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Transplantation tolerance mediated by regulatory T cells in mice

Chinese Medical Journal 2004年第8期117卷 1184-1189页

作者：冯宁翰吴宏飞吴军张炜眭元庚贺厚光张春雷郑峻松 Department of Urology Center of Kidney Transplantation First Affiliated HospitalNanjing Medical UniversityNanjing210029China Burn Research Institute Southwest Hospital Third Military Medical UniversityChongqing400038China

Background With potent suppressive effect on responder T cells, CD 4 +CD 25 + regulatory T (Treg) cells have become the focus of attention only recently and they may play an important role in transplantation tolerance However, the mechanism of action is not clear This study was designed to assess the possibility of using CD 4 +CD 25 + Treg cells to induce transplantation tolerance and to investigate their mechanism of action KH*2/5DMethods CD 4 +CD 25 + Treg cells were isolated using magnetic cell separation techniques Mixed lymphocyte reactions were used to assess the ability of Treg cells to suppress effector T cells Before skin transplantation, various numbers of CD 4 +CD 25 +Treg cells, which have been induced using complex skin antigens from the donor, were injected into the host mice either intraperitoneally (0 5×10 5, 1×10 5, 2×10 5, 3×10 5, 4×10 5, or 5×10 5) or by injection through the tail vein (5×10 3, 1×10 4, 2×10 4, 5×10 4, 1×10 5, 2×10 5) Skin grafts from two different donor types were used to assess whether the induced Treg cells were antigen-specific The survival time of the allografts were observed Single photon emission computed tomography was also used to determine the distribution of Treg cells before and after transplantation Results Treg cells have suppressive effect on mixed lymphocyte reactions Grafts survived longer in mice receiving CD 4 +CD 25 + Treg cell injections than in control mice There was a significant difference between groups receiving intraperitoneal injection of either 2×10 5 or 3×10 5 CD 4 +CD 25 +Treg cells and the control group ( P tolerance induced by CD 4 +CD 25 + Treg cells was donor-specific Analysis of the localization of Treg cells revealed that Treg cells mainly migrated from the liver to the allografts and th

关键词： T-lymphocytes immune tolerance skin transplantation lymphocyte culture test mixed

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Alterations in thymocyte populations under conditions of endotoxin tolerance

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Chinese Medical Journal 2021年第15期134卷 1855-1865页

作者： Yi-Jing Tao Juan-Juan Zhao Li-Hua Rao Song Yang Guo-Liang Zhang Meng-Meng Guo Chao Chen Lin Xu Department of Laboratory Medicine Jiangxi Hospital of Integrated Chinese and Western MedicineNanchangJiangxi 330009China Department of Immunology Zunyi Medical UniversityZunyiGuizhou 563000China

Background:Endotoxin tolerance(ET)is a protective phenomenon in which pre-treatment with a tolerance dose of lipopolysaccharide(LPS)leads to dramatically elevated survival.Accumulating evidence has shown that peripheral T cells contribute to the induction of ET.However,what happens to T cell development in the thymus under ET conditions remains unclear.The purpose of this study was to analyze the alterations in thymocyte populations(double-positive[DP]and single-positive[SP]cells)under ET conditions.Methods:Mice were intraperitoneally injected with LPS at a concentration of 5 mg/kg to establish an LPS tolerance model and were divided into two groups:a group examined 72 h after LPS injection(72-h group)and a group examined 8 days after LPS injection(8-day group).Injection of phosphate-buffered saline was used as a control(control group).Changes in thymus weight,cell counts,and morphology were detected in the three groups.Moreover,surface molecules such as CD4,CD8,CD44,CD69,and CD62L were analyzed using flow cytometry.Furthermore,proliferation,apoptosis,cytokine production,and extracellular signal-regulated kinase(ERK)pathway signaling were analyzed in thymocyte populations.The polymorphism and length of the T-cell receptor(TCR)P chain complementarity-determining region 3(CDR3)were analyzed using capillary electrophoresis DNA laser scanning analysis(ABI 3730).Results:Thymus weight and cell counts were decreased in the early stage but recovered by the late stage in a murine model of LPS-induced ET.Moreover,the proportions of DP cells(control:72.130±4.074,72-h:10.600±3.517,8-day:84.770±2.228),CD4+SP cells(control:15.770±4.419,72-h:44.670±3.089,8-day:6.367±0.513),and CD8+SP cells(control:7.000±1.916,72-h:34.030±3.850,8-day:5.133±0.647)were obviously different at different stages of ET.The polymorphism and length of TCR β chain CDR3 also changed obviously,indicating the occurrence of TCR rearrangement and thymocyte diversification.Further analysis showed that the expression of surface molecules,including CD44,CD69,and

关键词： immune tolerance Thymocytes T-cell receptor Gene rearrangement Adaptive immunity

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IL-10 Gene Modified Dendritic Cells Inhibit T Helper Type 1-Mediated Alloimmune Responses and Promote Immunological tolerance in Diabetes

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Cellular & Molecular Immunology 2008年第1期5卷 41-46页

作者： Huifen Zhu Wenhong Qiu Ping Lei Wei Zhou Xue Wen Fengrong He Li Li Hong Dai Guanxin Shen Feili Gong Department of Immunology Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China Medicine and Life Science College of Jianghan University Wuhan 430056 China These authors contributed equally to this work

Dendritic cells （DCs） have the potency to regulate the outcome of autoimmunity through the modulation of immune responses. The induction of antigen specific tolerance is critical for prevention and treatment of allograft rejection. In the present Study, we transfected IL-10 gene into DCs and investigated their effect on inhibition of lymphocyte activity in vitro and induction of immune tolerance on islet allograft in mice. An IDDM C57BL/6 mouse model was induced by streptozotocin. The islet cells isolated from the BALB/c mice were transplanted into the kidney capules of the model mice followed by injection of IL-10 modified DCs （mDCs）. The results showed that mDCs could significantly inhibit T lymphocyte proliferation mediated by allotype cells and induce its apoptosis, whereas, unmodified DCs （umDCs） could promote the murine lymphocyte proliferation markedly. The injection of mDCs could prolong the survival of allotype islet transplanted IDDM mice. The average plasma glucose （PG） level in mDCs treated mice returned to normal within 3 days and lasted for about 2 weeks. The rejection response in control mice occurred for 5 days after transplantation. The level of IFN-γ was lower while IL-4 was higher in mDCs treated mice than that in umDCs treated mice, which indicated that Thl/Th2 deviation occurred. Our studies suggest that IL-10 gene modified DCs can induce the immune tolerance to islet graft and prolong survival of the recipients by the inhibiting of T cell proliferation in allotype mice. Cellular ＆ Molecular Immunology.

关键词： IL-10 dendritic cell IDDM islet transplantation immune tolerance

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Cytological evaluation by Caco-2 and KU812 of non-allergenic peptides from simulated digestion of infant formula in vitro

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Food Science and Human Wellness 2023年第3期12卷 817-824页

作者： Zihao Xu Hao Bai Xin Ma Yong Wu Zhihua Wu Anshu Yang Weixiang Mao Xin Li Hongbing Chen State Key Laboratory Food Science and Technology Nanchang UniversityNanchang 330047China School of food science and Technology Nanchang UniversityNanchang 330047China Sino-German Joint Research Institute Nanchang UniversityNanchang 330047China Jiangxi Province Key Laboratory of Food Allergy Nanchang UniversityNanchang 330047China Jiangxi Institute of Quality and Standardization Nanchang 330046China

Milk allergy is a common allergic reaction found in infants and young children,most of them appear tolerance after growing up.In this study,infant formula was digested by simulated in vitro digestion method.The potential non-allergenic peptides were further screened from undigested products by exclusion of the known epitopes fromβ-lactoglobulin(BLG)andα-lactalbumin(ALA).These potential non-allergenic peptides were synthesized and their transferability were determined by Caco-2 cell monolayer model.Finally,the potential allergenicity were evaluated by KU812 cell degranulation model.The results showed that 7 peptides were screened as non-allergenic sequences,among which were 3 from ALA and 4 from BLG.The Caco-2 cell model showed that all the synthetic peptides were absorbed and transported well.However,only peptide BLG_(107-118)showed potential allegencity by KU812 model.In conclusion,6 peptides,including ALA_(29-51),ALA_(80-90),ALA_(94-103),BLG_(1-20),BLG_(24-50),and BLG_(123-139)were evaluated as hypoallergenic peptides,which could be used for candidates of peptides inducing immune tolerance for persons with milk allergy.

关键词： Milk allergy Epitopes Peptides Hypoallergenic immune tolerance

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A Study on Neonatal tolerance Against Graves＇ Disease in BALB/c Mice

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Chinese Medical Journal 2015年第23期128卷 3243-3246页

作者： Li-PingWu Li-Ru Xun Li Xu Amir Hussain Bing-Yin Shi Department of Endocrinology First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 China Department of Nephrology Shaanxi Province People's Hospital Xi'an Shaanxi 710068 China

INTRODUCTION Autoimmunity is defined as, a condition characterized by a specific humoral or cell-mediated immune response against the constituents of the body＇s own tissues （autoantigens）. In numerous autoimmune diseases, such an immune response is well recognized that causes damage to the self-constituents of body tissues by the products of the immune system. Graves＇ hyperthyroidism occurs after the loss of tolerance to the thyroid stimulating hormone receptor （TSHR） and the generation of thyroid stimulatory antibodies that mimic the action of thyroid-stimulating hormone （TSH）.

关键词： Animal Model Graves' Disease immune tolerance Thyroid Stimulating Hormone Receptor

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Liver immunity,autoimmunity,and inborn errors of immunity

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World Journal of Hepatology 2023年第1期15卷 52-67页

作者： Yavuz Emre Parlar Sefika Nur Ayar Deniz Cagdas Yasemin H Balaban Department of Gastroenterology Hacettepe University Faculty of MedicineAnkara 06100Turkey Department of Internal Medicine Hacettepe University Faculty of MedicineAnkara 06100Turkey Department of Pediatric Immunology Hacettepe University Ihsan Dogramaci Children's HospitalAnkara 06100Turkey

The liver is the front line organ of the immune system.The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens.This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens,such as food antigens or pathogens.As an immune active organ,the liver functions as a gatekeeping barrier from the outside world,and it can create a rapid and strong immune response,under unfavorable conditions.However,the liver's assumed immune status is anti-inflammatory or immuno-tolerant.Dynamic interactions between the numerous populations of immune cells in the liver are key for maintaining the delicate balance between immune screening and immune tolerance.The anatomical structure of the liver can facilitate the preparation of lymphocytes,modulate the immune response against hepatotropic pathogens,and contribute to some of its unique immunological properties,particularly its capacity to induce antigen-specific tolerance.Since liver sinusoidal endothelial cell is fenestrated and lacks a basement membrane,circulating lymphocytes can closely contact with antigens,displayed by endothelial cells,Kupffer cells,and dendritic cells while passing through the sinusoids.Loss of immune tolerance,leading to an autoaggressive immune response in the liver,if not controlled,can lead to the induction of autoimmune or autoinflammatory diseases.This review mentions the unique features of liver immunity,and dysregulated immune responses in patients with autoimmune liver diseases who have a close association with inborn errors of immunity have also been the emphases.

关键词： Liver immunity Autoimmunity immune tolerance Autoinflamation Autoimmune liver diseases Inborn errors of immunity

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Establishment of Nasal tolerance to Heat Shock Protein-60 Alleviates Atherosclerosis by Inducing TGF-β-dependent Regulatory T Cells

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2012年第1期32卷 24-30页

作者：李海禹丁艳萍易桂文曾秋棠杨文凯 Institute of Cardiology Union Hospital Tongji Medical CollegeHuazhong University of Science and Technology Department of Cardiac Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and Technology

Mounting evidence supports that a newly identified regulatory T cell (Treg),CD4+LAP+ Treg,is associated with oral tolerance induction and following inhibition of atherosclerosis,but little is described about whether nasal tolerance to antigen likewise induces the novel Tregs production and the relevant antiatherosclerotic benefit.We investigated the effect of nasal administration of heat shock protein-60 (HSP60) on atherogenesis.HSP60 or phosphate buffer solution (PBS) was nasally adminis-tered to six-week-old male ApoE-/-mice.At the 10th week after the nasal administration,there was a significant decrease in atherosclerotic plaque areas of aortic roots in the HSP60-treated mice as com-pared with those in the PBS-treated mice.Atherosclerosis suppression was accompanied with a signifi-cant increase in CD4+LAP+ and CD4+CD25+Foxp3+ Tregs and a concurrently increased production of TGF-β in the HSP60-treated mice.The protective effect of HSP60 was offset by injection of anti-TGF-βantibody.It is concluded that nasal administration of HSP60 can inhibit atherosclerotic formation through immune tolerance which is established by Tregs depending on the induction of anti-inflammatory cytokine TGF-β.immune tolerance induced by nasal administration of HSP60 may provide an alternative therapeutic method for atherosclerosis.

关键词： atherosclerosis inflammation immune tolerance heat shock protein regulatory T cells

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Immunological tolerance of human hepatocyte xenograft induced by adenovirus vector-mediated CTLA4Ig gene transfer

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Hepatobiliary & Pancreatic Diseases International 2012年第2期11卷 148-153页

作者： Yao-Kai Chen,Xiao-Cong Liu,Jun-Gang Li,Guo-Dong Liu,Yan Guo,Ling Cheng and Yu-Ming Wang Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and Department of Digestive Diseases, General Hospital of Chengdu Military Command, Chengdu 610083, China Institute of Infectious Diseases Southwest Hospital Third Military Medical University Chongqing 400038 China Department of Digestive Diseases General Hospital of Chengdu Military Command Chengdu 610083 China

BACKGROUND:Systemic administration of CTLA4Ig has been applied in inducing immunological tolerance of hepatocyte implants,but has potential for systemic immune inhibition.This study was designed to induce hepatocyte immunological tolerance by locally expressing CTLA4Ig in an attempt to improve the effectiveness of cell transplantation.METHODS:A normal human liver cell line(L02) was transfected with adenovirus vector containing the CTLA4Ig gene(Ad-CTLA4Ig-EGFP) in vitro,and the expression of CTLA4Ig by transfected cells was assessed by fluorescent imaging and immunocytochemical staining.Transfected cells then were injected into the spleen of Sprague-Dawley rats,the survival of cells was determined by immunohistochemistry,and the immune status was examined through CD4 + and CD69 + T cellcounts and ELISA detection of IL-2 in peripheral blood.RESULTS:L02 cells expressed CTLA4Ig in the cytoplasm for >4 weeks.Surviving L02 cells were observed in the experimental group at 3 and 4 weeks post-transplantation,while none was detected in the control group.Furthermore,the percentages of CD4 + and CD4 + CD69 + T cells in the CTLA4-transfected group were 24.5% and 45.1%,markedly lower than those in the control group at 4 weeks post-transplantation(Ptolerance in hepatocyte transplantation.

关键词： CTLA4Ig adenovirus vectors hepatocyte transplantation immune tolerance graft rejection

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Clinical operational tolerance in liver transplantation:state-of-the-art perspective and future prospects

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Hepatobiliary & Pancreatic Diseases International 2013年第1期12卷 12-33页

作者： Xi-Qiang Liu Zhi-Qiu Hu Yao-Fei Pei Ran Tao Center for Organ Transplantation and Department of Surgery Ruijin HospitalShanghai Jiaotong University School of Medicine Department of Surgery Central Hospital of Minghang District

BACKGROUND:Liver transplantation is the definite treatment for end-stage liver diseases with satisfactory results.However,untoward effects of life-long immunosuppression prevent the development of alternative strategies to achieve better longterm outcome.Achieving clinical operational tolerance is the ultimate goal.DATA SOURCES:A PubMed and Google Scholar search using terms:"immune tolerance","liver transplantation","clinical trial","operational tolerance" and "immunosuppression withdrawal" was performed,and relevant articles published in English in the past decade were reviewed.Full-text publications relevant to the field were selected and relevant articles from reference lists were also included.Priority was given to those articles which are relevant to the review.RESULTS:Because of the inherent tolerogenic property,around 20%-30% of liver transplantation recipients develop spontaneous operational tolerance after immunosuppression withdrawal,and the percentage may be even higher in pediatric living donor liver transplantation recipients.Several natural killer and γδT cell related markers have been identified to be associated with the tolerant state in liver transplantation patients.Despite the progress,clinical operational tolerance is still rare in liver transplantation.Reprogramming the recipient immune system by creating chimerism and regulatory cell therapies is among newer promising means to achieve clinical liver transplantation tolerance in the future.CONCLUSION:Although clinical operational tolerance is still rare in liver transplantation recipients,ongoing basic research and collaborative clinical trials may help to decipher the mystery of transplantation tolerance and extend the potential benefits of drug withdrawal to an increasing number of patients in a more predictable fashion.

关键词： immune tolerance liver transplantation clinical trial

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Islet transplantation-immunological challenges and current perspectives

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World Journal of Transplantation 2023年第4期13卷 107-121页

作者： Plamena Kabakchieva Yavor Assyov Stavros Gerasoudis Georgi Vasilev Monika Peshevska-Sekulovska Metodija Sekulovski Snezhina Lazova Dimitrina Georgieva Miteva Milena Gulinac Latchezar Tomov Tsvetelina Velikova Clinic of Internal Diseases Naval Hospital-VarnaMilitary Medical AcademyVarna 9010Bulgaria Clinic of Endocrinology Department of Internal DiseasesUniversity Hospital"Alexandrovska"Medical University-SofiaSofia 1434Bulgaria Faculty of Medicine Trakia UniversityStara Zagora 6000Bulgaria Department of Neurology Faculty of MedicineMedical University of PlovdivPlovdiv 4000Bulgaria Department of Gastroenterology University Hospital LozenetzSofia 1407Bulgaria Medical Faculty Sofia University St.Kliment OhridskiSofia 1407Bulgaria Department of Anesthesiology and Intensive Care University hospital LozenetzSofia 1407Bulgaria Department of Pediatric University Hospital"N.I.Pirogov"Sofia 1606Bulgaria Department of Healthcare Faculty of Public Health"Prof.Tsekomir VodenicharovMDDSc"Medical University of SofiaSofia 1527Bulgaria Department of Genetics Sofia University"St.Kliment Ohridski"Sofia 1164Bulgaria Department of General and Clinical Pathology Medical University of PlovdivPlovdiv 4000Bulgaria Department of Informatics New Bulgarian UniversitySofia 1618Bulgaria

Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes(T1D)by transplanting pancreatic beta cells.Overall,pancreatic islet transplantation has improved to a great extent,and cellular replacement will likely become the mainstay treatment.We review pancreatic islet transplantation as a treatment for T1D and the immunological challenges faced.Published data demonstrated that the time for islet cell transfusion varied between 2 and 10 h.Approximately 54%of the patients gained insulin independence at the end of the first year,while only 20%remained insulin-free at the end of the second year.Eventually,most transplanted patients return to using some form of exogenous insulin within a few years after the transplantation,which imposed the need to improve immunological factors before transplantation.We also discuss the immunosuppressive regimens,apoptotic donor lymphocytes,anti-TIM-1 antibodies,mixed chimerism-based tolerance induction,induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes,pretransplant infusions of donor apoptotic cells,B cell depletion,preconditioning of isolated islets,inducing local immunotolerance,cell encapsulation and immunoisolation,using of biomaterials,immunomodulatory cells,etc.

关键词： Islet transplantation Type 1 diabetes Diabetes mellitus immune tolerance Graft rejection T regulatory cells B regulatory cells

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