Diagnosis and therapy of tacrolimus toxicity in a liver transplant recipient during COVID-19 treatment

To the Editor:SARS-CoV-2,the pathogen responsible for the pandemic of coronavirus disease 2019(COVID-19),has had profound impacts on human health,and its antagonist Paxlovid is a commonly used treatment option[1].However,treatment selection for immunosuppressed patients,such as liver recipients,remains uncertain due to potential drug interactions and the risk of immunosuppressant dosage adjustment,which can cause liver injury[2].

Validation and performance of three scoring systems for predicting primary non-function and early allograft failure after liver transplantation

Background: Primary non-function(PNF) and early allograft failure(EAF) after liver transplantation(LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function(MEAF), PNF score by King's College(King-PNF) and Balance-and-Risk-Lactate(BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. Methods: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic(ROC) and the net reclassification improvement(NRI) and integrated discrimination improvement(IDI) analyses. Results: Of all 720 patients, 28(3.9%) developed PNF and 67(9.3%) developed EAF in 3 months. The overall early allograft dysfunction(EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0(3.5–6.3),-2.1(-2.6 to-1.2), and 5.0(2.0–11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves(AUCs) of 0.872 and 0.891, superior to BAR-Lac(AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. Conclusions: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies.

TPOL triggers apoptosis with mitochondrial injury through activating a ROS-dependent p53/p21/p27/Rb/Bax/Cyto C/caspase-mediated signaling

AIM:To explore the influence of ethyl(2,4,6-trimethylbenzoyl)phenylphosphinate(TPOL)on cell apoptosis and its potential mechanism.METHODS:HEK293T cells sensitive to TPOL were treated with different concentrations of TPOL with or without exposure to light radiation,before treatment with various inhibitors,N-acetyl-Lcysteine(NAC),pifithrin-αand Z-DVED-FMK.Cell viability was measured by CCK-8 assay.Annexin V/propidium iodide staining was used to count the number of apoptotic cells.DCFH-DA staining was used to detect reactive oxygen species(ROS)levels,and JC-1 staining was used to assess mitochondrial membrane potential by flow cytometry.The expression of apoptosis-related proteins and cell cycle-regulated molecules was measured by Western blot.RESULTS:TPOL enhanced the apoptosis of HEK293T cells in a dose-dependent manner(P<0.05),with a decrease in Bcl-2 and increases in Bax and cytochrome C(Cyto C),followed by up-regulation of activated caspase-9 and caspase-3,and the cleavage of PARP(P<0.05).The TPOL-enhanced cleavage of caspase-3 and PARP was rescued by Z-DVED-FMK(P<0.01).TPOL also led to a rapid increase in ROS,a reduction in mitochondrial membrane potential,and the release of Cyto C(P<0.01),all of which could be reversed by the ROS scavenger NAC.Moreover,the TPOL-caused alterations in p21,p27,Rb,and CDK2 were also recovered by the p53 inhibitor pifithrin-α(P<0.05).The TPOL-induced changes in Bax,Bcl-2,cleaved caspase-9,activated caspase-3,and cleaved PARP were subsequently rescued by pretreatment with pifithrin-α(P<0.05).CONCLUSION:TPOL can induce cellular apoptosis with ROS-mediated mitochondrial membrane damage through the activation of a ROS-dependent p53/p21/p27/Rb/Bax/Cyto C/caspase-mediated signal axis.

Regulating regulatory T cells to achieve transplant tolerance

BACKGROUND:Regulatory T cells(Tregs) play crucial roles in both induction and maintenance of tolerance. This active immune regulation may contribute not only to the control of immune responses to self-antigens and thereby prevent autoimmune diseases,but also the control of responses to non-self molecules in adaptive immunity. Numerous experimental and clinical studies indicate that manipulating the balance between regulatory and responder T cells is an effective strategy to control immune responsiveness after transplantation. DATA SOURCES:Literature search was conducted using PubMed on the related subjects. Part of the material was based on the most recent work in the authors’ laboratory. RESULTS:We propose some new strategies to achieve transplant tolerance in rodent animals via manipulating Treg function,including using histone deacetylase(HDAC) inhibitor to regulate Foxp3 transcription and enhance Treg suppression,induction of Treg-sparing apoptosis via Nur77,and identification of the co-inhibitory molecule herpes virus entry mediator(HVEM) as an effector molecule for Treg function. CONCLUSION:Regulation of Treg function will definitely provide us very promising tools to achieve clinical tolerance in the future.

Review on immunosuppression in liver transplantation

The optimal level of immunosuppression in solid organ transplantation,in particular for the liver,is a delicate balance between the benefit of preventing rejection and the adverse side effects of immunosuppression. There is uncertainty about when this level is achieved in any individual recipient. Immunosuppression regimens vary between individual centers and changes with time asnew agents and data are available. Presently concerns about the adverse side effects of calcineurin inhibitor,the main class of immunosuppressive agents used in liver transplantation(LT),has led to consideration of the use of antibody induction therapies for patients at higher risk of developing adverse side effects. The longevity of the transplanted organ is potentially improved by better management of rejection episodes and special consideration for tailoring of immunosuppression to the individual with viral hepatitis C,hepatocellular carcinoma or pregnancy. This review provides an overview of the current strategies for post LT immunosuppression and discusses modifications to consider for special patient populations.

Immunological aspects of liver cell transplantation

Within the field of regenerative medicine, the liver is of major interest for adoption of regenerative strategies due to its well-known and unique regenerative capacity. Whereas therapeutic strategies such as liver resection and orthotopic liver transplantation(OLT) can be considered standards of care for the treatment of a variety of liver diseases, the concept of liver cell transplantation(LCTx) still awaits clinical breakthrough. Success of LCTx is hampered by insufficient engraftment/long-term acceptance of cellular allografts mainly due to rejection of transplanted cells. This is in contrast to the results achieved for OLT where longterm graft survival is observed on a regular basis and, hence, the liver has been deemed an immuneprivileged organ. Immune responses induced by isolated hepatocytes apparently differ considerably from those observed following transplantation of solid organs and, thus, LCTx requires refined immunological strategies to improve its clinical outcome. In addition, clinical usage of LCTx but also related basic research efforts are hindered by the limited availability of high quality liver cells, strongly emphasizing the need for alternative cell sources. This review focuses on the various immunological aspects of LCTx summarizing data available not only for hepatocyte transplantation but also for transplantation of non-parenchymal liver cells and liver stem cells.

Common and small molecules as the ultimate regulatory and effector mediators of antigen-specific transplantation reactions

In spite of intensive research, the molecular basis of allograft and xenograft rejection still remains not fully understood. The acute rejection of an allograft is associated with the intragraft Th1 cytokine response, while tolerance of an allograft or xenograft rejection is accompanied by a higher production of the Th2 cytokines interleukin(IL)-4 and IL-10. Nevertheless, these cytokines are not the final regulatory and effector molecules mediating transplantation reactions. Data indicate that the functioning of common molecules with enzymatic activities, such are inducible nitric oxide synthase(i NOS), arginase, heme oxygenase-1(HO-1) or indoleamine-2,3-dioxygenase(IDO), the bioavailability of their substrates(L-arginine, tryptophan, heme) and the cytotoxic and regulatory actions of their small gaseous products(NO, CO) can be the ultimate mechanisms responsible for effector or regulatory reactions. Using models of transplantation immunity and tolerance we show that T cell receptor-mediated recognition of allogeneic or xenogeneic antigens as well as the balance between immunity/tolerance induces distinct cytokine production profiles. The ratio between Th1 and Th2 cytokines efficiently regulates the expression of genes for common enzymes, such as i NOS, arginase, HO-1 and IDO. These enzymes may compete for substrates, such as L-arginine or tryptophan, and the final product of their activity are small molecules(NO, CO) displaying effector or regulatory functions of the immune system. Thus, it is suggested that in spite of the high immunological specificity of transplatation reaction, the ultimate players in regulatory and effector functions could be small and common molecules.

De-novo hepatocellular carcinoma after pediatric living donor liver transplantation

De-novo malignancies carry an incidence ranging between 3%-26% after transplant and account for the second highest cause of post-transplant mortality behind cardiovascular disease. While the majority of de-novo malignancies after transplant usually consist of skin cancers, there has been an increasing rate of solid tumor cancers over the last 15 years. Although, recurrence of hepatocellular carcinoma(HCC) is well understood among patients transplanted for HCC, there are increasing reports of de-novo HCC in those transplanted for a non-HCC indication. The proposed pathophysiology for these cases has been mainly connected to the presence of advanced graft fibrosis or cirrhosis and always associated with the presence of hepatitis B or C virus. We report the first known case of de-novo HCC in a recipient, 14 years after a pediatric living related donor liver transplantation for end-stage liver disease due to biliary atresia without the presence of hepatitis B or C virus before and after transplant. We present this case report to increase the awareness of this phenomenon and address on the utility for screening and surveillance of hepatocellular carcinoma among these individuals. One recommendation is to use similar guidelines for screening, diagnosis, and treatment for HCC as those used for primary HCC in the pre-transplant patient, focusing on those recipients who have advanced fibrosis in the allograft, regardless of etiology.

Diverse Roles of Immune Cells in Transplant Rejection and Immune Tolerance

Organ transplant rejection(OTR)is a complex immune reaction involving multiple cells,and it determines graft survival and patient prognosis.At present,most transplant recipients are administered a combination of immunosuppressive and biological agents to protect them from OTR.However,immunosuppressive agents negatively impact the immune system of the patients,causing them to suffer from serious complications,such as chronic infection and malignant tumors.Therefore,a thorough understanding of the mechanisms involved in immune tolerance and immune rejection with regard to organ transplant(OT)is essential for developing better treatment options and improving patient outcomes.This article reviews the role of immune cells in OTR and organ transplant tolerance(OTT),including the novel cell therapies that are currently under clinical trials for transplant recipients.

Advances in liver transplantation allocation systems

With the growing number of patients in need of liver transplantation, there is a need for adopting new and modifying existing allocation policies that prioritize patients for liver transplantation. Policy should ensure fair allocation that is reproducible and strongly predictive of best pre and post transplant outcomes while taking into account the natural history of the potential recipients liver disease and its complications. There is wide acceptance for allocation policies based on urgency in which the sickest patients on the waiting list with the highest risk of mortality receive priority. Model for end-stage liver disease and Child-Turcotte-Pugh scoring system, the two most universally applicable systems are used in urgencybased prioritization. However, other factors must be considered to achieve optimal allocation. Factors affecting pre-transplant patient survival and the quality of the donor organ also affect outcome. The optimal system should have allocation prioritization that accounts for both urgency and transplant outcome. We reviewed past and current liver allocation systems with the aim of generating further discussion about improvement of current policies.

Host factors are dominant in the development of post-liver transplant non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease(NAFLD) is a recognized problem in patients after orthotopic liver transplantation and may lead to recurrent graft injury. As the increased demand for liver allografts fail to match the available supply of donor organs, split liver transplantation(SLT) has emerged as an important technique to increase the supply of liver grafts. SLT allows two transplants to occur from one donor organ, and provides a unique model for observing the pathogenesis of NAFLD with respect to the role of recipient environmental and genetic factors. Here we report on two recipients of a SLT from the same deceased donor where only one developed non-alcoholic steatohepatitis(NASH), suggesting that host factors are critical for the development of NASH.

New hope for esophageal stricture prevention:A prospective singlecentertrial on acellular dermal matrix

BACKGROUNDGiven the high incidence of esophageal cancer in China,an increasing number ofpatients there are undergoing endoscopic mucosal dissection(ESD).Although the5-year survival rate after ESD can exceed 95%,esophageal stricture,the mostcommon and serious postoperative complication,affects the long-term prognosisof patients and the quality of life.Autologous mucosal grafts have proven to besuccessful in preventing stricture after ESD for early esophageal cancer.AIMTo examine the viability of acellular dermal matrix(ADM)as an alternative to autologous mucosa for the prevention of stricture after ESD.METHODSThis is a prospective,single-center,controlled study.Consecutive patients who underwent ESD surgery and werewilling to undergo autologous mucosal transplantation were recruited between January 1 and December 31,2017.Consecutive patients who underwent ESD surgery and were willing to undergo ADM transplantation wererecruited between January 1 to December 31,2019.A final three-year follow-up of patients who receivedtransplants was conducted.RESULTSBased on the current incidence of esophageal stricture,the sample size required for both the autologous mucosalgraft group and the ADM group was calculated to be 160 cases.Due to various factors,a total of 20 patients withautologous mucosal grafts and 25 with ADM grafts were recruited.Based on the inclusion exclusion andwithdrawal criteria,9 patients ultimately received autologous mucosal grafts and completed the follow-up,while11 patients received ADM grafts and completed the follow-up.Finally,there were 2 cases of stenosis in theautologous mucosal transplantation group with a stenosis rate of 22.22%and 2 cases of stenosis in the ADMtransplantation group with a stenosis rate of 18.18%,with no significant difference noted between the groups(P=0.94).CONCLUSIONIn this prospective,single-center,controlled trial,we compared the effectiveness of autologous mucosatransplantation and ADM for the prevention of esophageal stricture.Due to certain condition limitations,we wereunable to recruit sufficient subjects meeting our target requirements.However,we implemented strict inclusion,exclusion,and withdrawal criteria and successfully completed three years of follow-up,resulting in valuableclinical insights.Based on our findings,we hypothesize that ADM may be similarly effective to autologousmucosal transplantation in the prevention of esophageal stricture,offering a comparable and alternative approach.This study provides a new therapeutic idea and direction for the prevention of esophageal stricture.

Polyethylene glycol crosslinked decellularized single liver lobe scaffolds with vascular endothelial growth factor promotes angiogenesis in vivo

Background: Improving the mechanical properties and angiogenesis of acellular scaffolds before transplantation is an important challenge facing the development of acellular liver grafts. The present study aimed to evaluate the cytotoxicity and angiogenesis of polyethylene glycol(PEG) crosslinked decellularized single liver lobe scaffolds(DLSs), and establish its suitability as a graft for long-term liver tissue engineering. Methods: Using mercaptoacrylate produced by the Michael addition reaction, DLSs were first modified using N-succinimidyl S-acetylthioacetate(SATA), followed by cross-linking with PEG as well as vascular endothelial growth factor(VEGF). The optimal concentration of agents and time of the individual steps were identified in this procedure through biomechanical testing and morphological analysis. Subsequently, human umbilical vein endothelial cells(HUVECs) were seeded on the PEG crosslinked scaffolds to detect the proliferation and viability of cells. The scaffolds were then transplanted into the subcutaneous tissue of Sprague-Dawley rats to evaluate angiogenesis. In addition, the average number of blood vessels was evaluated in the grafts with or without PEG at days 7, 14, and 21 after implantation. Results: The PEG crosslinked DLS maintained their three-dimensional structure and were more translucent after decellularization than native DLS, which presented a denser and more porous network structure. The results for Young’s modulus proved that the mechanical properties of 0.5 PEG crosslinked DLS were the best and close to that of native livers. The PEG-VEGF-DLS could better promote cell proliferation and differentiation of HUVECs compared with the groups without PEG cross-linking. Importantly, the average density of blood vessels was higher in the PEG-VEGF-DLS than that in other groups at days 7, 14, and 21 after implantation in vivo. Conclusions: The PEG crosslinked DLS with VEGF could improve the biomechanical properties of native DLS, and most importantly, their lack of cytotoxicity provides a new route to promote the proliferation of cells in vitro and angiogenesis in vivo in liver tissue engineering.

Outcomes in pediatric recipients of single kidney transplantation from pediatric donors with acute kidney injury:A single-center pilot study

To the Editor:The shortage of deceased donor(DD)kidneys for transplantation remains a persistent concern.Despite the potential reversibility of acute kidney injury(AKI)lesions,kidneys from pediatric donors with AKI are often underutilized,especially in the context of pediatric transplantation.By implementing single kidney transplantation(SKT)from pediatric donors to pediatric recipients(PTP),we can optimize the utilization of available kidneys and increase the number of pediatric recipients.

Human leukocyte antigen compatibility and incidence of donorspecific antibodies in pediatric liver transplant recipients

BACKGROUND Antibody-mediated rejection following liver transplantation(LT)has been increasingly recognized,particularly with respect to the emergence of de novo donor-specific antibodies(DSAs)and their impact on graft longevity.While substantial evidence for adult populations exists,research focusing on pediatric LT outcomes remains limited.AIM To investigate the prevalence of human leukocyte antigen(HLA)mismatches and DSA and evaluate their association with rejection episodes after pediatric LT.METHODS A cohort of pediatric LT recipients underwent HLA testing at Santa Casa de Porto Alegre,Brazil,between December 2013 and December 2023.Only patients who survived for>30 days after LT with at least one DSA analysis were included.DSA classes I and II and cross-matches were analyzed.The presence of de novo DSA(dnDSA)was evaluated at least 3 months after LT using the Luminex®single antigen bead method,with a positive reaction threshold set at 1000 MFI.Rejection episodes were confirmed by liver biopsy.RESULTS Overall,67 transplanted children were analyzed;61 received grafts from living donors,85%of whom were related to recipients.Pre-transplant DSA(class I or II)was detected in 28.3%of patients,and dnDSA was detected in 48.4%.The median time to DSA detection after LT was 19.7[interquartile range(IQR):4.3-35.6]months.Biopsyproven rejection occurred in 13 patients at follow-up,with C4d positivity observed in 5/13 Liver biopsies.The median time to rejection was 7.8(IQR:5.7-12.8)months.The presence of dnDSA was significantly associated with rejection(36%vs 3%,P<0.001).The rejection-free survival rates at 12 and 24 months were 76%vs 100%and 58%vs 95%for patients with dnDSA anti-DQ vs those without,respectively.CONCLUSION Our findings highlight the importance of incorporating DSA assessment into pre-and post-transplantation protocols for pediatric LT recipients.Future implications may include immunosuppression minimization strategies based on this analysis in pediatric LT recipients.

Potential triggering factors of acute liver failure as a first manifestation of autoimmune hepatitis-a single center experience of 52 adult patients

AIM To investigate potential triggering factors leading to acute liver failure(ALF) as the initial presentation of autoimmune hepatitis(AIH).METHODS A total of 565 patients treated at our Department between 2005 and 2017 for histologically-proven AIH were retrospectively analyzed. However, 52 patients(9.2%) fulfilled the criteria for ALF defined by the "American Association for the Study of the Liver(AASLD)". According to this definition, patients with "acute-on-chronic" or "acute-on-cirrhosis" liver failure were excluded. Following parameters with focus on potential triggering factors were evaluated: Patients' demographics, causation of liver failure, laboratory data(liver enzymes, MELD-score, autoimmune markers, virus serology), liver histology, immunosuppressive regime, and finally, outcome of our patients.RESULTS The majority of patients with ALF were female(84.6%) and mean age was 43.6 ± 14.9 years. Interestingly, none of the patients with ALF was positive for antiliver kidney microsomal antibody(LKM). We could identify potential triggering factors in 26/52(50.0%) of previously healthy patients presenting ALF as their first manifestation of AIH. These were drug-induced ALF(57.7%), virus-induced ALF(30.8%), and preceding surgery in general anesthesia(11.5%), respectively. Unfortunately, 6 out of 52 patients(11.5%) did not survive ALF and 3 patients(5.7%) underwent liver transplantation(LT). Comparing data of survivors and patients with non-recovery following treatment, MELDscore(P < 0.001), age(P < 0.05), creatinine(P < 0.01), and finally, ALT-values(P < 0.05) reached statistical significance. CONCLUSION Drugs, viral infections, and previous surgery may trigger ALF as the initial presentation of AIH. Advanced age and high MELD-score were associated with lethal outcome.

Novel epigenetic-based therapies useful in cardiovascular medicine

Epigenetic modifications include DNA methylation, his-tone modifications, and micro RNA. Gene alterations have been found to be associated with cardiovascular diseases, and epigenetic mechanisms are continuously being studied to find new useful strategies for the clinical management of afflicted patients. Numerous cardiovascular disorders are characterized by the abnormal methylation of Cp G islands and so specific drugs that could inhibit DNA methyltransferase directly or by reducing its gene expression(e.g., hydralazine and procainamide) are currently under investigation. The anti-proliferative and anti-inflammatory properties of histone deacetylase inhibitors and their cardio-protective effects have been confirmed in preclinical studies. Furthermore, the regulation of the expression of micro RNA targets through pharmacological tools is still under development. Indeed, large controlled trials are required to establish whether current possible candidate antisense micro RNAs could offer better therapeutic benefits in clinical practice. Here, we updated therapeutic properties, side effects, and feasibility of eme-rging epigenetic-based strategies in cardiovascular diseases by highlighting specific problematic issues that still affect the development of large scale novel therapeutic protocols.

Cartilage oligomeric matrix protein: A novel non-invasive marker for assessing cirrhosis and risk of hepatocellular carcinoma

AIM: To assess serum cartilage oligomeric matrix protein(COMP) as a marker of cirrhosis and risk of progression to hepatocellular carcinoma(HCC). METHODS: A COMP enzyme-linked immunosorbentassay was used to test 187 patients with chronic liver diseases at the time point of first evaluation. The selected patients included 72 with chronic hepatitis B infection, 75 with chronic hepatitis C infection, 22 with primary biliary cirrhosis, 7 with autoimmune hepatitis type 1, and 11 with alcoholic liver disease. Demographic, biochemical, histological and clinical characteristics of the patients were recorded at the first evaluation. One hundred and forty-seven patients were followed for a median [interquartile range(IQR)] duration of 96.5(102) mo. The clinical, biochemical and histological data, as well as the development of cirrhosis, HCC according to internationally accepted criteria and in case of death, a liver-related cause during the follow-up period, were recorded at the electronic database of our clinic. COMP determination was also performed in 43 healthy individuals who served as the control study group.RESULTS: COMP positivity(> 15 U/L) was detected in 22%-36% among chronic liver disease groups. Strikingly, almost 83% of COMP-positive patients were cirrhotic at baseline, independently of cause of liver disease. Among the patients who developed HCC during follow-up, 73.7%(14/19) were COMP positive at baseline. COMP positivity was significantly associated with older age(P < 0.001), advanced fibrosis(P = 0.001) and necroinflammatory activity(P = 0.001), higher aspartate aminotransferase(P < 0.001), alanine aminotransferase(P < 0.02), γ-glutamyl transpeptidase(P = 0.003), alkaline phosphatase(P = 0.001), bilirubin(P < 0.05), international normalized ratio(P = 0.002) and alpha-fetoprotein levels(P < 0.02), and lower albumin(P < 0.001), and platelet count(P = 0.008). COMP levels [median(IQR)] were significantly higher in cirrhotics compared to non-cirrhotics [13.8(7.9) U/L vs 9.8(4.6) U/L, respectively; P < 0.001]. On multivariate logistic regression analysis, COMP-positivity was independently associated only with cirrhosis(OR = 4.40, 95%CI: 1.33-14.69, P = 0.015). Kaplan-Meier analysis showed that COMP positivity was significantly associated with HCC development(P = 0.007) and higher incidence of liver-related death(P < 0.001). CONCLUSION: Elevated COMP levels are strongly associated with cirrhosis and HCC progression. Serum COMP is a new promising non-invasive biomarker for HCC risk assessment in surveillance programs.

Helicobacter pylori and autoimmune disease:Cause or bystander

Helicobacter pylori(H.pylori)is the main cause of chronic gastritis and a major risk factor for gastric cancer.This pathogen has also been considered a potential trigger of gastric autoimmunity,and in particular of autoimmune gastritis.However,a considerable number of reports have attempted to link H.pylori infection with the development of extra-gastrointestinal autoimmune disorders,affecting organs not immediately relevant to the stomach.This review discusses the current evidence in support or against the role of H.pylori as a potential trigger of autoimmune rheumatic and skin diseases,as well as organ specific autoimmune diseases.We discuss epidemiological,serological,immunological and experimental evidence associating this pathogen with autoimmune diseases.Although over one hundred autoimmune diseases have been investigated in relation to H.pylori,we discuss a select number of papers with a larger literature base,and include Sj grens syndrome,rheumatoid arthritis,systemic lupus erythematosus,vasculitides,autoimmune skin conditions,idiopathic thrombocytopenic purpura,autoimmune thyroid disease,multiple sclerosis,neuromyelitis optica and autoimmune liver diseases.Specific mention is given to those studies reporting an association of anti-H.pylori antibodies with the presence of autoimmune disease-specific clinical parameters,as well as those failing to find such associations.We also provide helpful hints for future research.

漆黄素对淋巴细胞和巨噬细胞分泌NO的免疫调节作用(英文)

目的探讨漆黄素(fisetin)在体外对小鼠T淋巴细胞增殖、活化、凋亡、ROS的释放和巨噬细胞NO释放功能的影响。方法 CFDA-SE标记技术结合流式细胞术检测漆黄素对T淋巴细胞增殖及增殖指数(PI)的影响。荧光抗体染色结合流式细胞术分析漆黄素对T淋巴细胞在Con A的刺激下CD25的表达水平的影响。DIOC染色检测细胞线粒体膜电势的变化情况,H2DCFDA染色检测细胞ROS释放的变化。Griess试剂盒用以检测巨噬细胞NO释放功能。结果漆黄素(2.5,5和10μmol/L)明显抑制T淋巴细胞增殖,增殖指数(PI)降低并具有剂量依赖性。漆黄素可明显抑制CD25的表达(P<0.01)及ROS的释放。DiOC6(3)染色分析显示,漆黄素可促进细胞的凋亡。巨噬细胞在LPS和IFN-γ的刺激下的NO释放量明显增加,而在漆黄素作用下NO释放量明显下降(P<0.01)。结论漆黄素是一种潜在的免疫调节剂。