After in vitro stimulation, the percentage of IL-17A-producing γδ T cells and the levels of supernatant IL-17A from total hepatic lymphocytes or purified γδ T cells markedly increased in the presence with IL-23. Importantly, IL-23 and IL-17A were

reduced after inhibition of macrophages and could not be induced in Toll-like receptor TLR4−/− mice after acetaminophen challenge. Meanwhile, serum high-mobility group box 1 (HMGB1), a damage-associated molecule released from necrotic hepatocytes, increased HM781-36B concentration after acetaminophen challenge, and the HMGB1 inhibitor glycyrrhizin markedly reduced the production of IL-23 and IL-17A and the recruitment of hepatic neutrophils. HMGB1 stimulated the production of IL-23 by TLR4+/+ but not by TLR4−/− macrophages. Conclusion: The HMGB1-TLR4-IL-23 pathway in macrophages makes the generation of IL-17-producing γδ T cells, which mediates neutrophil infiltration and damage-induced liver inflammation. (HEPATOLOGY 2013) Acetaminophen is usually used as an over- the-counter analgesic and antipyretic drug. However, acetaminophen overdose has become a frequent cause of intentional or accidental death in many countries.1, 2 Acetaminophen is metabolized by hepatic CYP2E1 into the toxic intermediate N-acetyl-p-benzoquinone-imine, which is then detoxified by hepatic glutathione. However,

excessive N-acetyl-p-benzoquinone-imine consumes hepatic glutathione ATM/ATR phosphorylation and covalently binds cellular proteins, resulting in hepatocyte necrosis.3, 4 Because the innate immune response following hepatocyte necrosis has been noted to cause a second wave of liver destruction,5, 6 the overall progression is now described by a “two-hit” model.7 Natural killer (NK) and natural killer T (NKT) cells have been reported to play a pathogenic role in the progression of acetaminophen-induced liver injury by up-regulating Fas ligand and secreting interferon

(IFN)-γ. Depletion of NK/NKT cells significantly ameliorates liver injury.8 However, Masson et al.9 revealed that the role of NK and NKT cells in these studies was dependent on dimethyl sulfoxide (DMSO), the solvent used to dissolve acetaminophen in the experiments. That group found Sclareol that low levels of DMSO could recruit NKT cells to the liver and activate NK and NKT cells. In the absence of DMSO, NK and NKT cells did not produce IFN-γ after acetaminophen challenge, and depletion of these cells did not protect mice from acetaminophen-induced liver injury. However, increasing evidence has demonstrated that the innate immune response does participate in the pathogenesis of acetaminophen-induced injury, even in the absence of DMSO. Thus, understanding the critical immune cells and cytokines that mediate acetaminophen-induced liver injury is important. Imaeda et al.

The production of each miRNA was quantified with the StepOne Real-Time PCR System (Applied Biosystems). All reactions were carried out in triplicate. The mean value of the threshold cycle (Ct), the intersection between the amplification curve and the threshold line, was normalized using the value of RNU48, a small RNA serving as endogenous control. In addition, a single sample was used as the calibrator sample to correct the values. Then, 2-ΔΔCt values find more were calculated as relative values.[19] Using a comparative Ct method, relative

expressions of each miRNA were compared between healthy controls and patients with each disease. Parameters related to clinical presentation for miRNA and PBC included ALT, ALP, GGT, total bilirubin (TB), IgG, IgM, and AMA-M2 at the time of miRNA sampling. In addition, histopathological assessment was performed according to the new histologic and grading system for PBC.[20] Briefly, scores for fibrosis and bile duct loss were combined for staging: stage 1, total score of 0; stage 2, score of 1–2; stage 3, score of 3–4; and stage 4, score of 5–6. Cholangitis activity (CA) and hepatitis activity (HA) were graded as CA0-3 and HA0-3, respectively. Response to PBC treatment was defined by a decrease in ALP of more than 40% of the baseline

value or normal level within 1 year of treatment with ursodeoxycholic acid (UDCA) at a maximum dose of 900 mg/day (n = 7), according to the Barcelona criteria.[21] Administration of Bezafibrate within selleck chemicals llc one year after the start of UDCA therapy in some patients was decided on the basis of response to monotherapy with UDCA. Blood samples from PBC patients were obtained during treatment with UDCA and/or bezafibrate. Similarly, blood samples from patients with AIH, PBC-AIH selleckchem overlap and SLE were obtained during treatment with prednisolone (5–10 mg/day) and/or UDCA (600 mg/day). The baseline characteristics of PBC and other patients at the time of miRNA sampling

are summarized in Table 1. Data were expressed as mean ± standard deviation (SD). Statistical analysis was performed using Student’s t-test, Pearson’s correlation coefficient and differences were considered statistically significant when the P-value was less than 0.05 in the two-sided test. As shown in Figure 1, there were significant differences in the expression of some miRNAs between healthy controls and patients with autoimmune liver diseases. In PBC, expressions of miR-155 and miR-146a were significantly increased compared to those in healthy controls. Similarly, increased miR-155 expression and decreased miR-26a expression were observed in AIH, and significantly increased expression of miR-155 was observed in PBC-AIH overlap syndrome. In SLE, expressions of miR-155 and miR-16 were significantly increased compared to those in healthy controls.

38) (Fig. S1). Fifteen eligible studies[4, 13, 14, 16-18, 23, 25, 29, 30, 39, 44, 51, 56, 58] were selected in this part, 12 of which provided data about combination of both markers.[13, 16-18, 23, 25, 29, 30, 39, 44, 51, 56] Sensitivity estimates for DCP, AFP and combination of both markers ranged from 0.19 to 0.92, 0.08 to 0.63, and 0.48 to 0.92 and the specificities estimates for DCP, AFP selleck compound and combination of both markers

were from 0.70 to 0.99, 0.63 to 1.00, and 0.62 to 0.99, respectively (Fig. 5). The summary sensitivity and specificity were 45% (95% CI, 35%–57%) and 95% (95% CI, 91%–97%) for DCP, 48% (95% CI, 39%–57%) and 89% (95% CI, 79%–95%) for AFP, 70% (95% CI, 61%–78%) and 83% (95% CI, 79%–86%) for the combination of both markers. The AUROC of DCP 0.84 (95% CI, 0.81–0.87) was better than Ivacaftor price AFP 0.68 (95% CI, 0.64–0.72) and combination markers 0.83 (95% CI, 0.79–0.86) for detecting early stage HCC (Fig. 4b).

An analysis for funnel plot asymmetry suggested that there was no evidence of publication bias for DCP (P = 0.99), AFP (P = 0.11) and combination of both markers (P = 0.56) (Fig. S2). Based on the forest plot (Fig. 3) and the SROC plot (Fig. 4a), it was clear that the Marrero study[19] and sterling study[33] were important outliers for DCP, the Sassa’s study[14] and Morroto’s study[32] were the primary heterogeneity for AFP. After excluding the outlier studies, the summary sensitivity, specificity and AUROC of DCP were 62%, 91% and 0.83. The estimated values of AFP were 61%, 85% and 0.74. Therefore, the findings that serum DCP was superior to AFP for detecting HCC were robust. According to forest plot (Fig. 5) and the SROC plot (Fig. 4b), the main heterogeneity originated from Sassa’s study[14] for AFP and Volk’s study[25] for DCP. After excluding

the above studies, the summary sensitivity of AFP (54%) was better than DCP (42%), while the AUROC of DCP (0.71) was higher than AFP (0.55). Hence, it was robust that the diagnostic accuracy of Interleukin-3 receptor serum DCP was better than AFP for early stage HCC. Results of the present study show that the sensitivity and specificity of DCP are superior to AFP in diagnosing HCC. Furthermore the diagnosis accuracy of DCP is better than AFP for detection of early stage HCC, and the combination of both markers does not improve results when comparing with DCP alone in diagnosing early stage HCC. These results indicate that DCP might be better than AFP as a single marker for detection of HCC. α-fetoprotein is the most commonly used surveillance marker for HCC. But AFP has a suboptimal performance,[59] as a serological test, its levels may also elevate in patients with cirrhosis or chronic hepatitis in absence of HCC.[60] DCP is a useful marker not only in diagnosing HCC, but also in evaluating the effect of treatment, prognosis, and the risk of recurrence of HCC.[61] DCP has been widely adopted in surveillance and diagnosis of HCC in Japan since the late 1990s, and appeared to have promising results.

Reduced hepcidin levels leads to increased release of iron from intestinal cells and macrophages, elevating plasma ICG-001 in vivo transferrin saturation and causing deposition of iron in the liver and other tissues.4 Individuals homozygous for the mutation that leads to the C282Y substitution of tyrosine for cysteine at amino acid 282 in the HFE protein are at increased risk of iron overload5 and account

for 82%–90% of clinical diagnoses of hereditary hemochromatosis for those individuals of northern European descent.6 We have recently shown that the majority of C282Y homozygotes (82% of men and 65% of women) have elevated serum ferritin and, based on objective criteria, 28% of male and 1% of female C282Y homozygotes develop iron overload-related disease by, on average, 65 years of age. People having a single copy of both the C282Y and H63D (substitution of aspartic acid for histidine at amino acid 63) mutations in HFE (described as compound heterozygotes) have, on average, higher serum ferritin and transferrin saturation levels than people with neither HFE mutation, although they are not at increased risk of iron overload–related disease.7 Previous studies of the association

between HFE genotype and risk of colorectal cancer and breast cancer have provided inconsistent results,8–17 possibly related to the small numbers of C282Y homozygous participants (see Supporting Doxorubicin purchase Materials). We assessed the relationships between the risk of cancer including breast, colorectal, and prostate cancers and the C282Y variant acetylcholine of the HFE gene using a prospective cohort study. C282Y, substitution of tyrosine for cysteine at amino acid 282; CI, confidence interval; H63D, substitution of aspartic acid for histidine at amino acid 63; HFE, hemochromatosis protein; HR, hazards ratio. From 1990–1994, the Melbourne Collaborative Cohort Study

enrolled 41,514 people (24,469 women) aged between 27 and 75 years (99.3% were 40–69 years) in Melbourne, Australia. Participants were recruited using Electoral Rolls (voting is compulsory for Australian citizens) and by advertisements and community announcements. Approximately one-quarter of the participants were born in Greece, Italy, or Malta, but because the prevalence of the C282Y variants in the HFE gene was low in this group,18 genotyping was restricted to the 31,181 participants born in Australia, New Zealand, the United Kingdom, or Ireland. Because cancer diagnosis was ascertained prospectively, 1245 participants who had been diagnosed with any cancer before enrollment in the study were excluded from the analysis. A further 41 were excluded because their baseline blood samples were missing or they had insufficient DNA for genotyping, leaving 29,895 eligible participants. The study protocol was approved by the Cancer Council Victoria’s Human Research Ethics Committee (Project No. HREC0105).

Aspiration pneumonia and delayed perforation caused disseminated intravascular coagulation and death in the affected patients. Three patients with stage IV cancer died from progression (metastasis)

of advanced stage cancer of other organs within 6 months, and 12 patients remain alive over a follow-up period of 23.6 ± 17.1 months. Conclusion: Patients with advanced stage cancer of other organs are at high risk for poor prognosis due to complications related to ESD for EGC. Key Word(s): 1. Endoscopic submucosal dissection Presenting Author: ANDREW BUCKLE Additional Authors: WILLIAM TAM, MARK SCHOEMAN, JOHN ARGYRIDES Corresponding Author: ANDREW BUCKLE Affiliations: Royal Adelaide Hospital, Royal Adelaide Hospital, Royal Adelaide Hospital Objective: The thiopurines azathioprine (aza) and 6-mercaptopurine (6-MP) have been a mainstay of inflammatory Selleckchem H 89 bowel disease treatment for over 20 years. Cytomegalovirus (CMV) infection has long been associated

with IBD and suggested an aetiological factor in steroid-resistant colonic disease. Despite extensive experience with thiopurine therapy it is unclear if these medications predispose to CMV infection/reactivation. Methods: We present 4 case reports of patients with CMV viraemia of varying clinical severity whilst on thiopurine therapy. Results: Case 1 is a 28 year old male with Torin 1 research buy UC on 5-MP who presented with a febrile illness with pancytopaenia and a CMV viral load of 380000 copies. Case 2 is a 55 year old woman with a 4 year history of Crohn’s disease on aza who presented with a febrile illness following contact with a work colleague with confirmed CMV infection. Her CMV titre on admission was 880 000 copies. Case 3 is of a 44 year old female with ulcerative colitis controlled on 6-MP. She presented with a febrile illness, neutropaenia, deranged

LFTs, and a CMV titre of 63 000. In all cases prompt therapy with ganciclovir resulted in complete recovery. Case 4 is of a fatal CMV infection in a 57 year old female with a 5 year history of Crohn’s disease on 6-MP for 3 years. She presented with a febrile illness and macular rash, with bloods revealing neutropaenia, deranged LFTs, and acute kidney injury. Her else CMV titre was 85 000 copies. Unfortunately despite early ganciclovir therapy her condition continued to decline requiring respiratory and inotropic support and she died shortly thereafter. Conclusion: We present 4 case reports of CMV viraemia whilst receiving thiopurine therapy for IBD, highlighting the need for early consideration of CMV infection/reactivation in any patient in this population presenting with febrile illness and neutropaenia. Key Word(s): 1. Thiopurines; 2. azathioprine; 3. mercaptopurine; 4. Aza; 5. 6-Mp; 6. ulcerative colitis; 7. Crohn’s disease; cytomegalovirus Presenting Author: SOO-CHEON CHAE Additional Authors: J. MO, K. ALAM, S.

We then analyzed two additional cytokines induced by polyI:C, TNF-α and IL-1, which have been shown to modulate CYP expression when administered in patients or animals.31 However, both TNF-α-deficient mice (Tnfa−/−) and IL-1 receptor-deficient mice (IL-1R−/−) were protected by polyI:C against

APAP-induced hepatotoxicity (Supporting Fig. 4). TLR3 is the primary membrane-bound receptor for mediating the innate immune response to polyI:C.21 In the absence of TLR3, APAP-induced hepatotoxicity was suppressed when mice were pretreated with polyI:C (Fig. 6B). This finding was confirmed using mice deficient in TRIF, the adaptor protein required for TLR3 signaling18 (Fig. 6A). Moreover, mice lacking Cardif, the adaptor protein for cytoplasmic receptors Ipatasertib molecular weight EGFR inhibition of polyI:C, were also protected against APAP-induced hepatic injury18 (Fig. 6C). However, polyI:C pretreatment in double knockout mice deficient in both Cardif and TLR3 failed to protect against APAP-induced hepatotoxicity (Fig. 6D). These findings suggest that membrane-bound and cytosolic receptors of polyI:C play complementary roles in this animal model. There are many documented examples of impaired drug metabolism in patients with viral infections.1, 2 These effects have been attributed to modulation of CYP enzymes in response to activation of the innate immune system.4 Although the activity and expression levels of CYPs have been shown to

be altered during viral infection or inflammatory states, the underlying molecular mechanisms are not well characterized. Our previous work identified a potential mechanism of how innate immune activation can Resveratrol lead to enhanced ASA-induced hepatotoxicity through down-regulation of CYP3A11, the CYP enzyme required

for the clearance of the toxic intermediate of ASA.5 PolyI:C stimulation can lead to transcriptional down-regulation of RXRα and subsequently decreasing the presence of RXRα on the PXR/RXR ER6 binding region on the promoter of CYP3A4 (human homolog of Cyp3a11) in Huh7 cells.5 Here we studied the effects of such crosstalk between antiviral responses and nuclear hormone receptors on the transcriptional regulation of CYPs involved in the metabolism and toxicity of another commonly used analgesic, APAP. In this study we report that VSV infection as well as polyI:C pretreatment results in attenuated APAP-induced hepatotoxicity in mice. Early studies have also reported similar phenomena; however, the molecular mechanism by which such protection is mediated was never studied in detail.32 Our findings suggest that this protection against APAP-induced toxicity can potentially be due to inhibition of nuclear hormone receptor-regulated metabolism, as we have shown that polyI:C suppresses expression of PXR, RXRα, and their target genes, CYP3A11 and CYP1A2. The transcription of the other CYP involved in APAP metabolism, CYP2E1, however, was not altered, as this gene is not downstream of any known nuclear hormone receptors.

Manfredi et al. [1] had chosen a 10-day levofloxacin containing triple therapy that achieved a cure rate below 80%. Meta-analyses have shown that 7-day fluoroquinolone triple therapy typically provides unacceptably low treatment success, 10-day regimens yield borderline acceptable results (e.g. 84–89% treatment success), and neither provides reliable >90 or 95% cure rates [6,7]. Recently, a trial of 14-day fluoroquinolone triple therapy provided 95% success suggesting that it is possible to achieve high level success with this combination [8]. However, resistance to

fluoroquinolones is rapidly increasing worldwide, and the presence of resistance is a likely explanation for the relatively low cure rates experienced by Manfredi et al. Increasingly common resistance suggests that fluoroquinolone-containing regimens should only be used in areas where resistance RGFP966 in vitro is known to still be low or pretreatment susceptibility testing has been performed

[9]. Furthermore, fluoroquinolones are expensive and have “black box” warnings. Thus, we can not concur with the Manfredi et al. [1] suggestion that a 10-day fluoroquinolone triple therapy would be an excellent choice to “eradicate Helicobacter pylori infection in only two rounds”. We recommend that the same considerations for choosing first-line empiric therapy be employed for choosing second-line

therapy (i.e. that drugs used in previous H. pylori treatment schedules for which resistance has likely MK-1775 mw developed or those with predictable high primary resistance rates should be avoided). The second line should be the combination that is known to work best locally (Fig. 2) [5,9]. Where available, bismuth-containing quadruple therapy is often an excellent choice provided that one prescribe appropriate doses and for at least 10 or preferably 14 days. 4��8C Seven-day bismuth-containing quadruple therapy is insufficient to overcome metronidazole resistance [10], which likely explains why a recent meta-analysis reported that 7-day bismuth quadruple was inferior to 10-day levofloxacin triple therapy as a second-line therapy [6]. In conclusion, the best locally available therapy should be used for both first-line and for second-line therapy. After the failure of a clarithromycin-containing four-drug first-line therapy (e.g. sequential or concomitant), current best alternatives are either a bismuth quadruple therapy where available or a fluoroquinolone-containing triple therapy. Our suggestion, however, is to give both for 14 days and avoid levofloxacin in areas where H. pylori fluoroquinolone resistance is known to have increased enough to jeopardize therapy results. The final goal should be achieving at least 90% treatment success also with second-line therapy. Dr.

Key Word(s): 1. HCV; 2. hepatitis; 3. chemokine; 4. IP-10; Presenting Author: GANG SHI Additional Authors: WEI LU Corresponding Author: GANG SHI Affiliations: Tianjin Second People’s Hospital Objective: To implement two-way connection of found scientific research and clinical application about the traditional Chinese medicine prevention and cure viral hepatitis by translational medicine mode. Methods: At the moment of undertaking “The 11th Five Years Key Programs for Science and Technology Development of China”, to organize research team of translational

medicine, manage projects distribution and application selleck compound of the traditional Chinese medicine prevention and cure viral hepatitis as a whole and share scientific research equipment, biological specimen, bio-information ERK inhibitor base. Put research outcomes into practice by scientific operation

mechanism. Results: Our hospital has 4 national level items understudied and 4 bureau level items after implement translational medicine mode in recent 2 years. We has cultivated 3 doctors on combination of traditional Chinese medicine with Western medicine, designated 4 people to receive Master of medicine and Doctor Education, 3 people has got master academic degree. Conclusion: Translational medicine mode of the traditional Chinese medicine prevention and cure viral hepatitis can break traditional medicine research separation, re-establish research system of the traditional Chinese medicine prevention and cure viral hepatitis and carry out two-way Translation from bench to bedside. Key Word(s): 1. translational medi; 2. viral hepatitis; 3. Chinese medicine; Presenting Author: CHUNYAN WANG Corresponding Author: CHUNYAN WANG Affiliations: Tianjin Tenofovir solubility dmso Second People’s Hospital Objective: To investigate the diagnostic value of CAP by transient elastography technique for liver steatosis in patients with chronic hepatitis B

(CHB). Methods: Eighty-eight patients with CHB were enrolled in this study. All of the patients underwent CAP by transient elastography technique, and they underwent liver biopsy at the same term. With liver biopsy as the gold standard, ROC curves were delineated for different endpoints. The area under the ROC curves (AUC) was used to evaluate the diagnostic value for liver steatosis in patients with CHB. Results: There was a positive correlation between the AUCs of CAP and liver pathological stage (r = 0.582, p < 0.05). The CAP between S0, S1, S2, S3 were significantly different (F = 17.79, P < 0.01). The AUC values of CAP were 0.711 (0.592–0.870), 0.868 (0.748–0.989), 0.974 (0.922–1.026) for S > 0, S > 1, S > 2, respectively. The optimal cut-off values were 219.5, 230.0, 283.5 dB/m. Conclusion: CAP is a novel tool to assess the degree of steatosis. Key Word(s): 1. LSM; 2. CAP; 3. hepatitis B; 4.

[24, 25, 27, 43] In addition, it was reported that platelet-derived serotonin mediated liver regeneration and that thrombocytopenia resulted in the failure to initiate hepatocyte proliferation.[44] In the clinical setting, platelet-rich plasma, which is an autologous concentration of platelets in a small volume of plasma, has been already used in the dental implantation, maxillofacial surgery, and plastic surgery

for the promotion of regenerating damaged tissue.[45, 46] Thrombocytopenia is a common complication of CLD and is due to various causes, including decrease of thrombopoietin (TPO) production, increment of platelet destruction with splenomegaly, and the inability of hematopoiesis by the bone marrow.[47-50] Therefore, thrombocytopenia is thought to have the intimate relation to pathogenesis of CLD and cirrhosis. selleck inhibitor Kondo et al. reported that the accumulation of platelets in the liver with CLD and cirrhosis might be

one of the important contributory factors to thrombocytopenia and liver fibrosis.[51] On the other hand, Kodama et al. reported that thrombocytopenia could exacerbate liver fibrosis in mice through the suppression of type I collagen expression via the HGF-Met signaling pathway without the deterioration of liver pathological changes.[52] In liver fibrosis model induced by chronic injection of carbon tetrachloride, similar exacerbation of liver fibrosis under conditions of thrombocytopenia was observed.[52] The effect of thrombocytopenia

on liver damage and Roxadustat price the exact mechanisms leading to thrombocytopenia in CLD and cirrhosis is still unclear, and further study would be required. Currently, liver fibrosis is known to be part of a dynamic process of continuous extracellular matrix (ECM) remodeling in the setting of chronic liver injury, which leads to the excessive accumulation of several extracellular proteins, not proteoglycans, and carbohydrates.[3, 53] Among the cellular populations in the liver, HSCs are reported to have the most involvement in liver fibrosis through the production of large amounts of ECM and the secretion of TGF-β, which appears to be a key mediator of liver fibrogenesis.[3, 53] In the normal liver, HSCs reside in the space of Disse, and their primary function is the storage of vitamin A and other retinoids.[54] In addition, HSCs are now well established as the key cellular element involved in the development of liver fibrosis.[54, 55] In the response to liver injury, HSCs undergo morphologic and functional trans-differentiation, converting from vitamin A-storing, star-like cells into contractile myofibroblastic cells, a process called activation.[56, 57] Ikeda et al. reported that human platelets contributed to the suppression of both HSC activation and type I collagen production via a cyclic adenosine monophosphate (cAMP) signaling pathway in vitro.[29] The level of intracellular cAMP is increased by adenosine through its receptors on HSCs.

In line with their transient reconstitution,

these populations continued to express high levels of CTLA-4 and Bim. The lack of reversal of their proapoptotic phenotype in the face of effective suppression of circulating HBV DNA may reflect the inability of antiviral therapy to adequately switch off intrahepatic production of covalently closed circular (cccDNA), manifested in high residual serum HBsAg levels. Patients in this study were only followed for a maximum of 18 months after the initiation of therapy; it will be important in future studies to assess whether there is more effective T-cell reprogramming in at least a subset of patients after more prolonged treatment. The lack of sustained off-treatment responses generally seen in CHB, accompanied by the ineffective T-cell reprogramming www.selleckchem.com/products/ABT-263.html that we observed, point to the need for Selleck PD332991 a more directed therapeutic approach. We therefore investigated the potential to rescue HBV-specific CD8 T cell responses in vitro, using the approach of mAbs blocking the CTLA-4 receptor already used in human cancer trials.16 The fact that this was able to increase the expansion of functional HBV-specific

responses in a number of patients supports a role for CTLA-4 in T-cell exhaustion in CHB. However, in some cases in the large cohort examined, a lack of detectable T-cell reconstitution upon CTLA-4 blockade is likely to reflect a dominant role for other coinhibitory pathways. This is supported by our data showing nonredundant roles for the CTLA-4 and PD-1 pathways in the T-cell tolerance of CHB, with a similar number of patients only responding to blockade of one or other pathway and some responding synergistically to dual blockade. Complementary roles for different coinhibitory pathways have been recently highlighted in the LCMV model,23 in HCV,9 and in HIV, where another coinhibitory molecule, Tim-3, was found to

be expressed on largely nonoverlapping T-cell populations to those expressing PD-1.24 It remains to be determined whether the contribution of different coinhibitors is stochastic or is predictable Orotidine 5′-phosphate decarboxylase from the baseline expression of these receptors on HBV-specific T cells in different patients, such that the selection of blocking strategies could be individually tailored. Our findings suggest that whereas CTLA-4 may promote exhaustion of HBV-specific CD8, it may also serve as a brake on liver inflammation through its increased expression on CD8 of other specificities. Recent work has highlighted the critical role for CTLA-4-expressing antigen-specific effector T cells in regulating peripheral tolerance after secondary encounter with antigen in target tissues.15 Restoration of effective antiviral immunity through blockade of CTLA-4 may therefore be at the expense of control of collateral tissue damage, emphasizing the need for a targeted therapeutic approach.25 In summary, we demonstrate a contributory role for CTLA-4 in driving Bim-dependent apoptosis of the antiviral response in CHB.