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<h4><br>In accordance with the Chinese Yin-Yang theory and the western critical thinking, our immune system is under a dynamic equilibrium at all times. The immune network consisting immune organs, immune tissues and immune cells rely on each other and promote each other, which is a both unified and varying state that we call as immune homeostasis, with immune response and immune tolerance as two most critical features. On one hand, immune response helps us get rid of antigens, eradicating harmful factors against human body; while on the other hand, immune tolerance helps us distinguishing the enemies from our own, avoiding any harm from overreaction and indiscriminate destruction. Thus, the immune homeostasis is a prerequisite for our healthy life, once the balance is no longer maintained a series of diseases will occur and physical functions may fail. If immune tolerance shows more potency than immune response, the human body will be in an immune inhibited state, where pathogens and cancer cells are left uncontrolled leading to the onset of severe infection and malignancy. If immune response gains the upper hand over immune tolerance, normal cells will be targeted for elimination leading to diseases we call as autoimmune diseases, for example rheumatoid arthritis (RA), systematic lupus erythromatosis, autoimmune type I diabetes, etc. In this way, finding a way to recover the immune homeostasis becomes an essential strategy in dealing with these two types of diseases.</h4> | <h4><br>In accordance with the Chinese Yin-Yang theory and the western critical thinking, our immune system is under a dynamic equilibrium at all times. The immune network consisting immune organs, immune tissues and immune cells rely on each other and promote each other, which is a both unified and varying state that we call as immune homeostasis, with immune response and immune tolerance as two most critical features. On one hand, immune response helps us get rid of antigens, eradicating harmful factors against human body; while on the other hand, immune tolerance helps us distinguishing the enemies from our own, avoiding any harm from overreaction and indiscriminate destruction. Thus, the immune homeostasis is a prerequisite for our healthy life, once the balance is no longer maintained a series of diseases will occur and physical functions may fail. If immune tolerance shows more potency than immune response, the human body will be in an immune inhibited state, where pathogens and cancer cells are left uncontrolled leading to the onset of severe infection and malignancy. If immune response gains the upper hand over immune tolerance, normal cells will be targeted for elimination leading to diseases we call as autoimmune diseases, for example rheumatoid arthritis (RA), systematic lupus erythromatosis, autoimmune type I diabetes, etc. In this way, finding a way to recover the immune homeostasis becomes an essential strategy in dealing with these two types of diseases.</h4> | ||
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<h4 align=middle>Figure1. Therapeutic targets and interference strategies of rheumatoid arthritis</h4> | <h4 align=middle>Figure1. Therapeutic targets and interference strategies of rheumatoid arthritis</h4> | ||
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<h4><br>An imbalance in immune cell’s function is often found in them. Sometime the immune system cannot recognize the target cell, sometime a certain type of immune cell may proliferate. Thus, remodeling the function of a crucial type of immune cell turns into a key point. Cytotherapy has, therefore, become a rising star against these diseases, with CAR-T and TCR-T as the representatives in this technology. The trick in these therapies lies in transforming T cells with synthetic biology approaches, inserting and expressing artificial genes of chimeric antigen receptor into T cell genome and enabling them to recognize and eradicate target cells precisely. Obviously, such strategy has achieved a certain success. This year, the CAR-T product from Novartis was officially approved by FDA to treat acute lymphoblastic leukemia(ALL) in enfants and young adults, which has shown high efficacy in the treatment of non-solid tumors.</h4> | <h4><br>An imbalance in immune cell’s function is often found in them. Sometime the immune system cannot recognize the target cell, sometime a certain type of immune cell may proliferate. Thus, remodeling the function of a crucial type of immune cell turns into a key point. Cytotherapy has, therefore, become a rising star against these diseases, with CAR-T and TCR-T as the representatives in this technology. The trick in these therapies lies in transforming T cells with synthetic biology approaches, inserting and expressing artificial genes of chimeric antigen receptor into T cell genome and enabling them to recognize and eradicate target cells precisely. Obviously, such strategy has achieved a certain success. This year, the CAR-T product from Novartis was officially approved by FDA to treat acute lymphoblastic leukemia(ALL) in enfants and young adults, which has shown high efficacy in the treatment of non-solid tumors.</h4> | ||
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<h4 align=middle>Figure2. The design of CAR-T system</h4> | <h4 align=middle>Figure2. The design of CAR-T system</h4> | ||
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<h4><br>FOXP3 is the most important transcription factor in Treg, taking part in most of the transcription and expression of Treg structural genes. We can assume that the expression and stability of FOXP3 protein determines the function level of Treg. Under inflammation environment, a series of cytokines, such as IL-6, will activate a ubiquitinase Stub1 which will ubiquitinate FOXP3, thus leading to its deactivation and degradation. Consequently, Treg loses its immune inhibitory function, which is mainly why Treg cannot function properly in RA patients. In this way, how to engineer Treg cell to maintain its FOXP3 stability under inflammation conditions and how to direct Treg to target RA specific inflammatory cells to exert its immune inhibitory function becomes a new strategy against RA.</h4> | <h4><br>FOXP3 is the most important transcription factor in Treg, taking part in most of the transcription and expression of Treg structural genes. We can assume that the expression and stability of FOXP3 protein determines the function level of Treg. Under inflammation environment, a series of cytokines, such as IL-6, will activate a ubiquitinase Stub1 which will ubiquitinate FOXP3, thus leading to its deactivation and degradation. Consequently, Treg loses its immune inhibitory function, which is mainly why Treg cannot function properly in RA patients. In this way, how to engineer Treg cell to maintain its FOXP3 stability under inflammation conditions and how to direct Treg to target RA specific inflammatory cells to exert its immune inhibitory function becomes a new strategy against RA.</h4> | ||
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<h4 align=middle>Figure4. Post-translational modification and interference targets of FOXP3 protein</h4> | <h4 align=middle>Figure4. Post-translational modification and interference targets of FOXP3 protein</h4> | ||
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<h4><br>In yeast cells, Gal4 protein can specifically recognize the UAS sequence in its genome. If we attach an artificial transcription factor VP64 to Gal4 and insert UAS sequence before the promoter of target gene, we can presume that the transcription of target gene will be specifically activated. Thus, we add a Gal4-VP64 fusion protein sequence after the cleavage site in SynNotch system, meanwhile we add the UAS sequence before USP7 promoter. Now with the presence of the inflammatory cytokine IL-17A, SynNotch system will be activated and the cleavage will take place. Gal4-VP64 will be freed from cell membrane before entering the cell nucleus and binding with the UAS sequence before USP7 promoter. Then USP7 protein will be expressed and will deubiquitinate FOXP3, stabilizing FOXP3 under inflammation conditions, making it possible for Treg to survive the inflammatory environment and to exert its immune inhibitory function. Above is the shield we equip Treg with.</h4> | <h4><br>In yeast cells, Gal4 protein can specifically recognize the UAS sequence in its genome. If we attach an artificial transcription factor VP64 to Gal4 and insert UAS sequence before the promoter of target gene, we can presume that the transcription of target gene will be specifically activated. Thus, we add a Gal4-VP64 fusion protein sequence after the cleavage site in SynNotch system, meanwhile we add the UAS sequence before USP7 promoter. Now with the presence of the inflammatory cytokine IL-17A, SynNotch system will be activated and the cleavage will take place. Gal4-VP64 will be freed from cell membrane before entering the cell nucleus and binding with the UAS sequence before USP7 promoter. Then USP7 protein will be expressed and will deubiquitinate FOXP3, stabilizing FOXP3 under inflammation conditions, making it possible for Treg to survive the inflammatory environment and to exert its immune inhibitory function. Above is the shield we equip Treg with.</h4> | ||
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<h4 align=middle>Figure6. Design of SynNotch system and CAR system</h4> | <h4 align=middle>Figure6. Design of SynNotch system and CAR system</h4> | ||
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<h4><br>Based on our design, we name our engineered Treg as “Human Engineered Anti-Autoimmune-Diseases Regulatory T cell (HEAD-Treg) System”. We hope it can serve as a mighty warrior, leading the immune system to rebalance itself, to conquer the disease and to reestablish the patient’s health.</h4> | <h4><br>Based on our design, we name our engineered Treg as “Human Engineered Anti-Autoimmune-Diseases Regulatory T cell (HEAD-Treg) System”. We hope it can serve as a mighty warrior, leading the immune system to rebalance itself, to conquer the disease and to reestablish the patient’s health.</h4> | ||
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<h4 align=middle>Figure7. HEAD-Treg System</h4> | <h4 align=middle>Figure7. HEAD-Treg System</h4> | ||
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<h4><br>In order to further evaluate the clinical value of our system and provide a theoretical reference for the next in vivo and preclinical experiments, we also establish a systematic mathematical model for the local and overall immune environment of rheumatoid arthritis (See the Model section for details). Thus, we have a theoretical explanation of the relationships among the cytokines, different cell subpopulations and rheumatoid arthritis, which lays a solid foundation for further improvement of our research ideas regarding the subsequent in vivo and preclinical experiments </h4> | <h4><br>In order to further evaluate the clinical value of our system and provide a theoretical reference for the next in vivo and preclinical experiments, we also establish a systematic mathematical model for the local and overall immune environment of rheumatoid arthritis (See the Model section for details). Thus, we have a theoretical explanation of the relationships among the cytokines, different cell subpopulations and rheumatoid arthritis, which lays a solid foundation for further improvement of our research ideas regarding the subsequent in vivo and preclinical experiments </h4> | ||
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<h4 align=middle>Figure8. The overall therapy strategies of HEAD-Treg system</h4> | <h4 align=middle>Figure8. The overall therapy strategies of HEAD-Treg system</h4> | ||
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Revision as of 14:48, 1 November 2017