecules, CAR-T can continue to play a lethal role, thus achieving the CAR-T "activate-close-reactivation" of the cyclic precision regulation.
industry experts said that the study is guided by clinical scientific issues, innovatively applied CAR-T technology to rheumatoid arthritis as the representative of the systemic autoimmune disease, combined with immunology, chemistry, biology and other interdisciplinary disciplines, set up a controlled, universal CAR-T platform method, for safer and more effective CAR-T applications to provide a new technical reserve, and for autoimmune diseases and tumor precision treatment provides a broad clinical application prospects.
it is learned that Beijing Concord Hospital's National Key Laboratory Platform for Severe and Rare Diseases, Dr. Zhang Bo, is the first author of the thesis, and Zhang Wei and Zhou Demin are co-authors of the communication. (Source: Zhang Siwei, China Science Journal)
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