Heart failure （HF） is the end stage of various kinds of cardiovascular diseases and leads to a high mortality worldwide. Numerous studies have demonstrated that frequencies of CD4＋CD25＋Foxp3＋ regulatory T cells ...Heart failure （HF） is the end stage of various kinds of cardiovascular diseases and leads to a high mortality worldwide. Numerous studies have demonstrated that frequencies of CD4＋CD25＋Foxp3＋ regulatory T cells （Tregs） are reduced in HF patients and properly expanding Tregs attenuates HF progression. Histone deacetylase （HDAC） 9 has been revealed to contribute to several cardiovascular and cerebrovascular diseases. Plenty of studies showed that HDAC9 negatively regulated the number and function of Tregs. Thus, we aim to investigate the expression of HDAC 9 in patients with chronic heart failure （CHF） and the relationship among HDAC9, Tregs and CHF. Our research showed a reduced number of Tregs and an increased expression of HDAC9 mRNA in CHF patients. Patients with CHF were divided into two groups by heart function grade of New York Heart Association （NYHA）, we found that the HDAC9 mRNA expression level in NYHA grade Ⅱ -Ⅲ group were lower than that in NYHA grade IV group. More importantly, the correlation study suggested that the expression of HDAC9 mRNA was negatively correlated to Tregs frequency and left ventricular ejection fraction （LVEF）, whereas positively correlated to larger left ventricular end-diastolic dimension （LVEDD） and B-type natriuretic peptide （BNP） in patients with CHF. The correlation studies also showed a positive correlation between HDAC9 and the severity of CHF. Our research suggests that HDAC9 may be a new indicator for assessing CHF and it may offer a new direction for research of CHF.展开更多
CD4+CD25hi T cells are thought to be crucial for the maintenance of immunological tolerance to self antigens. In this study, we investigated the frequencies of these cells in the early stage of type 1 diabetes, as wel...CD4+CD25hi T cells are thought to be crucial for the maintenance of immunological tolerance to self antigens. In this study, we investigated the frequencies of these cells in the early stage of type 1 diabetes, as well as in a setting of possible pre-diabetic autoimmunity. Hence, the expression of FOXP3, CTLA-4, and CD27 in CD4+ CD25hi T cells was analyzed using flow cytometry in 14 patients with recent onset type 1 diabetes, in 9 at-risk individuals, and 9 healthy individuals with no known risk for type 1 diabetes. Our results show there were no differences in the frequency of CD4+CD25hi cells between groups. However, compared to controls, recent-onset type 1 diabetic patients had higher expression of FOXP3, CTLA-4, and CD27 in CD4+ CD25hi cells from peripheral blood. The median fluorescence intensity of FOXP3 was significantly higher in CD4+CD25hi cells from patients with type 1 diabetes than from controls. Furthermore, a positive correlation between the frequency of FOXP3+ cells and the median fluorescence intensity of FOXP3 was observed among patients with type 1 diabetes. These data suggest that the frequency of CD4+CD25hi FOXP3+ T cells in the periphery is not decreased but rather increased at onset of type 1 diabetes. Thus, functional deficiencies rather than reduced numbers of CD4+CD25hi cells could contribute to the development of type 1 diabetes.展开更多
Objective:To investigate the function of cytokines,chemokines,and regulatory T cells(Tregs)in the pathogenesis of Type 1 diabeles mellitus(T1DM)in children.Methods:A total of 35 children with T1DM and 30 healthy contr...Objective:To investigate the function of cytokines,chemokines,and regulatory T cells(Tregs)in the pathogenesis of Type 1 diabeles mellitus(T1DM)in children.Methods:A total of 35 children with T1DM and 30 healthy controls were enrolled in this study.Levels of serum cytokines(IL-1α,IL-6,IL-10,IL-12,and TNF-α)and chemokines(MIP-1α,MIP-1βand MCP-1)were detected by enzyme-linked immunosorbent assay.Peripheral blood mononuclear cells(PBMCs)were isolated and culture supernatant of phytohaemagglutinin(PHA)-stimulatcd PBMCs was subjecled to ELISA for levels of cytokines(IL-1α,IL-6,IL-10,IL-12 and TNV-α)in T1DM and control group.Furthermore,flow cytometty was used to determine the percentage of Tregs in PBMCs of two groups.Results:Levels of serum cytokines including IL-1α,IL-6,IL-10 andd TNF-αas well as chemokines,such as MIP-1αand MIP-1βin children with T1DM children were significantly higher than those in healthy controls(P<0.05,respectively).PBMCs with PHA stimulation in T1DM group secreted more IL-1αand TNF-α(P<0.05,respectively),but less IL-10(P<0.05),as compared with control group.Furthermore,the proportion of CD4^+,CD25^+,Foxp3.Tregs in PBMCs isolated from children with T1DM was obviously lower than those in heathy controls(P<0.05).Conclusions:Immune dysfunction.with uprcgulation of inflanunatory factors such as IL-1α.IL-6.TNF-αand MIP-1α.downregulation of IL-10 and Tregs,plays an important role in the pathogenesis of T1DM in children.展开更多
AIM To determine the immune-modulatory and thehepatoprotective effects of oral administration of twosoy extracts in immune mediated liver injury and nonalcoholicsteatohepatitis （NASH）.METHODS： Two soy extracts, M1 ...AIM To determine the immune-modulatory and thehepatoprotective effects of oral administration of twosoy extracts in immune mediated liver injury and nonalcoholicsteatohepatitis （NASH）.METHODS： Two soy extracts, M1 and OS, were orallyadministered to mice with concanavalin A （ConA）immune-mediated hepatitis, to high-fat diet （HFD） miceand to methionine and choline reduced diet combinedwith HFD mice. Animals were followed for disease andimmune biomarkers.RESULTS： Oral administration of OS and M1 had anadditive effect in alleviating ConA hepatitis manifestedby a decrease in alanine aminotransferase and aspartateaminotransferase serum levels. Oral administration ofthe OS and M1 soy derived fractions, ameliorated liverinjury in the high fat diet model of NASH, manifested bya decrease in hepatic triglyceride levels, improvementin liver histology, decreased serum cholesterol andtriglycerides and improved insulin resistance. In themethionine and choline reduced diet combined withthe high fat diet model, we noted a decrease inhepatic triglycerides and improvement in blood glucoselevels and liver histology. The effects were associated with reduced serum tumor necrosis factor alpha andalteration of regulatory T cell distribution.CONCLUSION： Oral administration of the combinationof OS and M1 soy derived extracts exerted an adjuvanteffect in the gut-immune system, altering the distributionof regulatory T cells, and alleviating immune mediatedliver injury, hyperlipidemia and insulin resistance.展开更多
As a T cell-mediated autoimmune disease,type 1 diabetes mellitus(T1DM)is marked by insulin defect resulting from the destruction of pancreaticβ-cells.The understanding of various aspects of T1DM,such as its epidemiol...As a T cell-mediated autoimmune disease,type 1 diabetes mellitus(T1DM)is marked by insulin defect resulting from the destruction of pancreaticβ-cells.The understanding of various aspects of T1DM,such as its epidemiology,pathobiology,pathogenesis,clinical manifestations,and complications,has been greatly promoted by valuable research performed during the past decades.However,these findings have not been translated into an effective treatment.The ideal treatment should safely repair the destroyed immune balance in a longlasting manner,preventing or stopping the destruction ofβ-cells.As a type of immune hypo-responsiveness to the orally administrated antigen,oral tolerance may be induced by enhancement of regulatory T cells(Tregs)or by anergy/deletion of T cells,depending on the dosage of orally administrated antigen.Acting as an antigen-specific immunotherapy,oral tolerance therapy for T1DM has been mainly performed using animal models and some clinical trials have been completed or are still ongoing.Based on the review of the proposed mechanism of the development of T1DM and oral tolerance,we give a current overview of oral tolerance therapy for T1DM conducted in both animal models and clinical trials.展开更多
相比传统糖皮质激素联合氨甲蝶呤、硫唑嘌呤等改善自身免疫疾病方案治疗周期长、不良反应程度重的特点,近年来研究显示恢复或逆转调节性T细胞(regulatory T cells,Treg)相关的免疫失衡能有效治疗自身免疫性疾病,在自身免疫性疾病的临床...相比传统糖皮质激素联合氨甲蝶呤、硫唑嘌呤等改善自身免疫疾病方案治疗周期长、不良反应程度重的特点,近年来研究显示恢复或逆转调节性T细胞(regulatory T cells,Treg)相关的免疫失衡能有效治疗自身免疫性疾病,在自身免疫性疾病的临床应用方面具有巨大的潜力。本文就近年来Treg细胞过继治疗在常见自身免疫性疾病中的研究进展进行概述。展开更多
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 isl...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.展开更多
The lack of immune response to an antigen, a process known as immune tolerance, is essential for the preservation of immune homeostasis. To date, two mechanisms that drive immune tolerance have been described extensiv...The lack of immune response to an antigen, a process known as immune tolerance, is essential for the preservation of immune homeostasis. To date, two mechanisms that drive immune tolerance have been described extensively： central tolerance and peripheral tolerance. Under the new nomenclature, thymus-derived regulatory T （tTreg） ceils are the major mediators of central immune tolerance, whereas peripherally derived regulatory T （PTreg） cells function to regulate peripheral immune tolerance. A third type of Treg ceils, termed iTreg, represents only the in vitro-induced Treg cellsz. Depending on whether the cells stably express Foxp3, pTreg, and iTreg cells may be divided into two subsets： the classical CD4＋Foxp3＋ Treg cells and the CD4＋Foxp3- type 1 regulatory T （Trl） cells2. This review focuses on the discovery, associated biomarkers, regulatory functions, methods of induction, association with disease, and clinical trials of Trl cells.展开更多
As an important subset of regulatory T （Treg） cells, IL-10-producing type 1 regulatory T cells （Trl）, have some different features to thymic-derived naturally occurring CD4^＋CD25^＋Foxp3^＋ Treg cells（nTreg cell...As an important subset of regulatory T （Treg） cells, IL-10-producing type 1 regulatory T cells （Trl）, have some different features to thymic-derived naturally occurring CD4^＋CD25^＋Foxp3^＋ Treg cells（nTreg cells）. Similar to nTreg cells, Trl also play important roles in the control of allergic inflammation in several ways. There is a fine balance between Trl and Th2 responses in healthy subjects. Skewing of allergic-specific effctor T cells to a Trl phenotype appears to be a critical event in successful allergen-specific immunotherapy and glucocorticoids and β2-agonists treatment. Trl suppress Th2 cells and effector cells of allergic inflammation, such as eosinophils, mast cells, basophils, through producing IL-10, and perhaps TGF-β. Understanding of Trl may be helpful in developing new strategies for treatment of allergic diseases.展开更多
Type 1 diabetes mellitus(T1D)is a chronic autoimmune condition in which the immune system destroys insulin-producing pancreatic β cells.In addition to well-established pathogenic effector T cells,regulatory T cells(T...Type 1 diabetes mellitus(T1D)is a chronic autoimmune condition in which the immune system destroys insulin-producing pancreatic β cells.In addition to well-established pathogenic effector T cells,regulatory T cells(Tregs)have also been shown to be defective in T1D.Thus,an increasing number of therapeutic approaches are being developed to target Tregs.However,the role and mechanisms of TGF-β-induced Tregs(iTregs)in T1D remain poorly understood.Here,using a streptozotocin(STZ)-induced preclinical T1D mouse model,we found that iTregs could ameliorate the development of T1D and preserve β cell function.The preventive effect was associated with the inhibition of type 1 cytotoxic T(Tel)cell function and rebalancing the Treg/Tc1 cell ratio in recipients.Furthermore,we showed that the underlying mechanisms were due to the TGF-β-mediated combinatorial actions of mTOR and TCF1.In addition to the preventive role,the therapeutic effects of iTregs on the established STZ-T1D and nonobese diabetic(NOD)mouse models were tested,which revealed improved β cell function.Our findings therefore provide key new insights into the basic mechanisms involved in the therapeutic role of iTregs in T1D.展开更多
Several subsets of T-regulatory （Tr） cells with distinct phenotypes and distinct mechanisms of action have been identified. These include Tr type 1 （Trl） cells; Th3 cells, which primarily secrete transforming grow...Several subsets of T-regulatory （Tr） cells with distinct phenotypes and distinct mechanisms of action have been identified. These include Tr type 1 （Trl） cells; Th3 cells, which primarily secrete transforming growth factor （TGF）-β; and CD4^＋CD25^＋ T cells, which inhibit immune responses through cell to cell contact.1 It has been shown that CD4^＋CD25^＋ immunoregulatory T cells induced by the blockade of CD154-CD40 pathway are tolerant to alloantigen, resulting in secondary mixed lymphocyte reaction （MLR） hyporesponsiveness in vitro and tolerance to alloantigen in vivo. Previous studies mainly paid attention to CD4^＋CD25^＋ immunoregulatory T cells induced by CD154-CD40 blockade, but it was unclear whether CD154-CD40 blockade might induce Trl or Tr1-like cells.展开更多
文摘Heart failure （HF） is the end stage of various kinds of cardiovascular diseases and leads to a high mortality worldwide. Numerous studies have demonstrated that frequencies of CD4＋CD25＋Foxp3＋ regulatory T cells （Tregs） are reduced in HF patients and properly expanding Tregs attenuates HF progression. Histone deacetylase （HDAC） 9 has been revealed to contribute to several cardiovascular and cerebrovascular diseases. Plenty of studies showed that HDAC9 negatively regulated the number and function of Tregs. Thus, we aim to investigate the expression of HDAC 9 in patients with chronic heart failure （CHF） and the relationship among HDAC9, Tregs and CHF. Our research showed a reduced number of Tregs and an increased expression of HDAC9 mRNA in CHF patients. Patients with CHF were divided into two groups by heart function grade of New York Heart Association （NYHA）, we found that the HDAC9 mRNA expression level in NYHA grade Ⅱ -Ⅲ group were lower than that in NYHA grade IV group. More importantly, the correlation study suggested that the expression of HDAC9 mRNA was negatively correlated to Tregs frequency and left ventricular ejection fraction （LVEF）, whereas positively correlated to larger left ventricular end-diastolic dimension （LVEDD） and B-type natriuretic peptide （BNP） in patients with CHF. The correlation studies also showed a positive correlation between HDAC9 and the severity of CHF. Our research suggests that HDAC9 may be a new indicator for assessing CHF and it may offer a new direction for research of CHF.
基金supported by the Swedish Child Diabetes Foundationthe Medical Research Council of Southeast Sweden(FORSS-8847).
文摘CD4+CD25hi T cells are thought to be crucial for the maintenance of immunological tolerance to self antigens. In this study, we investigated the frequencies of these cells in the early stage of type 1 diabetes, as well as in a setting of possible pre-diabetic autoimmunity. Hence, the expression of FOXP3, CTLA-4, and CD27 in CD4+ CD25hi T cells was analyzed using flow cytometry in 14 patients with recent onset type 1 diabetes, in 9 at-risk individuals, and 9 healthy individuals with no known risk for type 1 diabetes. Our results show there were no differences in the frequency of CD4+CD25hi cells between groups. However, compared to controls, recent-onset type 1 diabetic patients had higher expression of FOXP3, CTLA-4, and CD27 in CD4+ CD25hi cells from peripheral blood. The median fluorescence intensity of FOXP3 was significantly higher in CD4+CD25hi cells from patients with type 1 diabetes than from controls. Furthermore, a positive correlation between the frequency of FOXP3+ cells and the median fluorescence intensity of FOXP3 was observed among patients with type 1 diabetes. These data suggest that the frequency of CD4+CD25hi FOXP3+ T cells in the periphery is not decreased but rather increased at onset of type 1 diabetes. Thus, functional deficiencies rather than reduced numbers of CD4+CD25hi cells could contribute to the development of type 1 diabetes.
基金supported by a grant from the National Natural Science Foundation of China(no.81200867)
文摘Objective:To investigate the function of cytokines,chemokines,and regulatory T cells(Tregs)in the pathogenesis of Type 1 diabeles mellitus(T1DM)in children.Methods:A total of 35 children with T1DM and 30 healthy controls were enrolled in this study.Levels of serum cytokines(IL-1α,IL-6,IL-10,IL-12,and TNF-α)and chemokines(MIP-1α,MIP-1βand MCP-1)were detected by enzyme-linked immunosorbent assay.Peripheral blood mononuclear cells(PBMCs)were isolated and culture supernatant of phytohaemagglutinin(PHA)-stimulatcd PBMCs was subjecled to ELISA for levels of cytokines(IL-1α,IL-6,IL-10,IL-12 and TNV-α)in T1DM and control group.Furthermore,flow cytometty was used to determine the percentage of Tregs in PBMCs of two groups.Results:Levels of serum cytokines including IL-1α,IL-6,IL-10 andd TNF-αas well as chemokines,such as MIP-1αand MIP-1βin children with T1DM children were significantly higher than those in healthy controls(P<0.05,respectively).PBMCs with PHA stimulation in T1DM group secreted more IL-1αand TNF-α(P<0.05,respectively),but less IL-10(P<0.05),as compared with control group.Furthermore,the proportion of CD4^+,CD25^+,Foxp3.Tregs in PBMCs isolated from children with T1DM was obviously lower than those in heathy controls(P<0.05).Conclusions:Immune dysfunction.with uprcgulation of inflanunatory factors such as IL-1α.IL-6.TNF-αand MIP-1α.downregulation of IL-10 and Tregs,plays an important role in the pathogenesis of T1DM in children.
基金Supported by Grants from The Roaman-Epstein Liver Research Foundation(partly,to Ilan Y)
文摘AIM To determine the immune-modulatory and thehepatoprotective effects of oral administration of twosoy extracts in immune mediated liver injury and nonalcoholicsteatohepatitis （NASH）.METHODS： Two soy extracts, M1 and OS, were orallyadministered to mice with concanavalin A （ConA）immune-mediated hepatitis, to high-fat diet （HFD） miceand to methionine and choline reduced diet combinedwith HFD mice. Animals were followed for disease andimmune biomarkers.RESULTS： Oral administration of OS and M1 had anadditive effect in alleviating ConA hepatitis manifestedby a decrease in alanine aminotransferase and aspartateaminotransferase serum levels. Oral administration ofthe OS and M1 soy derived fractions, ameliorated liverinjury in the high fat diet model of NASH, manifested bya decrease in hepatic triglyceride levels, improvementin liver histology, decreased serum cholesterol andtriglycerides and improved insulin resistance. In themethionine and choline reduced diet combined withthe high fat diet model, we noted a decrease inhepatic triglycerides and improvement in blood glucoselevels and liver histology. The effects were associated with reduced serum tumor necrosis factor alpha andalteration of regulatory T cell distribution.CONCLUSION： Oral administration of the combinationof OS and M1 soy derived extracts exerted an adjuvanteffect in the gut-immune system, altering the distributionof regulatory T cells, and alleviating immune mediatedliver injury, hyperlipidemia and insulin resistance.
基金Supported by National Natural Science Foundation of China,No.81803418Natural Science Foundation of the Jiangsu Higher Education Institutions,No.18KJD350001and Project for Youth Scholar of Jiangsu Collaborative Innovation Center of Regional Modern Agriculture and Environmental Projection,No.HSXT2-314.
文摘As a T cell-mediated autoimmune disease,type 1 diabetes mellitus(T1DM)is marked by insulin defect resulting from the destruction of pancreaticβ-cells.The understanding of various aspects of T1DM,such as its epidemiology,pathobiology,pathogenesis,clinical manifestations,and complications,has been greatly promoted by valuable research performed during the past decades.However,these findings have not been translated into an effective treatment.The ideal treatment should safely repair the destroyed immune balance in a longlasting manner,preventing or stopping the destruction ofβ-cells.As a type of immune hypo-responsiveness to the orally administrated antigen,oral tolerance may be induced by enhancement of regulatory T cells(Tregs)or by anergy/deletion of T cells,depending on the dosage of orally administrated antigen.Acting as an antigen-specific immunotherapy,oral tolerance therapy for T1DM has been mainly performed using animal models and some clinical trials have been completed or are still ongoing.Based on the review of the proposed mechanism of the development of T1DM and oral tolerance,we give a current overview of oral tolerance therapy for T1DM conducted in both animal models and clinical trials.
文摘相比传统糖皮质激素联合氨甲蝶呤、硫唑嘌呤等改善自身免疫疾病方案治疗周期长、不良反应程度重的特点,近年来研究显示恢复或逆转调节性T细胞(regulatory T cells,Treg)相关的免疫失衡能有效治疗自身免疫性疾病,在自身免疫性疾病的临床应用方面具有巨大的潜力。本文就近年来Treg细胞过继治疗在常见自身免疫性疾病中的研究进展进行概述。
基金Supported by European Union-NextGenerationEU,through The National Recovery and Resilience Plan of the Republic of Bulgaria,No.BG-RRP-2.004-0008-C01.
文摘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.
文摘The lack of immune response to an antigen, a process known as immune tolerance, is essential for the preservation of immune homeostasis. To date, two mechanisms that drive immune tolerance have been described extensively： central tolerance and peripheral tolerance. Under the new nomenclature, thymus-derived regulatory T （tTreg） ceils are the major mediators of central immune tolerance, whereas peripherally derived regulatory T （PTreg） cells function to regulate peripheral immune tolerance. A third type of Treg ceils, termed iTreg, represents only the in vitro-induced Treg cellsz. Depending on whether the cells stably express Foxp3, pTreg, and iTreg cells may be divided into two subsets： the classical CD4＋Foxp3＋ Treg cells and the CD4＋Foxp3- type 1 regulatory T （Trl） cells2. This review focuses on the discovery, associated biomarkers, regulatory functions, methods of induction, association with disease, and clinical trials of Trl cells.
文摘As an important subset of regulatory T （Treg） cells, IL-10-producing type 1 regulatory T cells （Trl）, have some different features to thymic-derived naturally occurring CD4^＋CD25^＋Foxp3^＋ Treg cells（nTreg cells）. Similar to nTreg cells, Trl also play important roles in the control of allergic inflammation in several ways. There is a fine balance between Trl and Th2 responses in healthy subjects. Skewing of allergic-specific effctor T cells to a Trl phenotype appears to be a critical event in successful allergen-specific immunotherapy and glucocorticoids and β2-agonists treatment. Trl suppress Th2 cells and effector cells of allergic inflammation, such as eosinophils, mast cells, basophils, through producing IL-10, and perhaps TGF-β. Understanding of Trl may be helpful in developing new strategies for treatment of allergic diseases.
基金supported by the National Key R&D Program of China(2017YFAO105803)the general program of the National Natural Science Foundation of China(81770826)+2 种基金the Science and Technology Plan Projects of Guangdong Province(2019B020227003)the Key Special Projects of Medical and Health of Guangzhou City(202007040003)the 5010 Clinical Research Projects of Sun Yatsen University(2015015).
文摘Type 1 diabetes mellitus(T1D)is a chronic autoimmune condition in which the immune system destroys insulin-producing pancreatic β cells.In addition to well-established pathogenic effector T cells,regulatory T cells(Tregs)have also been shown to be defective in T1D.Thus,an increasing number of therapeutic approaches are being developed to target Tregs.However,the role and mechanisms of TGF-β-induced Tregs(iTregs)in T1D remain poorly understood.Here,using a streptozotocin(STZ)-induced preclinical T1D mouse model,we found that iTregs could ameliorate the development of T1D and preserve β cell function.The preventive effect was associated with the inhibition of type 1 cytotoxic T(Tel)cell function and rebalancing the Treg/Tc1 cell ratio in recipients.Furthermore,we showed that the underlying mechanisms were due to the TGF-β-mediated combinatorial actions of mTOR and TCF1.In addition to the preventive role,the therapeutic effects of iTregs on the established STZ-T1D and nonobese diabetic(NOD)mouse models were tested,which revealed improved β cell function.Our findings therefore provide key new insights into the basic mechanisms involved in the therapeutic role of iTregs in T1D.
文摘Several subsets of T-regulatory （Tr） cells with distinct phenotypes and distinct mechanisms of action have been identified. These include Tr type 1 （Trl） cells; Th3 cells, which primarily secrete transforming growth factor （TGF）-β; and CD4^＋CD25^＋ T cells, which inhibit immune responses through cell to cell contact.1 It has been shown that CD4^＋CD25^＋ immunoregulatory T cells induced by the blockade of CD154-CD40 pathway are tolerant to alloantigen, resulting in secondary mixed lymphocyte reaction （MLR） hyporesponsiveness in vitro and tolerance to alloantigen in vivo. Previous studies mainly paid attention to CD4^＋CD25^＋ immunoregulatory T cells induced by CD154-CD40 blockade, but it was unclear whether CD154-CD40 blockade might induce Trl or Tr1-like cells.
