调节性T细胞与非酒精性脂肪性肝病
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摘要
非酒精性脂肪性肝病已成为全世界常见的慢性肝病。近年来研究表明,免疫调节紊乱在NAFLD发病中具有重要作用,特别是适应性免疫的调节性T细胞(Treg)在NAFLD发病机制中的作用不容忽视。本文对NAFLD疾病过程中Treg的变化、影响Treg分化发育的因素,以及目前报道与调节Treg相关的治疗等进行综述。
Non-alcoholic fatty liver disease has become the most common chronic liver disease in the world. Studies recently have shown that immunoregulatory disorders,especially adaptive immune regulatory T cells( Treg),play a key role in the pathogenesis of NAFLD,which can not be ignored. This article reviews the changes in Treg during NAFLD disease,the factors influencing the differentiation and development of Tregs,and the current reports on the treatment associated with regulatory Tregs.
Non-alcoholic fatty liver disease has become the most common chronic liver disease in the world. Studies recently have shown that immunoregulatory disorders,especially adaptive immune regulatory T cells( Treg),play a key role in the pathogenesis of NAFLD,which can not be ignored. This article reviews the changes in Treg during NAFLD disease,the factors influencing the differentiation and development of Tregs,and the current reports on the treatment associated with regulatory Tregs.
引文
[1] Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis[J]. N Engl J Med,2017,377(21):2063-2072.
[2]张少鹏,倪绪皓,吕凌.外泌体及其对调节性T细胞作用的研究进展[J].中国免疫学杂志,2018,34(3):450-459.Zhang SP,Ni XH,LüL. Progress on exosome and effect on regulatory T cells[J]. Chin J Immunol,2018,34(3):450-459.
[3] Tsuda M,Tone Y,Ogawa C,et al. A bacterial artificial chromosome reporter system for expression of the human FOXP3 gene in mouse regulatory T-cells[J]. Front Immunol,2017,8(5609):279.
[4] Munn David H,Sharma Madhav D,Johnson Theodore S. Treg destabilization and reprogramming:implications for cancer immunotherapy[J]. Cancer Res,2018,78:5191-5199.
[5]马巧平,钱毅,李岭.不同程度的非酒精性脂肪肝患者CD4+CD25+Foxp3T细胞的检测及其意义[J].临床消化病杂志,2011,23(5):289-291.Ma QP,Qian Y,Li L. Significance of the changes of CD4+CD25+Foxp3 T cells in patients with thelevel of non-alcoholic fatty liver disease[J]. Chin J Clin Gastroenterol,2011,23(5):289-291.
[6]谢中华,汪铁军,赵振中.非酒精性脂肪性肝病患者外周血CD4+CD25+Foxp3+调节性T细胞的变化及意义[J].中国预防医学杂志,2012,13(1):62-65.Xie ZH,Wang TJ,Zhao ZZ. Clinical significance of peripheral CD4+CD25+Foxp3+regulatory T cells in nonalcoholic fatty liver disease patients[J]. Chin Prev Med,2012,13(1):62-65.
[7] Rau M,Schilling A K,Meertens J,et al. Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of Th17 cells in the liver and an increased Th17/resting regulatory T cell ratio in peripheral blood and in the liver[J]. J Immunol,2016,196(1):96-105.
[8] Speletas M,Argentou N,Germanidis G,et al. Foxp3 expression in liver correlates with the degree but not the cause of inflammation[J]. Mediators Inflamm,2011,2011:827565.
[9] Sderberg C,Marmur J,Eckes K,et al. Microvesicular fat,inter cellular adhesion molecule-1 and regulatory T-lymphocytes are of importance for the inflammatory process in livers with non-alcoholic steatohepatitis[J]. APMIS,2011,119(7):412-420.
[10] Ma X,Hua J,Mohamood AR,et al. A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury.[J]. Hepatology,2007,46(5):1519-1529.
[11] Sakaguchi S,Yamaguchi T,Nomura T,et al. Regulatory T cells and immune tolerance[J]. Cell,2008,133(5):775-787.
[12] Vonghia L,Ruyssers N,Schrijvers D,et al. CD4+RORγt++and Tregs in a mouse model of diet-induced nonalcoholic steatohepatitis[J]. Mediators Inflamm,2015,2015:239623.
[13] Ma C,Kesarwala AH,Eggert T,et al. NAFLD causes selective CD4+T lymphocyte loss and promotes hepatocarcinogenesis[J].Nature,2016,531(7593):253-257.
[14] Chatzigeorgiou A,Chung KJ,Garcia-Martin R,et al. Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation[J]. Hepatology,2014,60(4):1196-1210.
[15] Poggi M,Morin SO,Bastelica D,et al. CD28 deletion improves obesity-induced liver steatosis but increases adiposity in mice[J]. Int J Obesity,2015,39:977-985.
[16] Wolf D,Jehle F,Michel NA,et al. Coinhibitory suppression of T cell activation by CD40 protects against obesity and adipose tissue inflammation in mice[J]. Circulation,2014,129(23):2414-2425
[17] Poggi M,Engel D,Christ A,et al. CD40L deficiency ameliorates adipose tissue inflammation and metabolic manifestations of obesity in mice[J]. Arterioscler Thromb Vasc Biol,2011,31(10):2251-2260.
[18] Berod L,Friedrich C,Nandan A,et al. Erratum:De novo fatty acid synthesis controls the fate between regulatory T and T helper17 cells[J]. Nat Med,2014,20(11):1327-1333.
[19] Laplante Mathieu,Sabatini David M. An emerging role of m TOR in lipid biosynthesis[J]. Curr Biol,2009,19(22):R1046-1052.
[20] Mascanfroni ID,Takenaka MC,Yeste A,et al. Metabolic control of type 1 regulatory(Tr1)cell differentiation by AHR and HIF1-α[J]. Nat Med,2015,21(6):638-646.
[21] Siegmund B,Sennello J A,Jonescarson J,et al. Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice[J]. Gut,2004,53(7):965-972.
[22] De Rosa V,Procaccini C,CalìG,et al. A Key Role of Leptin in the control of regulatory T cell proliferation[J]. Immunity,2007,26(2):241-255.
[23] Cipolletta D,Feuerer M,Li A,et al. PPARγis a major driver of the accumulation and phenotype of adipose-tissue Treg cells[J].Nature,2012,486(7404):549-553.
[24] Smith PM,Howitt MR,Panikov N,et al. The microbial metabolites,short-chain fatty acids,regulate colonic Treg cell homeostasis[J]. Science,2013,341(6145):567-573.
[25] Arpaia N,Campbell C,Fan X,et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.[J]. Nature,2013,504(7480):451-455.
[26] Zhou D,Pan Q,Liu X,et al. Clostridium butyricum B1 alleviates high-fat diet-induced steatohepatitis in mice via enterohepatic immunoregulation[J]. J Gastroenterol Hepatol,2017,32(9):1640-1648.
[27] Fabrizi M,Marchetti V,Mavilio M,et al. IL-21 is a major negative regulator of IRF4-dependent lipolysis affecting Tregs in adipose tissue and systemic insulin sensitivity[J]. Diabetes,2014,63(6):2086-2096.
[28] Hfer T,Krichevsky O,Altanbonnet G. Competition for IL-2between regulatory and effector T cells to chisel immune responses[J]. Front Immunol,2012,3(3):268.
[29] Ilan Y,Sakaguchi S. Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice.[J]. Proc Natl Acad Sci U S A,2010,107(21):9765-9770.
[30] Ilan Y,Shailubhai K,Sanyal A. Immunotherapy with oral administration of humanized anti-CD3 monoclonal antibody:a novel gut-immune system-based therapy for metaflammation and NASH[J]. Clin Exp Immunol,2018,193:275-283.
[31] Ilan Y,Zigmond E,Lalazar G,et al. Oral administration of OKT3monoclonal antibody to human subjects induces a dose-dependent immunologic effect in T cells and dendritic cells[J]. J Clin Immunol,2010,30(1):167-177.
[32] Lalazar G,Mizrahi M,Turgeman I,et al. Oral administration of OKT3 m Ab to patients with NASH,promotes regulatory T-cell induction,and alleviates insulin resistance:results of a phaseⅡa blinded placebo-controlled trial[J]. J Clin Immunol,2015,35(4):399-407.
[33] Shaaltiel Y,Ya'Acov AB,Shabat Y,et al. Tu2029 A novel method for anti-TNF based-oral immunotherapy:Oral administration of a plant cell-expressed recombinant anti-TNF fusion protein for treating of Crohn's disease[J].Gastroenterology,2014,146(5):S-901.
[34] Almon E,Khoury T,Drori A,et al. An oral administration of a recombinant anti-TNF fusion protein is biologically active in the gut promoting regulatory T cells:Results of a phaseⅠclinical trial using a novel oral anti-TNF alpha-based therapy[J]. J Immunol Methods,2017,446:21-29.
[35] Adar T,Ben YA,Lalazar G,et al. Oral administration of immunoglobulin G-enhanced colostrum alleviates insulin resistance and liver injury and is associated with alterations in natural killer T cells[J]. Clin Exp Immunol,2012,167(2):252-260.
[36] Mizrahi MLG,Shabat Y,Adar T,et al. Alleviation of insulin resistance and liver damage by oral administration of etec colostrumsis mediated by increased GLP-1,adiponectin serum levels and tregs:results of a phaseⅠ/Ⅱclinical trial in NASH[J]. Hepatology,2010,52:163A.
[2]张少鹏,倪绪皓,吕凌.外泌体及其对调节性T细胞作用的研究进展[J].中国免疫学杂志,2018,34(3):450-459.Zhang SP,Ni XH,LüL. Progress on exosome and effect on regulatory T cells[J]. Chin J Immunol,2018,34(3):450-459.
[3] Tsuda M,Tone Y,Ogawa C,et al. A bacterial artificial chromosome reporter system for expression of the human FOXP3 gene in mouse regulatory T-cells[J]. Front Immunol,2017,8(5609):279.
[4] Munn David H,Sharma Madhav D,Johnson Theodore S. Treg destabilization and reprogramming:implications for cancer immunotherapy[J]. Cancer Res,2018,78:5191-5199.
[5]马巧平,钱毅,李岭.不同程度的非酒精性脂肪肝患者CD4+CD25+Foxp3T细胞的检测及其意义[J].临床消化病杂志,2011,23(5):289-291.Ma QP,Qian Y,Li L. Significance of the changes of CD4+CD25+Foxp3 T cells in patients with thelevel of non-alcoholic fatty liver disease[J]. Chin J Clin Gastroenterol,2011,23(5):289-291.
[6]谢中华,汪铁军,赵振中.非酒精性脂肪性肝病患者外周血CD4+CD25+Foxp3+调节性T细胞的变化及意义[J].中国预防医学杂志,2012,13(1):62-65.Xie ZH,Wang TJ,Zhao ZZ. Clinical significance of peripheral CD4+CD25+Foxp3+regulatory T cells in nonalcoholic fatty liver disease patients[J]. Chin Prev Med,2012,13(1):62-65.
[7] Rau M,Schilling A K,Meertens J,et al. Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of Th17 cells in the liver and an increased Th17/resting regulatory T cell ratio in peripheral blood and in the liver[J]. J Immunol,2016,196(1):96-105.
[8] Speletas M,Argentou N,Germanidis G,et al. Foxp3 expression in liver correlates with the degree but not the cause of inflammation[J]. Mediators Inflamm,2011,2011:827565.
[9] Sderberg C,Marmur J,Eckes K,et al. Microvesicular fat,inter cellular adhesion molecule-1 and regulatory T-lymphocytes are of importance for the inflammatory process in livers with non-alcoholic steatohepatitis[J]. APMIS,2011,119(7):412-420.
[10] Ma X,Hua J,Mohamood AR,et al. A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury.[J]. Hepatology,2007,46(5):1519-1529.
[11] Sakaguchi S,Yamaguchi T,Nomura T,et al. Regulatory T cells and immune tolerance[J]. Cell,2008,133(5):775-787.
[12] Vonghia L,Ruyssers N,Schrijvers D,et al. CD4+RORγt++and Tregs in a mouse model of diet-induced nonalcoholic steatohepatitis[J]. Mediators Inflamm,2015,2015:239623.
[13] Ma C,Kesarwala AH,Eggert T,et al. NAFLD causes selective CD4+T lymphocyte loss and promotes hepatocarcinogenesis[J].Nature,2016,531(7593):253-257.
[14] Chatzigeorgiou A,Chung KJ,Garcia-Martin R,et al. Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation[J]. Hepatology,2014,60(4):1196-1210.
[15] Poggi M,Morin SO,Bastelica D,et al. CD28 deletion improves obesity-induced liver steatosis but increases adiposity in mice[J]. Int J Obesity,2015,39:977-985.
[16] Wolf D,Jehle F,Michel NA,et al. Coinhibitory suppression of T cell activation by CD40 protects against obesity and adipose tissue inflammation in mice[J]. Circulation,2014,129(23):2414-2425
[17] Poggi M,Engel D,Christ A,et al. CD40L deficiency ameliorates adipose tissue inflammation and metabolic manifestations of obesity in mice[J]. Arterioscler Thromb Vasc Biol,2011,31(10):2251-2260.
[18] Berod L,Friedrich C,Nandan A,et al. Erratum:De novo fatty acid synthesis controls the fate between regulatory T and T helper17 cells[J]. Nat Med,2014,20(11):1327-1333.
[19] Laplante Mathieu,Sabatini David M. An emerging role of m TOR in lipid biosynthesis[J]. Curr Biol,2009,19(22):R1046-1052.
[20] Mascanfroni ID,Takenaka MC,Yeste A,et al. Metabolic control of type 1 regulatory(Tr1)cell differentiation by AHR and HIF1-α[J]. Nat Med,2015,21(6):638-646.
[21] Siegmund B,Sennello J A,Jonescarson J,et al. Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice[J]. Gut,2004,53(7):965-972.
[22] De Rosa V,Procaccini C,CalìG,et al. A Key Role of Leptin in the control of regulatory T cell proliferation[J]. Immunity,2007,26(2):241-255.
[23] Cipolletta D,Feuerer M,Li A,et al. PPARγis a major driver of the accumulation and phenotype of adipose-tissue Treg cells[J].Nature,2012,486(7404):549-553.
[24] Smith PM,Howitt MR,Panikov N,et al. The microbial metabolites,short-chain fatty acids,regulate colonic Treg cell homeostasis[J]. Science,2013,341(6145):567-573.
[25] Arpaia N,Campbell C,Fan X,et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.[J]. Nature,2013,504(7480):451-455.
[26] Zhou D,Pan Q,Liu X,et al. Clostridium butyricum B1 alleviates high-fat diet-induced steatohepatitis in mice via enterohepatic immunoregulation[J]. J Gastroenterol Hepatol,2017,32(9):1640-1648.
[27] Fabrizi M,Marchetti V,Mavilio M,et al. IL-21 is a major negative regulator of IRF4-dependent lipolysis affecting Tregs in adipose tissue and systemic insulin sensitivity[J]. Diabetes,2014,63(6):2086-2096.
[28] Hfer T,Krichevsky O,Altanbonnet G. Competition for IL-2between regulatory and effector T cells to chisel immune responses[J]. Front Immunol,2012,3(3):268.
[29] Ilan Y,Sakaguchi S. Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice.[J]. Proc Natl Acad Sci U S A,2010,107(21):9765-9770.
[30] Ilan Y,Shailubhai K,Sanyal A. Immunotherapy with oral administration of humanized anti-CD3 monoclonal antibody:a novel gut-immune system-based therapy for metaflammation and NASH[J]. Clin Exp Immunol,2018,193:275-283.
[31] Ilan Y,Zigmond E,Lalazar G,et al. Oral administration of OKT3monoclonal antibody to human subjects induces a dose-dependent immunologic effect in T cells and dendritic cells[J]. J Clin Immunol,2010,30(1):167-177.
[32] Lalazar G,Mizrahi M,Turgeman I,et al. Oral administration of OKT3 m Ab to patients with NASH,promotes regulatory T-cell induction,and alleviates insulin resistance:results of a phaseⅡa blinded placebo-controlled trial[J]. J Clin Immunol,2015,35(4):399-407.
[33] Shaaltiel Y,Ya'Acov AB,Shabat Y,et al. Tu2029 A novel method for anti-TNF based-oral immunotherapy:Oral administration of a plant cell-expressed recombinant anti-TNF fusion protein for treating of Crohn's disease[J].Gastroenterology,2014,146(5):S-901.
[34] Almon E,Khoury T,Drori A,et al. An oral administration of a recombinant anti-TNF fusion protein is biologically active in the gut promoting regulatory T cells:Results of a phaseⅠclinical trial using a novel oral anti-TNF alpha-based therapy[J]. J Immunol Methods,2017,446:21-29.
[35] Adar T,Ben YA,Lalazar G,et al. Oral administration of immunoglobulin G-enhanced colostrum alleviates insulin resistance and liver injury and is associated with alterations in natural killer T cells[J]. Clin Exp Immunol,2012,167(2):252-260.
[36] Mizrahi MLG,Shabat Y,Adar T,et al. Alleviation of insulin resistance and liver damage by oral administration of etec colostrumsis mediated by increased GLP-1,adiponectin serum levels and tregs:results of a phaseⅠ/Ⅱclinical trial in NASH[J]. Hepatology,2010,52:163A.