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Cellular strategies to induce immune tolerance after liver transplantation:Clinical perspectives

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World Journal of Gastroenterology 2024年第13期30卷 1791-1800页

作者： Ai-Wei Zhou Jing Jin Yuan Liu Department of Liver Surgery Renji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200127China Department of Nursing Renji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200127China Department of Liver transplantation Shanghai Immune Therapy InstituteShanghai 200127China

Liver transplantation(Lt)has become the most efficient treatment for pediatric and adult end-stage liver disease and the survival time after transplantation is becoming longer due to the development of surgical techniques and perioperative management.However,long-term side-effects of immunosuppressants,like infection,metabolic disorders and malignant tumor are gaining more attention.Immune tolerance is the status in which Lt recipients no longer need to take any immunosuppressants,but the liver function and intrahepatic histology maintain normal.the approaches to achieve immune tolerance after transplantation include spontaneous,operational and induced tolerance.the first two means require no specific intervention but withdrawing immunosuppressant gradually during follow-up.No clinical factors or biomarkers so far could accurately predict who are suitable for immunosuppressant withdraw after transplantation.With the understanding to the underlying mechanisms of immune tolerance,many strategies have been developed to induce tolerance in Lt recipients.Cellular strategy is one of the most promising methods for immune tolerance induction,including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory immune cells.the safety and efficacy of various cell products have been evaluated by prospective preclinical and clinical trials,while obstacles still exist before translating into clinical practice.Here,we will summarize the latest perspectives and concerns on the clinical application of cellular strategies in Lt recipients.

关键词： Cellular therapy Induced tolerance Liver transplantation regulatory t cells regulatory dendritic cells

regulatory t cells in transplantation from rejection to tolerance

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South China Journal of Cardiology 2014年第1期15卷 76-83页

作者：王世强庄建陈寄梅朱平 Southern Medical University Department of Cardiovascular Surgery Guangdong Cardiovascular InstituteGuangdong General HospitalGuangdong Academy of Medical Sciences

Organ transplantation has been the only treatment for end-stage organ failure patients. With the development of organ transplantation, more and more patients benefit from it. However, the efficacy of organ transplantation is afflicted with graft rejection, which might lead to serious complications. Induction of antigen-specific immune tolerance has become a promising therapeutic strategy for graft rejection. this strategy could be achieved by application of regulatory t cells.

关键词： immune tolerance immunoregulation transplant tolerance regulatory t cells

Involvement of CD4^＋CD25^＋ regulatory t cells in the pathogenesis of polycythaemia vera

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Chinese Medical Journal 2008年第18期 1781-1786页

作者： ZHAO Wen-bo LI Ying LIU Xin ZHANG Ling-yan WANG Xin Department of Hematology Shandong Provincial Hospital Affiliated to Shandong University Jinan Shandong 250021 China

Background regulatory t cells （mreg） have been shown to play an important role in the regulation of hematopoietic activity. However, there is no information about the effect of treg cells in the pathogenesis of polycythaemia vera （PV）. Methods In this study, we investigated the percentage and function of treg cells in the peripheral blood of 21 PV patients and 25 healthy donors, mreg cells were identified and characterized as CD4^＋CD25^＋FOXP3^＋ by flow cytometry. the suppressive activity of CD4^＋CD25^＋ treg cells was assessed by the proliferation and cytokine secretion of the co-cultured CD4^＋CD25^- fractions. Results the results showed that the percentage of treg cells in the peripheral blood of PV patients significantly increased compared to healthy controls （（10.93±4.02）% vs （5.86±1.99）%, P 〈0.05）. Moreover, the mRNA and protein expression of FOXP3 was higher in CD4^＋CD25^＋ treg cells. Coordinately, when co-cultured with the activated CD4^＋CD25^- cells, the CD4^＋CD25^＋ treg cells showed enhanced suppressive function in PV. Yet, the underlying mechanism for the increased frequency and function of CD4^＋CD25^＋ treg cells is still to be clarified. Conclusion treg cells expansion might account for the abnormal t cell immunity in PV patients and thus contribute to the pathogenesis of PV.

关键词： polycythaemia vera regulatory t cells pathogenesis

th17/treg balance and macrophage polarization ratio in lower extremity arteriosclerosis obliterans

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Asian Pacific Journal of tropical Biomedicine 2024年第3期14卷 127-136,I0006-I0009页

作者： Zhen-Zhen Li Min Liu Xiong-Hui He Zhen-Dong Liu Zhan-Xiang Xiao Hao Qian You-Fei Qi Cun-Chuan Wang Department of Metabolic and Bariatric Surgery The First Affiliated Hospital of Jinan UniversityGuangzhouGuangdong Province510632China Department of Vascular Surgery Hainan General HospitalHainan Affiliated Hospital of Hainan Medical UniversityHaikouHainan Province570311China Department of Physical Examination Hainan General HospitalHainan Affiliated Hospital of Hainan Medical UniversityHaikouHainan Province570311China Department of Gastrointestinal Surgery Hainan General HospitalHainan Affiliated Hospital of Hainan Medical UniversityHaikouHainan Province570311China

Objective:to explore the balance of peripheral blood t helper 17 cells/regulatory t cell(th17/treg)ratio and the polarization ratio of M1 and M2 macrophages in lower extremity arteriosclerosis obliterans(ASO).Methods:A rat model of lower extremity ASO was established,and blood samples from patients with lower extremity ASO before and after surgery were obtained.ELISA was used to detect interleukin 6(IL-6),IL-10,and IL-17.Real-time RCR and Western blot analyses were used to detect Foxp3,IL-6,IL-10,and IL-17 expression.Moreover,flow cytometry was applied to detect the th17/treg ratio and M1/M2 ratio.Results:Compared with the control group,the iliac artery wall of ASO rats showed significant hyperplasia,and the concentrations of cholesterol and triglyceride were significantly increased(Pting the successful establishment of ASO.Moreover,the levels of IL-6 and IL-17 in ASO rats were pronouncedly increased(Pthe IL-10 level was significantly decreased(Ption to increased IL-6 and IL-17 levels,the mRNA and protein levels of Foxp3 and IL-10 in ASO rats were significantly decreased compared with the control group.the th17/treg and M1/M2 ratios in the ASO group were markedly increased(Pthese alternations were also observed in ASO patients.After endovascular surgery(such as percutaneous transluminal angioplasty and arterial stenting),all these changes were significantly improved(Pthe th17/treg and M1/M2 ratios were significantly increased in ASO,and surgery can effectively improve the balance of th17/treg,and reduce the ratio of M1/M2,and the expression of inflammatory factors.

关键词： Lower extremity arteriosclerosis regulatory t cells regulatory B cells Inflammatory factors M1 macrophages M2 macrophages

Matrine ameliorates experimental autoimmune encephalomyelitis by regulating the differentiation of encephalitogenic th1/th17 and th2/regulatory t cells

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中国药理学与毒理学杂志 2016年第10期30卷 1037-1038页

作者： ZHANG Ming-liang KAN Quan-cheng ZHANG Hui-jun ZHU Lin Department of Pharmacy The First Affiliated Hospital of Zhengzhou University the First Affiliated Hospital of Zhengzhou University

OBJECtIVE Experimental autoimmune encephalomyelitis(EAE),the classical animal model for multiple sclerosis(MS)is triggered by an impaired balance of t helper(th)cells and regulatory t(tregs)cells.Matrine(MAt),a quinolizidine alkaloid derived from the herb Radix Sophorae Flave,has been shown to ameliorate the clinical signs,inflammatory infiltration,demyelination in acute EAE rats.However,whether MAt protect from EAE by adjusting th and treg cells response in specific-cellular and molecular level is unknown.MEtHODS Herein,MAt was tested for its effects on th1,th2,th17 and treg cells in the spinal cord of EAE mice and splenocyte-extracted from EAE mice with MOG35-55-restimulated,respectively.RESULtS Our findings revealed that MAt significantly inhibit the proliferation of splenocyte,and remarkably down-regulate the differentiation of th1/th17 cells with decreased expressions of CD4+IFN-γ+cells and CD4+IL-17+cells in vivo and IL-17,IFN-γ,ROR-γt,t-bet in vitro,meanwhile it dramatically up-regulate the th2/treg cells response associated with increased levels of CD4+tGF-β+1cells and CD4+IL-10+cells in vivo and IL-4,IL-10,tGF-β1,Foxp3 and GAtA3in vitro.CONCLUSION Considering the effective therapeutic effects of MAt on EAE,it′s worth to find its new values on other autoimmune diseases.

关键词： matrine experimental autoimmune encephalomyelitis t helper cells regulatory t cells

the role of regulatory t cells in immune dysfunction during sepsis

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World Journal of Emergency Medicine 2015年第1期6卷 5-9页

作者： Chao Cao tao Ma Yan-fen Chai Song-tao Shou Emergency Department Tianjin Medical University General Hospital Department of General Surgery Tianjin Medical University General Hospital

BACKGROUND: Although regulatory t cells(tregs) are key to the maintenance of immunologic homeostasis and tolerance, little is known about treg-mediated immunosuppression in the stage of sepsis. this article aimed to review the current literature on the role of tregs in the pathophysiology of septic response, attempting to investigate the role of tregs in immune dysfunction during sepsis.DAtA SOURCES: A literature search was conducted in January 2014 using the China National Knowledge Infrastructure and Pub Med. Articles on the role of tregs in immune dysfunction during sepsis were identified.RESULtS: the identified articles indicated that treg levels can be used for the assessment of the course of sepsis. the inhibition of treg activity can promote the recovery of immune function.CONCLUSION: Since the mechanism of tregs is complex during the sepsis, more studies are needed.

关键词： regulatory t cells Sepsis Immune dysfunction

regulatory t cells attenuate hyperhomocysteinemia-accelerated atherosclerosis in ApoE-KO mice

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Regulatory T cells attenuate hyperhomocysteinemia-accelerate...

Reversal of the immunosuppressive tumor microenvironment via platinum-based neoadjuvant chemotherapy in cervical cancer

2008北京国际生理科学学术大会

作者： FENG Juan~1,XU Qing-Bo~2,WANG Xian~1 1 Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Peking University,Beijing,100083,China 2 Cardiovascular Division,the James Black Centre,Kings College London,London SE5 9NU,UK

Atherosclerosis is an inflammatory disease of the arterial wall where both innate and adaptive immunoinflammatory responses contribute to disease development.Most CD4 t cells of murine and human atherosclerotic plaques are of the th1 cell type.And several consistent experimental studies have clearly shown a critical pathogenic role for th1-mediated response in atherosclerosis.Novel subtypes of t cells,called the regulatory t cells(tregs),have been shown to play a critical role in the maintenance of immunological tolerance against self and non-self antigens and prevent the development of various immunoinflammatory diseases.We investigated the importance and potential role of tregs in hyperhomocysteinemia(HHcy)-accelerated atherosclerosis in apolipoprotein E-knockout(ApoE-KO)mice.the effect of homocystein(Hcy)was tested on the number and functional properties of tregs in vitro and in vivo,between HHcy ApoE-KO mice and ApoE-KO alone mice.the results showed that Hcy attenuated the number and suppressive properties of tregs in vitro and in vivo.With clinically relevant level of plasma Hcy(16.81±1.35μmol/L),atherosclerotic lesions were slightly increased as early as 2-week HHcy ApoE-KO mice.the number of CD4CD25 t cells was reduced by about 40%in 2-week HHcy ApoE-KO mice compared with ApoE-KO alone mice.the coculture-experiment assay,which has been wellvalidated to assess tregs function,showed that the CD4CD25 effector t cells(teffs)exhibited increased proliferation after treatment with 30μmol/L Hcy for 72 h in vitro compared with control.teffs proliferation was also enhanced in 2-week HHcy ApoE-KO mice in vivo.these data suggest that the function of tregs was reduced in 2-week HHcy ApoE-KO mice.Hcy decreased Foxp3 gene and protein expressions in t cells in vitro and in vivo. transfer of tregs from age-matched normal C57BL/6J mice to 2-week HHcy ApoE-KO mice resulted in significant attenuation of atherosclerosis lesion compared with that after delivery of phosphate-buffered saline(Pta demonstrated for the

关键词： atherosclerosis regulatory t cells hyperhomocysteinemia

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Cancer Pathogenesis and therapy 2024年第1期2卷 38-49页

作者： Xue Feng Xiaolin Meng Dihong tang Shuaiqingying Guo Qiuyue Liao Jing Chen Qin Xie Fengyuan Liu Yong Fang Chaoyang Sun Yingyan Han Jihui Ai Kezhen Li Department of Gynecological Oncology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430000China National Clinical Research Center for Obstetrics and Gynecology Cancer Biology Research Center(Key Laboratory of the Ministry of Education)Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430000China Department of Gynecologic Oncology Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaHunan 410000China

Background Immunotherapy favors patients with tumors;however,only 3-26.3%of patients with cervical cancer benefit from single-agent immune checkpoint inhibitors.Combined immunotherapy and chemotherapy has been explored against tumor;however,the combination remains controversial.this study aimed to investigate the tumor immune microenvironment(tIME)and the effects of platinum-based neoadjuvant chemotherapy(NACt)in cervical cancer to identify the clinical value of combining chemotherapy with immunotherapy.Methods Multiplex immunohistochemistry(IHC)with 11 markers(cluster of differentiation[CD]3,CD8,CD4,CD11c,CD68,forkhead box P3[Foxp3],programmed cell death 1[PD-1],programmed cell death 1 ligand 1[PD-L1],indoleamine 2,3-dioxygenase[IDO],cyclin-dependent kinase inhibitor 2A[p16],and cytokeratin[CK])was performed to evaluate tIME from 108 matched pre-and post-NACt cervical cancer samples.the mechanism of antitumor immunity triggered by NACt was explored using RNA sequencing(RNA-seq)from four paired samples and subsequently verified in 41 samples using IHC.Results the infiltration rate of the CD8^(+)t cells in treatment-naive cervical cancer was 0.73%,and those of Foxp3^(+)regulatory t cells(tregs)and IDO^(+)cells were 0.87%and 17.15%,respectively.Moreover,immunoreactive t cells,dendritic cells,and macrophages were more in the stromal than the intratumor region.NACt increased dendritic,CD3^(+)t,CD8^(+)t,and CD4^(+)t cells and decreased tregs.the aforementioned alterations occurred predominantly in the stromal region and were primarily in responders.Non-responders primarily showed decreased tregs and no increase in CD8^(+)t or dendritic cell infiltration.Furthermore,dendritic cells interacted more closely with CD3^(+)t cells after NACt,an effect primarily observed in responders.RNA-seq data revealed activation of the antigen receptor-mediated signaling pathway and upregulation of major histocompatibility complex(MHC)I and MHC II after chemotherapy,validated using IHC.Conclusions NACt can reduce tregs,and when tumor cel

关键词： Neoadjuvant chemotherapy Cervical cancer tumor immune microenvironment Spatial architecture CD8 regulatory t cells

Populational change of CD4^(+)CD25^(+)treg cells is responsible for the synergistic effect of the combination of RAMP2 with baicalin in treating recurrent spontaneous abortion mouse models

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traditional Medicine Research 2024年第8期9卷 59-66页

作者： Cong Chen Zhuo-Lan Li Jing-tian Guo Wen-Yao Xue Wei Guo Department of Gynecology Jiangsu Province Hospital of Chinese MedicineAffiliated Hospital of Nanjing University of Chinese MedicineNanjing 210029China Jiangsu Key Laboratory of Druggability of Biopharmaceuticals State Key Laboratory of Natural MedicinesSchool of Life Science and TechnologyChina Pharmaceutical UniversityNanjing 211198China

Background: the absence of a safe and effective therapy for recurrent spontaneous abortion due to a maternofetal failure in immunological tolerance remains an intractable clinical obstacle for surgeons. Recently, traditional Chinese medicine has become a feasible alternative for certain diseases, including recurrent spontaneous abortion. However, because of the complex composition of the traditional Chinese medicine formula, its action mechanism remains unclear. Methods: We selected two isolated active ingredients (RAMP and baicalin) from the traditional Chinese medicine formula and used an abortion-prone CBA/J × DBA/2 model to simulate human RSA and compared the changes in fetal resorption rate, treg cell percentage, and relevant cytokines before and after combination therapy. In addition, the mechanisms were preliminarily discussed using in vitro differentiation models. Results: In CBA/J × DBA/2 abortion-prone mice, the combination therapy resulted in a lower embryo resorption rate compared to that obtained with individual delivery of either RAMP or baicalin, thereby playing an embryo-protective role through the increase in treg cells for the maintenance of maternal-fetal immune tolerance. In in vitro primary cell differentiation experiments, the concentration of treg cells significantly increased from 11% to 17.9% after the combination therapy compared to that of the single administration group. Conclusion: the synergistic effects of RAMP and baicalin were responsible for treg differentiation. the present study provides a solid basis for improving the applicability of traditional Chinese herbs in the treatment of recurrent spontaneous abortion.

关键词： recurrent spontaneous abortion Atractylodes macrocephala Koidz. Scutellaria baicalensis Georgi CBA/J×DBA/2 regulatory t cells