Autoimmune hepatitis is an uncommon condition that affects both adults and children and is characterized by chronic and recurrent inflammatory activity in the liver.This inflammation is accompanied by elevated IgG and...Autoimmune hepatitis is an uncommon condition that affects both adults and children and is characterized by chronic and recurrent inflammatory activity in the liver.This inflammation is accompanied by elevated IgG and autoantibody levels.Historically,treatment consists of steroids with the addition of azathioprine,which results in remission in approximately 80%of patients.Despite significant advancements in our understanding of the immune system over the past two decades,few modifications have been made to treatment algorithms,which have remained largely unchanged since they were first proposed more than 40 years ago.This review summarized the various treatment options currently available as well as our experiences using them.Although steroids are the standard treatment for induction therapy,other medications may be considered.Cyclosporin A,a calcineurin inhibitor that decreases T cell activation,has proven effective for induction of remission,but its long-term side effects limit its appeal for maintenance.Tacrolimus,a drug belonging to the same family,has been used in patients with refractory diseases with fewer side effects.Sirolimus and everolimus have interesting effects on regulatory T cell populations and may become viable options in the future.Mycophenolate mofetil is not effective for induction but is a valid alternative for patients who are intolerant to azathioprine.B celldepleting drugs,such as rituximab and belimumab,have been successfully used in refractory cases and are useful in both the short and long term.Other promising treatments include anti-tumor necrosis factors,Janus kinases inhibitors,and chimeric antigen receptor T cell therapy.This growing armamentarium allows us to imagine a more tailored approach to the treatment of autoimmune hepatitis in the near future.展开更多
In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing(MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hosp...In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing(MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hospitalizations, surgeries, and prolonged clinical remission. MH may be achieved with several therapeutic strategies reaching success rates up to 80% for both, ulcerative colitis(UC) and Crohn's disease(CD). Various scoring systems for UC and for the transmural CD, have been proposed to standardize the definition of MH. Several attempts have been undertaken to de-escalate therapy once MH is achieved, thus, reducing the risk of adverse events. In this review, we analysed the available studies regarding the achievement of MH and the subsequent treatment de-escalation according to disease type and administered therapy, together with non-invasive markers proposed as predictors for relapse. The available data are not encouraging since de-escalation after the achievement of MH is followed by a high number of clinical relapses reaching up to 50% within one year. Unclear is also another question, in case of combination therapies, which drug is more appropriate to stop, in order to guarantee a durable remission. Predictors of unfavourable outcome such as disease extension, perianal disease, or early onset disease appear to be inadequate to foresee behaviour of disease. Further studies are warranted to investigate the role of histologic healing for the further course of disease.展开更多
The optimal duration of biological treatment, particularly anti-TNF, in inflammatory bowel disease （IBD） is a very important question both for patients and physicians. There is no published evidence to clearly and d...The optimal duration of biological treatment, particularly anti-TNF, in inflammatory bowel disease （IBD） is a very important question both for patients and physicians. There is no published evidence to clearly and definitely answer this question. However data on natural history of IBD, long term safety of biologics, immunosuppressors （IS） cessation and some preliminary studies on biologics cessation may help us to discuss this topic. The decision to stop a biological treatment is currently based on a compromise between the benefits and risks associated with the prolongation of this treatment. IBD, more particularly CD, are characterized by the development of complications and the need for recurrent hospitalizations and surgeries in approximately 2/3 of cases. In these patients potentially in need of biological treatments, it is probable that, as it has been demonstrated for IS, the longer a stable remission has be achieved under treatment, the lower the risk of relapse is alter treatment cessation. Further prospective studies should now aim at disclosing patient characteristics associated with a low risk of relapse to imple- ment this strategy.展开更多
AIM To study the influence of different doses of tacrolimus(FK506)on gut microbiota after liver transplantation(LT)in rats.METHODS Specific pathogen-free Brown Norway(BN)rats and Lewis rats were separated into five gr...AIM To study the influence of different doses of tacrolimus(FK506)on gut microbiota after liver transplantation(LT)in rats.METHODS Specific pathogen-free Brown Norway(BN)rats and Lewis rats were separated into five groups:(1)Tolerance group(BN-BN LT,n=8);(2)rejection group(Lewis-BN LT,n=8);(3)high dosage FK506(FK506-H)group(Lewis-BN LT,n=8);(4)middle dosage FK506(FK506-M)group(Lewis-BN LT,n=8);and(5)low dosage FK506(FK506-L)group(LewisBN LT,n=8).FK506 was administered to recipients at a dose of 1.0 mg/kg,0.5 mg/kg,and 0.1 mg/kg body weight for 29 d after LT to the FK506-H,FK506-M,and FK506-L groups,respectively.On the 30^(th) day after LT,all rats were sampled and euthanized.Blood samples were harvested for liver function and plasma endotoxin testing.Hepatic graft and ileocecal tissues were collected for histopathology observation.Ileocecal contents were used for DNA extraction,Real-time quantitative polymerase chain reaction(RT-PCR)and digital processing of denaturing gradient gel electrophoresis(DGGE)profiles and analysis.RESULTS Compared to the FK506-H and FK506-L groups,FK506-M was optimal for maintaining immunosuppression and inducing normal graft function;the FK506-M maintained gut barrier integrity and low plasma endotoxin levels;furthermore,DGGE results showed that FK506-M induced stable gut microbiota.Diversity analysis indicated that FK506-M increased species richness and rare species abundance,and cluster analysis confirmed the stable gut microbiota induced by FK506-M.Phylogenetic tree analysis identified crucial bacteria associated with FK506-M;seven of the nine bacteria that were decreased corresponded to Bacteroidetes,while increased bacteria were of the Bifidobacterium species.FK506-M increased Faecalibacterium prausnitzii and Bifidobacterium spp.and decreased Bacteroides-Prevotella and Enterobacteriaceae,as assessed by RT-PCR,which confirmed the crucial bacterial alterations identified through DGGE.CONCLUSION Compared to the low or high dosage of FK506,an optimal dosage of FK506 induced immunosuppression,normal graft function and stable gut microbiota following LT in rats.The stable gut microbiota presented increased probiotics and decreased potential pathogenic endotoxin-producing bacteria.These findings provide a novel strategy based on gut microbiota for immunosuppressive dosage assessment for recipients following LT.展开更多
Fibrinogen-like 2(FGL2) encompasses a transmembrane(m FGL2) and a soluble(s FGL2) form with differential tertiary structure and biological activities. Typically, m FGL2 functions as prothrombinase that is capable of i...Fibrinogen-like 2(FGL2) encompasses a transmembrane(m FGL2) and a soluble(s FGL2) form with differential tertiary structure and biological activities. Typically, m FGL2 functions as prothrombinase that is capable of initiating coagulation in tissue without activation of the blood clotting cascade, whereas s FGL2 largely acts as an immunosuppressor that can repress proliferation of alloreactive T lymphocytes and maturation of bone marrow dendritic cells. Protein sequences of FGL2 exhibit evolutionary conservation across wide variety of species, especially at the carboxyl terminus that contains fibrinogen related domain(FRED). The FRED of FGL2 confers specificity and complexity in the action of FGL2, including receptor recognition, calcium affiliation, and substrate binding. Constitutive expression of FGL2 during embryogenesis and in mature tissues suggests FGL2 might be physiologically important. However, excessive induction of FGL2 under certain medical conditions(e.g. pathogen invasion) could trigger complement activation, inflammatory response,cellular apoptosis, and immune dysfunctions. On the other hand, complete absence of FGL2 is also detrimental as lack of FGL2 can cause autoimmune glomerulonephritis and acute cellular rejection of xenografts. All these roles involve m FGL2, s FGL2, or their combination. Although it is not clear how m FGL2 is cleaved off its host cells and secreted into the blood, circulating s FGL2 has been found correlated with disease severity and viral loading among patients with human hepatitis B virus or hepatitis C virus infection. Further studies are warranted to understand how FGL2 expression is regulated under physiological and pathological conditions. Even more interesting is to determine whether m FGL2 can fulfill an immunoregulatory role through its FRED at carboxyl end of the molecule and, and vice versa, whether s FGL2 is procoagulant upon binding to a target cell. Knowledge in this area should shed light on development of s FGL2 as an alternative immunosuppressive agent for organ transplantation or as a biomarker for predicting disease progression, monitoring therapeutic effects, and targeting FGL2 for repression in ameliorating fulminant viral hepatitis.展开更多
Twenty one health hybrid dogs weighted （7±3.2） kg were intramuscularly injected with tetracyclinum in a dose of 10 mg/kg body weight for continuous 5 days while the blood eperythrozoon test showing negative rea...Twenty one health hybrid dogs weighted （7±3.2） kg were intramuscularly injected with tetracyclinum in a dose of 10 mg/kg body weight for continuous 5 days while the blood eperythrozoon test showing negative reaction and divided randomly into three groups. The treating methods were respectively GroupⅠ, lienectomy, Group Ⅱ, both lienectomy and injection of immunosuppressor and Group Ⅲ, control. All dogs were intraperitoneal injected with 4ml anticoagulative blood from dog with eperythrozoonosis (the erythrozoon infection rate was 94 %, erythrocyte was 3.8×106/mm3). The result shown the eperythrozoon infection rate in GroupⅠ and Ⅱ were respectively 1.5 % and 2.1 % on the first day after administration. On the sixth day, the infection rate of GroupⅠ, Ⅱ and Ⅲ were 81.3 %, 86.5 % and 75.2 % respectively. The hematological changes in GroupⅠ and Ⅱ included both decrease in packed cell volume （HCT PCV）, hemoglobin, total erythrocyte, acidocyte number and lymphocyte, and rise in total leukocyte, neutrocyte and monocyte. Five dogs in GroupⅠ and seven dogs in Group Ⅱ showed apparent symptoms of anaemia, icterus, high fever, anorexia, diarrhea and emesis,etc. The morbidity in GroupⅠ and Ⅱ were respectively 71 % and 100 %, and two dogs in Group Ⅱdied. The changes in clinical symptoms, the hemogram and the physiological indexes in GroupⅠ and Ⅱ were the same as those in natural eperythrozoonosis.展开更多
文摘Autoimmune hepatitis is an uncommon condition that affects both adults and children and is characterized by chronic and recurrent inflammatory activity in the liver.This inflammation is accompanied by elevated IgG and autoantibody levels.Historically,treatment consists of steroids with the addition of azathioprine,which results in remission in approximately 80%of patients.Despite significant advancements in our understanding of the immune system over the past two decades,few modifications have been made to treatment algorithms,which have remained largely unchanged since they were first proposed more than 40 years ago.This review summarized the various treatment options currently available as well as our experiences using them.Although steroids are the standard treatment for induction therapy,other medications may be considered.Cyclosporin A,a calcineurin inhibitor that decreases T cell activation,has proven effective for induction of remission,but its long-term side effects limit its appeal for maintenance.Tacrolimus,a drug belonging to the same family,has been used in patients with refractory diseases with fewer side effects.Sirolimus and everolimus have interesting effects on regulatory T cell populations and may become viable options in the future.Mycophenolate mofetil is not effective for induction but is a valid alternative for patients who are intolerant to azathioprine.B celldepleting drugs,such as rituximab and belimumab,have been successfully used in refractory cases and are useful in both the short and long term.Other promising treatments include anti-tumor necrosis factors,Janus kinases inhibitors,and chimeric antigen receptor T cell therapy.This growing armamentarium allows us to imagine a more tailored approach to the treatment of autoimmune hepatitis in the near future.
文摘In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing(MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hospitalizations, surgeries, and prolonged clinical remission. MH may be achieved with several therapeutic strategies reaching success rates up to 80% for both, ulcerative colitis(UC) and Crohn's disease(CD). Various scoring systems for UC and for the transmural CD, have been proposed to standardize the definition of MH. Several attempts have been undertaken to de-escalate therapy once MH is achieved, thus, reducing the risk of adverse events. In this review, we analysed the available studies regarding the achievement of MH and the subsequent treatment de-escalation according to disease type and administered therapy, together with non-invasive markers proposed as predictors for relapse. The available data are not encouraging since de-escalation after the achievement of MH is followed by a high number of clinical relapses reaching up to 50% within one year. Unclear is also another question, in case of combination therapies, which drug is more appropriate to stop, in order to guarantee a durable remission. Predictors of unfavourable outcome such as disease extension, perianal disease, or early onset disease appear to be inadequate to foresee behaviour of disease. Further studies are warranted to investigate the role of histologic healing for the further course of disease.
文摘The optimal duration of biological treatment, particularly anti-TNF, in inflammatory bowel disease （IBD） is a very important question both for patients and physicians. There is no published evidence to clearly and definitely answer this question. However data on natural history of IBD, long term safety of biologics, immunosuppressors （IS） cessation and some preliminary studies on biologics cessation may help us to discuss this topic. The decision to stop a biological treatment is currently based on a compromise between the benefits and risks associated with the prolongation of this treatment. IBD, more particularly CD, are characterized by the development of complications and the need for recurrent hospitalizations and surgeries in approximately 2/3 of cases. In these patients potentially in need of biological treatments, it is probable that, as it has been demonstrated for IS, the longer a stable remission has be achieved under treatment, the lower the risk of relapse is alter treatment cessation. Further prospective studies should now aim at disclosing patient characteristics associated with a low risk of relapse to imple- ment this strategy.
基金Supported by the National Natural Science Foundation of China,No.81672422,No.81600506,and No.81702757Open Project in State Key Laboratory for Diagnosis and Treatment of Infectious Disease,No.2015KF03+4 种基金National S&T Major Project of China,No.2018ZX10301201Natural Science Foundation of Zhejiang Province,No.LY15H160033China Postdoctoral Science Foundation,No.2017464Zhejiang Province Health Department Program,No.2014KYB081,and No.2017KY322Academician Jieshou Li Mucosal Barrier Fund,No.201208
文摘AIM To study the influence of different doses of tacrolimus(FK506)on gut microbiota after liver transplantation(LT)in rats.METHODS Specific pathogen-free Brown Norway(BN)rats and Lewis rats were separated into five groups:(1)Tolerance group(BN-BN LT,n=8);(2)rejection group(Lewis-BN LT,n=8);(3)high dosage FK506(FK506-H)group(Lewis-BN LT,n=8);(4)middle dosage FK506(FK506-M)group(Lewis-BN LT,n=8);and(5)low dosage FK506(FK506-L)group(LewisBN LT,n=8).FK506 was administered to recipients at a dose of 1.0 mg/kg,0.5 mg/kg,and 0.1 mg/kg body weight for 29 d after LT to the FK506-H,FK506-M,and FK506-L groups,respectively.On the 30^(th) day after LT,all rats were sampled and euthanized.Blood samples were harvested for liver function and plasma endotoxin testing.Hepatic graft and ileocecal tissues were collected for histopathology observation.Ileocecal contents were used for DNA extraction,Real-time quantitative polymerase chain reaction(RT-PCR)and digital processing of denaturing gradient gel electrophoresis(DGGE)profiles and analysis.RESULTS Compared to the FK506-H and FK506-L groups,FK506-M was optimal for maintaining immunosuppression and inducing normal graft function;the FK506-M maintained gut barrier integrity and low plasma endotoxin levels;furthermore,DGGE results showed that FK506-M induced stable gut microbiota.Diversity analysis indicated that FK506-M increased species richness and rare species abundance,and cluster analysis confirmed the stable gut microbiota induced by FK506-M.Phylogenetic tree analysis identified crucial bacteria associated with FK506-M;seven of the nine bacteria that were decreased corresponded to Bacteroidetes,while increased bacteria were of the Bifidobacterium species.FK506-M increased Faecalibacterium prausnitzii and Bifidobacterium spp.and decreased Bacteroides-Prevotella and Enterobacteriaceae,as assessed by RT-PCR,which confirmed the crucial bacterial alterations identified through DGGE.CONCLUSION Compared to the low or high dosage of FK506,an optimal dosage of FK506 induced immunosuppression,normal graft function and stable gut microbiota following LT in rats.The stable gut microbiota presented increased probiotics and decreased potential pathogenic endotoxin-producing bacteria.These findings provide a novel strategy based on gut microbiota for immunosuppressive dosage assessment for recipients following LT.
文摘Fibrinogen-like 2(FGL2) encompasses a transmembrane(m FGL2) and a soluble(s FGL2) form with differential tertiary structure and biological activities. Typically, m FGL2 functions as prothrombinase that is capable of initiating coagulation in tissue without activation of the blood clotting cascade, whereas s FGL2 largely acts as an immunosuppressor that can repress proliferation of alloreactive T lymphocytes and maturation of bone marrow dendritic cells. Protein sequences of FGL2 exhibit evolutionary conservation across wide variety of species, especially at the carboxyl terminus that contains fibrinogen related domain(FRED). The FRED of FGL2 confers specificity and complexity in the action of FGL2, including receptor recognition, calcium affiliation, and substrate binding. Constitutive expression of FGL2 during embryogenesis and in mature tissues suggests FGL2 might be physiologically important. However, excessive induction of FGL2 under certain medical conditions(e.g. pathogen invasion) could trigger complement activation, inflammatory response,cellular apoptosis, and immune dysfunctions. On the other hand, complete absence of FGL2 is also detrimental as lack of FGL2 can cause autoimmune glomerulonephritis and acute cellular rejection of xenografts. All these roles involve m FGL2, s FGL2, or their combination. Although it is not clear how m FGL2 is cleaved off its host cells and secreted into the blood, circulating s FGL2 has been found correlated with disease severity and viral loading among patients with human hepatitis B virus or hepatitis C virus infection. Further studies are warranted to understand how FGL2 expression is regulated under physiological and pathological conditions. Even more interesting is to determine whether m FGL2 can fulfill an immunoregulatory role through its FRED at carboxyl end of the molecule and, and vice versa, whether s FGL2 is procoagulant upon binding to a target cell. Knowledge in this area should shed light on development of s FGL2 as an alternative immunosuppressive agent for organ transplantation or as a biomarker for predicting disease progression, monitoring therapeutic effects, and targeting FGL2 for repression in ameliorating fulminant viral hepatitis.
基金Item supported by Shanghai scientific andtechnological commission
文摘Twenty one health hybrid dogs weighted （7±3.2） kg were intramuscularly injected with tetracyclinum in a dose of 10 mg/kg body weight for continuous 5 days while the blood eperythrozoon test showing negative reaction and divided randomly into three groups. The treating methods were respectively GroupⅠ, lienectomy, Group Ⅱ, both lienectomy and injection of immunosuppressor and Group Ⅲ, control. All dogs were intraperitoneal injected with 4ml anticoagulative blood from dog with eperythrozoonosis (the erythrozoon infection rate was 94 %, erythrocyte was 3.8×106/mm3). The result shown the eperythrozoon infection rate in GroupⅠ and Ⅱ were respectively 1.5 % and 2.1 % on the first day after administration. On the sixth day, the infection rate of GroupⅠ, Ⅱ and Ⅲ were 81.3 %, 86.5 % and 75.2 % respectively. The hematological changes in GroupⅠ and Ⅱ included both decrease in packed cell volume （HCT PCV）, hemoglobin, total erythrocyte, acidocyte number and lymphocyte, and rise in total leukocyte, neutrocyte and monocyte. Five dogs in GroupⅠ and seven dogs in Group Ⅱ showed apparent symptoms of anaemia, icterus, high fever, anorexia, diarrhea and emesis,etc. The morbidity in GroupⅠ and Ⅱ were respectively 71 % and 100 %, and two dogs in Group Ⅱdied. The changes in clinical symptoms, the hemogram and the physiological indexes in GroupⅠ and Ⅱ were the same as those in natural eperythrozoonosis.
