Trastuzumab Deruxtecan Dosing in Human Epidermal Growth Factor Receptor 2-Positive Gastric Cancer: Population Pharmacokinetic Modeling and Exposure-Response Analysis.

This study evaluated the benefit/risk of trastuzumab deruxtecan (T-DXd) 6.4 mg/kg in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer using pharmacometrics. A population pharmacokinetic (PopPK) model was developed using data from patients with gastric cancer, breast cancer, or other tumors in T-DXd clinical trials, primarily conducted in Asia. Post hoc model-estimated pharmacokinetic metrics were used in exposure-efficacy (objective response rates, ORRs) and exposure-safety analyses. The PopPK analysis included 808 patients (217 with gastric cancer, 512 with breast cancer, and 79 with other cancers). In gastric cancer, the T-DXd 6.4 mg/kg steady-state exposure metrics were lower compared with 6.4 mg/kg in breast cancer, but were similar to 5.4 mg/kg in breast cancer. Tumor type was selected as a significant covariate on T-DXd clearance. In exposure-efficacy analysis among 160 patients with gastric cancer, the T-DXd steady-state minimum concentration was associated with a confirmed ORR in univariate logistic regression analysis (P = .023). The model-predicted confirmed ORRs in gastric cancer were 36.0% (90%CI 29.3% to 43.7%) with 5.4 mg/kg and 40.0% (90%CI 33.1% to 47.6%) with 6.4 mg/kg. Among 808 patients in the exposure-safety analyses, the model-predicted estimates for the rates of any-grade interstitial lung disease (ILD) over a period of 180 days were 10.2% (90%CI 8.7% to 12.8%) with 6.4 mg/kg in gastric cancer and 9.7% (90%CI 8.2% to 11.8%) with 5.4 mg/kg in breast cancer. In gastric cancer, the efficacy of T-DXd was higher at 6.4 mg/kg than at 5.4 mg/kg. Exposure and ILD rates were comparable between 6.4 mg/kg in gastric cancer and 5.4 mg/kg in breast cancer. This study identified T-DXd 6.4 mg/kg as the recommended dose in HER2-positive gastric cancer.

Ursodeoxycholic acid impairs liver-infiltrating T-cell chemotaxis through IFN-γ and CX3CL1 production in primary biliary cholangitis.

Ursodeoxycholic acid (UDCA) is the primary treatment for primary biliary cholangitis (PBC), but its mechanism of action remains unclear. Studies suggest that UDCA enhances NF erythroid 2-related factor 2 (NFE2L2) expression and that the interaction between IFN-γ and C-X3-C motif chemokine ligand 1 (CX3CL1) facilitates biliary inflammation in PBC. Therefore, we examined the effects of UDCA on the expression of IFN-γ and CX3CL1 in in vitro and in vivo PBC models such as human liver tissue, a murine model, cell lines, and isolated human intrahepatic biliary epithelial cells (IHBECs). We observed a significant decrease in IFN-γ mRNA levels and positive correlations between IFN-γ and CX3CL1 mRNA levels post-UDCA treatment in PBC livers. NFE2L2-mediated transcriptional activation was significantly enhanced in UDCA-treated Jurkat cells. In 2-octynoic acid-immunized mice, IFN-γ production by liver-infiltrating T cells was dependent on NFE2L2 activation. IFN-γ significantly and dose-dependentlyinduced CX3CL1 expression, which was significantly decreased in HuCC-T1 cells and IHBECs upon UDCA treatment. These results suggest that UDCA-induced suppression of IFN-γ and CX3CL1 production attenuates the chemotactic and adhesive abilities of liver-infiltrating T cells in PBC.

[A case of obstructive pancreatitis induced by extramedullary pancreatic metastasis in a patient with immunoglobulin D multiple myeloma].

A 51-year-old Brazilian female who had IgD-lambda type multiple myeloma presented with epigastralgia and obstructive jaundice during her follow-up. Contrast-enhanced computed tomography (CT) showed an enhanced mass of 25mm in the pancreatic head, and endoscopic retrograde cholangiopancreatography revealed smooth stenoses in the lower bile duct and main pancreatic duct (MPD) of the head. We diagnosed the patient with extramedullary pancreatic metastasis of multiple myelomas. Plastic stents were endoscopically placed into both the common bile duct and MPD. One week later, she suffered a repeat episode of epigastralgia. A subsequent CT scan showed obstructive pancreatitis due to another mass, 30mm in size, emerging rapidly in the pancreatic body. Pancreatitis improved after we replaced the plastic stent with a longer one so that the distal end reached beyond the stenosis at the MPD of the body. Although both the tumors were treated with radiotherapy and showed temporary reduction, the patient died 1 month later due to progression of the disease. While cases involving obstructive pancreatitis induced by extramedullary pancreatic metastasis of multiple myelomas are very rare, it is crucial that such patients are rapidly diagnosed and treated.

Clinical characteristics and risk factors for stent-stone complex formation following biliary plastic stent placement in patients with common bile duct stones.

BACKGROUND: Stent-stone complex (SSC) formation is one of the complications of endoscopic biliary stent placement. This study aimed to clarify the clinical characteristics and risk factors for SSC formation following plastic stent (PS) placement in patients with common bile duct (CBD) stones. METHODS: We retrospectively reviewed the charts of 78 patients with CBD stones who had undergone 107 biliary stent placements as palliative treatment. Demographic, historical, and stent-related data were collected and analyzed. RESULTS: At PS removal, SSC formations were observed in 18% of the 107 cases (SSC group) studied and not in the remaining 82% (non-SSC group). The duration of PS placement was significantly longer in the SSC group. The increase in CBD diameter during the stenting period as well as the incidence of cholangitis at PS removal was significantly greater in the SSC group. Multivariate analysis identified long-term (≥301 days) PS placement and the increase in CBD diameter during the stenting period as independent factors for SSC formation. CONCLUSIONS: Long-term PS placement induces a risk of SSC formation in patients with CBD stones. The increase in diameter of CBD during the period of PS placement is a predictive factor for SSC formation in this situation.

Rapid Changes in Serum Lipid Profiles during Combination Therapy with Daclatasvir and Asunaprevir in Patients Infected with Hepatitis C Virus Genotype 1b.

BACKGROUND/AIMS: Changes in lipid profiles in patients infected with hepatitis C virus (HCV) during direct-acting antiviral therapy have been reported in recent years. However, the clinical aspects of disturbed lipid metabolism in chronic HCV infection have not been fully elucidated. METHODS: Dynamic changes in serum total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol and apolipoprotein levels in patients infected with HCV genotype 1b were examined during combination therapy with daclatasvir (DCV) and asunaprevir (ASV). RESULTS: Total, LDL-, and HDL-cholesterol levels increased rapidly and persistently after week 4. Apolipoprotein (apo) A-I, apo B, apo C-II, and apo C-III levels were significantly higher at week 4 than at week 0. In contrast, apo A-II and apo E levels were significantly lower. The differences in LDL- and HDL-cholesterol levels were positively correlated with those of apo B and apo A-I, respectively. Interestingly, in patients with non-sustained virological response, these cholesterol levels decreased rapidly after viral breakthrough or viral relapse. Furthermore, similar changes were observed for apo A-I, apo B and apo C-III levels. CONCLUSIONS: Clearance of HCV using combination therapy with DCV and ASV results in rapid changes in serum lipid profiles, suggesting an influence of HCV infection on disturbed lipid metabolism.

A case of a primary hepatic so-called adenosarcoma with heterotopic ossification: possibly of biliary adenofibroma origin.

We present an autopsy case of a "so-called adenosarcoma with ossification of the liver" in a 63-year-old man. Macroscopically, the well-circumscribed tumor with portal vein invasion was observed in the right lobe of the liver. The cut surface of the tumor had a solid and microcystic appearance. Microscopically, the tumor was characterized by a benign epithelial component and a malignant mesenchymal component. We believe the presence of biliary adenofibroma-like areas and the von Meyenburg complexes suggests that the tumor is possibly associated with a biliary adenofibroma. In addition, the present tumor was unique in that it showed scattered heterotopic ossification. Immunohistochemical study showed that the mesenchymal atypical spindle cells had characteristics of undifferentiated mesenchymal cells. This is the first report of a primary hepatic so-called adenosarcoma.

[Spontaneous regression of pancreatic arteriovenous malformation under the influence of severe acute pancreatitis: a case report].

A 49-year-old man was diagnosed with severe acute pancreatitis because of pancreatic arteriovenous malformation (AVM). The pancreatic AVM spontaneously regressed during conservative treatment for severe acute pancreatitis. Transarterial embolization of an aneurysm in an artery branch flowing into the pancreatic AVM was performed using metallic coils, following amelioration of severe acute pancreatitis. The complete elimination of the pancreatic AVM was confirmed 1 year after embolization, and the patient has had no recurrence of pancreatic AVM and pancreatitis for over 6 years. Most cases of pancreatic AVMs with acute pancreatitis require surgical resection. This is a rare case in which the pancreatic AVM spontaneously regressed under the influence of acute severe pancreatitis.

Effect of Cotton Roll Biting on Auditory Evoked Magnetic Fields.

The effects of change in occlusal pressure on the cortical mechanisms responsible for hearing were investigated. Changes in the magnetic field in response to auditory stimulation when subjects (5 healthy, right-handed, male volunteers aged between 22 and 30 years) bit a cotton roll were analyzed by using magnetoencephalography. All equivalent current dipoles estimated from the fields obtained under 3 different bite force conditions were closely localized within 1 mm of those obtained in the non-bite control group. No significant difference was observed between the bite and non-bite conditions in the latency of the 100-ms component (N100 m) of the magnetic fields. The amplitude of the N100 m component decreased with increase in bite pressure in both the right and left hemispheres (p<0.05). These results suggest that an increase in bite pressure influences auditory function.

Critical role of CREBH-mediated induction of transforming growth factor ß2 by hepatitis C virus infection in fibrogenic responses in hepatic stellate cells.

Mechanisms of hepatic fibrogenesis induced by hepatitis C virus (HCV), one of the leading causes of liver fibrosis, are not fully understood. We studied transcriptional up-regulation of transforming growth factor ß (TGF-ß), especially TGF-ß2, which is mediated by activation of liver-enriched transcription factor cAMP-responsive element-binding protein, hepatocyte specific (CREBH) triggered by HCV infection and its functional significance for induction of profibrogenic phenotypes by interaction of HCV-infected cells with hepatic stellate cells (HSCs). Compared to TGF-ß1, expression of TGF-ß2 mRNA was induced faster and to a higher level upon HCV infection. Serum TGF-ß2 levels in hepatitis C patients were higher compared to those in healthy individuals and were positively correlated with hepatic fibrosis stages F0-F2. TGF-ß2 promoter activity was decreased and increased, respectively, by silencing and overexpression of CREBH. CREBH recognition sites were identified in the TGF-ß2 promoter. CREBH binding to the promoter and its increase in cells expressing HCV Core-NS2 were shown by gel mobility shift and chromatin immunoprecipitation, respectively. The active form of CREBH was detectable in HCV-infected chimeric mice with human livers and cells expressing HCV proteins. Involvement of CREBH in HCV-induced fibrogenic response was further demonstrated in the CREBH null-mutant mouse model. Fibrogenic phenotypes were assessed using co-cultures of HCV-infected cells and HSCs. Expressions of fibrogenic factors and TGF-ß1 increasing in the co-cultures was prevented by TGF-ß2- or CREBH silencing. CONCLUSION: CREBH was identified as a key positive regulator of TGF-ß2 transcription in HCV-infected cells. TGF-ß2 released from infected cells potentially contributes to cross-induction of TGF-ß in an autocrine manner through its own signaling pathway, leading to an increase in fibrogenic responses in adjacent HSCs. (Hepatology 2017;66:1430-1443).

Evaluation of serum bone alkaline phosphatase activity in patients with liver disease: Comparison between electrophoresis and chemiluminescent enzyme immunoassay.

BACKGROUND: Serum bone alkaline phosphatase (ALP) is a marker of bone formation and metabolism. However, existing methods for measuring it have their limitations and their accuracy has not been determined. METHODS: We measured serum bone ALP activity in 127 patients with liver disease using 2 methods: electrophoresis and chemiluminescent enzyme immunoassay (CLEIA). The results of these 2 methods were compared and analyzed according to gender, age and several serum biochemical markers. RESULTS: When ALP3 (%; bone-type isozyme activity as a percentage of total ALP activity) values were high, the 2 methods showed good correlation. However, with a decrease in ALP3 (%) levels, the correlation coefficient (R) also decreased. Starting with ALP3 (%)<23, R values markedly decreased to <0.50 (p>0.05). Five outliers displayed low ALP3 (%) activity levels. Furthermore, in regard to genders, there were significant differences in total cholesterol (TC), γ-glutamyltransferase (γ-GTP), ALP and ALP3 (%) levels (p<0.05). CONCLUSIONS: When serum ALP3 (%) levels were high in patients with liver disease, the accuracy of electrophoresis was comparable to that of CLEIA. However, the accuracy of electrophoresis needs to be evaluated with further when patient samples under certain conditions.

Component of Caramel Food Coloring, THI, Causes Lymphopenia Indirectly via a Key Metabolic Intermediate.

Caramel color is widely used in the food industry, and its many variations are generally considered to be safe. It has been known for a long time that THI (2-acetyl-4-(tetrahydroxybutyl)imidazole), a component of caramel color III, causes lymphopenia in animals through sphingosine 1-phosphate (S1P) lyase (S1PL) inhibition. However, this mechanism of action has not been fully validated because THI does not inhibit S1PL in vitro. To reconcile this situation, we examined molecular details of THI mechanism of action using "smaller" THI derivatives. We identified a bioactive derivative, A6770, which has the same lymphopenic effect as THI via S1PL inhibition. In the case of A6770 we observe this effect both in vitro and in vivo, and demonstrate that A6770 is phosphorylated and inhibits S1PL in the same way as 4-deoxypyridoxine. In addition, A6770 was detected in rat plasma following oral administration of THI, suggesting that A6770 is a key metabolic intermediate of THI.

Successful Interferon Therapy Reverses Enhanced Hepatic Progenitor Cell Activation in Patients with Chronic Hepatitis C.

The enhanced accumulation of hepatic progenitor cells (HPCs) is related to the risk of progression to hepatocellular carcinoma (HCC). Interferon (IFN) treatment reduces HCC risk in patients with chronic hepatitis C virus (HCV) infection. However, the underlying mechanisms remain unclear. The aim of this study was to examine the effects of IFN treatment on HPC activation in HCV patients. Immunohistochemical detection and computer-assisted quantitative image analyses of cytokeratin 7 (CK7) were performed to evaluate HPC activation in paired pre- and post-treatment liver biopsies from 18 HCV patients with sustained virological response (SVR) to IFN-based therapy and from 23 patients without SVR, as well as normal liver tissues obtained from surgical resection specimens of 10 patients. Pretreatment HCV livers showed increased CK7 immunoreactivity, compared with normal livers (HCV: median, 1.38%; normal: median, 0.69%, P=0.006). IFN treatment reduced hepatic CK7 immunoreactivity (median, 1.57% pre-IFN vs. 0.69% post-IFN, P=0.006) in SVR patients, but not in non-SVR patients. The development of HCC following IFN treatment was encountered in 3 non-SVR patients who showed high post-IFN treatment CK7 immunoreactivity (>4%). Successful IFN therapy can reverse enhanced HPC activation in HCV patients, which may contribute to the reduced risk of HCC development in these patients.

Pol I-transcribed hepatitis C virus genome RNA replicates, produces an infectious virus and leads to severe hepatic steatosis in transgenic mice.

Patients chronically infected with hepatitis C virus (HCV) are at risk of developing end-stage liver disease and hepatocellular carcinoma. Development of drugs to inhibit hepatocyte damage and a vaccine against HCV is hampered by the lack of a small animal model. We generated mice in which the viral genome RNA was always present in the hepatocytes using a special transgene. Here we show that the HCV genome RNA transcribed by Pol I polymerase can replicate and produce infectious viruses in mice. We obtained a transgenic mouse with 200 copies per haploid which we named the A line mouse. It produced ~ 3 × 10(6) HCV RNA copies/mL serum, which is at the comparable level as patients with chronic HCV infection. This mouse was immunotolerant to HCV and showed hepatic steatosis without any necroinflammation at the age of 6 months or hepatocellular carcinoma at the age of 15 months. Thus, the A line mouse can be used as an animal model for chronic HCV infection. This will enable better study of the abnormalities in metabolism and signal transduction in infected hepatocytes, and development of drugs that cure abnormalities.

Long-term pegylated interferon monotherapy following 72 weeks of pegylated interferon and ribavirin in hepatitis C virus genotype-1-infected slow responders.

OBJECTIVE: Slow responders to pegylated interferon (Peg-IFN) and ribavirin (RBV) among patients infected with hepatitis C virus (HCV) genotype 1 may benefit from an extended treatment course. The aim of this study was to determine the efficacy of persistent negative serum HCV RNA over 96 weeks during long-term Peg-IFN monotherapy following 72 weeks of combination therapy. METHODS: A total of 46 HCV genotype 1-infected slow responders were treated for 72 weeks with Peg-IFN and RBV combination therapy alone (n=25) or additional long-term biweekly treatment with 90 µg of Peg-IFN-α2a (n=21). The criterion for the completion of long-term Peg-IFN monotherapy was defined as the attainment of constantly negative HCV RNA in the serum over 96 weeks during IFN treatment. RESULTS: The patients with sustained negative serum HCV RNA during 96 weeks of IFN treatment had a higher rate of sustained virological response (SVR) than those without (81 vs. 40%, p=0.012). A multivariate analysis identified sustained negativity of serum HCV RNA over 96 weeks of IFN treatment to be a predictive factor for SVR. CONCLUSION: In the present study, sustained negative serum HCV RNA over 96 weeks during long-term Peg-IFN monotherapy following 72 weeks of combination therapy of Peg-IFN and RBV resulted in beneficial virological outcomes among HCV genotype 1-infected slow responders.

Improved Serum Alpha-Fetoprotein Levels after Iron Reduction Therapy in HCV Patients.

Background and Aims. To examine the changes in serum alpha-fetoprotein (AFP) levels after iron reduction by therapeutic phlebotomy in chronic hepatitis C patients. Methods. This retrospective study included 26 chronic hepatitis C patients. The patients were developed iron depletion by repeated therapeutic phlebotomies. Results. Iron reduction therapy significantly reduced the median level of serum AFP from 13 to 7 ng/mL, ALT from 96 to 50 IU/L, gamma-glutamyl transpeptidase (GGT) from 55 to 28 IU/L, and ferritin from 191 to 10 ng/mL (P < 0.001 for each). The rate of decline in the AFP level correlated positively only with that in GGT (r = 0.695, P = 0.001), although a spurious correlation was observed between the rates of decline for AFP and ALT. The AFP level normalized (<10 ng/mL) posttreatment in eight (50%) of 16 patients who had elevated pretreatment AFP levels. Normalized post-treatment ALT and GGT levels were seen in 12% (3 of 26) and 39% (7 of 18) of the patients, respectively. Multivariate analysis identified a post-treatment GGT level of <30 IU/L as an independent factor associated with post-treatment AFP normalization (odds ratio, 21; 95% confidence interval, 1.5-293; P = 0.024). Conclusions. Iron reduction by therapeutic phlebotomy can reduce serum AFP and GGT levels in chronic hepatitis C patients.

Does hepatic oxidative stress enhance activation of nuclear factor-E2-related factor in patients with nonalcoholic steatohepatitis?

The imbalance of hepatic oxidant and antioxidant status is an important pathophysiological mechanism in nonalcoholic steatohepatitis (NASH). The nuclear factor-E2-related factor (Nrf2) is a key transcription factor regulating a plethora of antioxidant genes involved in antioxidant defense. To clarify the mechanisms of hepatic antioxidant defenses in human NASH, the aim of the current study was to examine oxidative stress-induced Nrf2 activation in the livers of patients with NASH. Liver biopsies were obtained from 19 NASH patients. Normal liver tissue was obtained from surgical resection specimens of 15 patients. The proportion of hepatocytes with 8-hydroxydeoxyguanosine (8-OHdG)-positive nuclei was increased in NASH livers compared with that in normal livers. Hepatic Nrf2 protein levels were increased with enhanced accumulation of hepatocellular nuclear Nrf2, which was positively correlated with that of 8-OHdG. Hepatic expression of γ-glutamylcysteine synthetase (γGCS), glutathione peroxidase 2 (GPx2), thioredoxin (TRX), and heme oxygenese 1 (HO-1), but not thioredoxin reductase 1 (TrxR1), was upregulated, and the protein levels of γGCS were positively correlated with those of Nrf2. Collectively, our findings lead to the hypothesis that oxidative stress may enhance Nrf2 activation in the livers of patients with NASH.

Synthesis and structure-activity relationships of novel zwitterionic compounds as peroxisome proliferator activated receptor α/γ dual agonists with improved physicochemical properties.

We describe herein the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. In the previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a great glucose lowering effect in the db/db mice. However, this compound possessed fatal issues such as potent cytochrome P450 (CYP)3A4 direct inhibitory activity. Thus, we carried out the medicinal optimization to improve these while maintaining the potent PPAR agonistic activity. As a result, the issues were addressed by changing the furan ring to a low lipophilic 1,3,4-oxadiazole ring. Additionally, these oxadiazole derivatives exhibited a significant decrease in plasma glucose and plasma triglyceride levels without marked weight gain.

Differential expression of hepatic apurinic/apyrimidinic endonuclease 1, a DNA repair enzyme, in chronic hepatitis.

AIM: To determine hepatic expression of apurinic/apyrimidinic endonuclease 1 (APE-1) and 8-hydroxydeoxyguanosine (8-OHdG) in patients with chronic hepatitis B and C. METHODS: Liver biopsies were obtained from 27 patients with chronic hepatitis B virus (HBV), 30 with chronic hepatitis C virus (HCV), 6 with autoimmune hepatitis (AIH), and 6 with primary biliary cirrhosis (PBC). Normal liver tissue was obtained from surgical resection specimens of four patients. Hepatic APE-1 protein and mRNA expression were assayed by Western blot and by real-time polymerase chain reaction, respectively. Hepatocellular APE-1 and 8-OHdG expression were determined by immunohistochemistry. RESULTS: The staining intensity of hepatocellular nuclear APE-1 was lower in the HBV group than in the other groups (P < 0.05). Hepatic APE-1 protein levels were reduced in the HBV group relative to the other groups. Hepatic APE-1 mRNA levels were also lower in the HBV group. The proportion of hepatocytes with 8-OHdG-positive nuclei was increased in the HCV, AIH and PBC groups (P < 0.05), but not in the HBV group. Hepatocellular nuclear APE-1 levels were positively correlated with hepatocellular 8-OHdG levels in both the HBV and HCV groups (HBV, r = 0.34, P < 0.05; HCV, r = 0.54, P < 0.01). CONCLUSION: An imbalance between oxidative DNA damage and APE-1 expression may contribute to hepatocarcinogenesis in chronic viral hepatitis.

Clonality, activated antigen-specific CD8(+) T cells, and development of autoimmune cholangitis in dnTGFßRII mice.

UNLABELLED: There are several murine models described with features similar to human primary biliary cirrhosis (PBC). Among these models, the one which has the closest serologic features to PBC is a mouse with a T-cell-restricted expression of the dominant negative transforming growth factor ß receptor type II (dnTGFßRII). Our work has demonstrated that CD8(+) T cells from dnTGFßRII mice transfer autoimmune cholangitis to Rag1(-/-) recipients. However, it remained unclear whether the autoimmune cholangitis was secondary to an intrinsic function within CD8(+) T cells or due to the abnormal TGFßR environment within which CD8(+) T cells were generated. To address this mechanistic issue, we used our dnTGFßRII, OT-I/Rag1(-/-) , OT-II/Rag1(-/-) mice and in addition generated OT-I/dnTGFßRII/Rag1(-/-) , and OT-II/dnTGFßRII/Rag1(-/-) mice in which the entire T-cell repertoire was replaced with ovalbumin (OVA)-specific CD8(+) or CD4(+) T cells, respectively. Importantly, neither the parental OT-I/dnTGFßRII/Rag1(-/-) mice and/or OT-II/dnTGFßRII/Rag1(-/-) mice developed cholangitis. However, adoptive transfer demonstrated that only transfer of CD8(+) T cells from dnTGFßRII mice but not CD8(+) T cells from OT-I/Rag1(-/-) mice or from OT-I/dnTGFßRII/Rag1(-/-) mice transferred disease. These data were not secondary to an absence of CD4(+) T cell help since a combination of CD8(+) T cells from OT-I/dnTGFßRII/Rag1(-/-) and CD4(+) T cells from OT II/dnTGFßRII/Rag1(-/-) or CD8(+) T cells from OT-I/dnTGFßRII/Rag1(-/-) with CD4(+) T cells from OT-II/Rag1(-/-) mice failed to transfer disease. CONCLUSION: Defective TGFßRII signaling, in addition to clonal CD8(+) T cells that target biliary cells, are required for induction of autoimmune cholangitis.

The immunophysiology and apoptosis of biliary epithelial cells: primary biliary cirrhosis and primary sclerosing cholangitis.

Biliary epithelial cells (BECs) provide the first line of defense against lumenal microbes in the biliary system. BECs express a variety of pathogen recognition receptors and can activate several intracellular signaling cascades to initiate antimicrobial defenses, including production of several anti-microbial peptides, cytokines, chemokines, and adhesion molecules. BECs also secrete immunoglobulin A and interact with other cells through expression and release of adhesion molecules and immune mediators. Recently, several reports suggest a correlation between apoptosis and autoimmunity through ineffective clearance of self-antigens. Primary biliary cirrhosis (PBC) is a slowly progressive, autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated destruction of BECs. We have demonstrated that the AMA self-antigen, namely the E2 subunit of the pyruvate dehydrogenase complex, is detectable in its antigenically reactive form within apoptotic blebs from human intrahepatic biliary epithelial cells and activates innate immune responses. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and the presence of concentric fibrosis of intrahepatic and/or extrahepatic bile ducts, eventually leading to cirrhosis. However, apoptosis does not appear to play a central role in PSC. Despite both diseases involving immune-mediated injury to bile ducts, apoptosis occurs more commonly overall in PBC where it likely plays a unique role.