Akira Kawano

Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis

BACKGROUND & AIMS The mechanism for development of primary biliary cirrhosis (PBC) remains enigmatic, but molecular mimicry has been implicated because of well-known cross-reactivity of human mitochondrial autoantigens and equivalent bacterial antigens. Virtually all patients with PBC have antimitochondrial autoantibodies (AMA), but, interestingly, approximately 50% also manifest antinuclear antibodies (ANA). METHODS To determine whether generation of ANA are due to molecular mimicry of mitochondrial peptides, we established 6 T-cell clones selected by a peptide corresponding to the E2 subunit of mitochondrial pyruvate dehydrogenase complex and analyzed for reactivity to mimicry peptides derived from mitochondrial and nuclear autoantigens, including control sequences. RESULTS For mitochondrial autoantigens, 1 peptide from the E2 subunit of the pyruvate dehydrogenase complex, 1 peptide from the E2 subunit of the oxo-glutarate dehydrogenase complex, 1 peptide from the E2 subunit of the branched-chain 2-oxoacid dehydrogenase complex, and 1 peptide from the E3-binding protein cross-reacted with these T-cell clones. For the nuclear autoantigens, 5 peptides from gp210 and 1 from Sp100 cross-reacted with these clones. Furthermore, 1 of 3 T-cell clones selected by recombinant gp210 protein reacted with a mimicry peptide corresponding to amino acids 188-201 of gp210, indicating that this part of the protein is a naturally processed immunodominant T-cell epitope. CONCLUSIONS These results demonstrate molecular mimicry between mitochondrial and nuclear autoantigens in PBC and that a mimicry peptide may become an immunodominant T-cell epitope. These data have significance not only for PBC but also for the production of ANA in other disease processes.

Telaprevir can be successfully and safely used to treat older patients with genotype 1b chronic hepatitis C

BACKGROUND & AIMS This study was performed to evaluate the efficacy of a triple therapy in older Japanese patients; telaprevir (TVR) was added to pegylated interferon α2b and ribavirin. METHODS This prospective study enrolled 120 genotype 1b patients with chronic hepatitis C who received 12 weeks of triple therapy followed by a 12-week dual therapy that included pegylated interferon α2b and ribavirin. Patients were categorized according to age: group A, 64 patients aged >60 and group B, 56 patients aged ⩽60. Serum HCV RNA levels were monitored by COBAS TaqMan HCV test. RESULTS The rates of undetectable HCV RNA at week 4 (rapid virological response, RVR) were 73.4% in group A and 73.2% in group B. No significant difference in sustained virological response (SVR) was found between groups A (76.6%) and B (83.9%) (p=0.314). The SVR rates for patients with interleukin 28B (IL28B) (rs8099917) TT allele (89.4% and 91.9% for groups A and B) were significantly higher than for those with the IL28B TG/GG allele (41.2% and 68.4%, respectively) (both p<0.05). Multivariate analysis extracted IL28B TT and RVR as independent factors associated with SVR. Adverse effects resulted in treatment discontinuation by 12.5% in each group. Hemoglobin decrease significantly differed between groups A and B: the decrease to ≤100 g/L, to 85 - <100g/L, and to <85 g/L, was 9.4%, 40.6%, and 50% in group A patients, respectively, and 41.1%, 25%, and 33.9% in group B patients, respectively (p=0.0006). CONCLUSIONS TVR-based triple therapy can be successfully used to treat older patients with genotype 1b chronic hepatitis C.

Biliary epithelial cells regulate autoreactive T cells: Implications for biliary‐specific diseases

The biliary epithelial cell (BEC) is the target for several human immune mediated liver diseases, including primary biliary cirrhosis, but it is not always clear whether the BEC functions as an accessory cell or an antigen presenting cell, although it is well documented that BECs express high levels of human leukocyte antigen Class II, intercellular adhesion molecule‐1, and lymphocyte function–associated antigen‐3. To examine this issue, we established autoreactive T‐cell clones from human leukocyte antigen–DR53 patients with primary biliary cirrhosis and characterized BEC function as a function of the ability of BECs to regulate T‐cell activation. We report herein that BEC‐mediated T‐cell activation occurs partially via programmed death 1 ligands in a cell‐contact–dependent manner. Further, such activation occurs via prostaglandin E2 production in a cell‐contact–independent fashion. Moreover, the production of prostaglandin E2 was partially controlled by interleukin‐1β and tumor necrosis factor α. In conclusion, the regulatory activities of BECs are important for the maintenance of peripheral immune tolerance. Further, modulation of BEC function may be used for therapeutic modulation. (HEPATOLOGY 2005;41:151–159.)

Clinical milestones for the prediction of severe anemia by chronic hepatitis C patients receiving telaprevir-based triple therapy

BACKGROUND & AIMS Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PegIFN)α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PegIFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy. METHODS This prospective, multicenter study consisted of 292 patients (median age: 62 years) infected with HCV genotype 1. All received 12 weeks of TVR in combination with 24 weeks of PegIFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb)<85 g/L. RESULTS 101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb < 135 g/L (Hazard ratio [HR], 2.53; p = 0.0013), estimated glomerular filtration rate <80 ml/min/1.73 m(2) (HR, 1.83; p = 0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; p = 0.0024). For patients with ITPA CC (n = 227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; p = 0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; p = 0.0281). CONCLUSIONS Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment.

Telaprevir‐based triple therapy for chronic hepatitis C patients with advanced fibrosis: a prospective clinical study

Antiviral treatment is recommended for chronic hepatitis C patients with advanced fibrosis to reduce and prevent cirrhosis‐related complications.

Erratum for Fusion of the Nucleoporin Gene, NUP98, and the Putative RNA Helicase Gene, DZXX10, by Inversion 11 (p15q22) Chromosome Translocation in a Patient with Etoposide-related Myelodysplastic Syndrome

We report a 50-year-old man who developed therapy-related myelodysplastic syndrome after treatment with etoposide-including chemotherapy for extratesticular germ cell tumor. Chromosomal analysis showed inversion 11 (p15q22) translocation. Reverse transcriptase-polymerase chain reaction amplification of patient RNA showed a fusion transcript of nucleoporin gene NUP98, and putative DEAD-box RNA helicase gene DDX10. NUP98 is implicated in the transformation through aberrant nucleocytoplasmic transport. DDX10 is suggested to be involved in ribosome assembly. The NUP98-DDX10 fusion transcript may promote the development of secondary hematological malignancies caused by DNA-topoisomerase II inhibitors through aberrant nucleocytoplasmic transport and/or alteration in ribosome assembly.

Promiscuous T cells selected by Escherichia coli: OGDC-E2 in primary biliary cirrhosis.

The etiology of primary biliary cirrhosis (PBC) remains enigmatic. One theory that has attracted attention proposes that PBC is induced via molecular mimicry with Escherichia coli. If molecular mimicry is responsible for the immunogenic response in PBC, then T cell clones specific for E. coli antigens should stimulate and be cross-reactive with peptides specific for the human immunodominant autoepitopes. To address this issue, we developed T cell clones specific for E. coli OGDC-E2 peptide. Importantly, we demonstrate the presence of T cell clones specific for E. coli OGDC-E2 that react promiscuously with the human mitochondrial equivalents. Indeed, there was a significant increase in the liver derived T cell precursor frequency of such reactivity and such liver clones were only found in patients with PBC. In conclusion, these data suggest that PBC is a multi-hit disease involving a genetic predisposition, a mucosal response, and activation of promiscuous T cells; such activation may occur either directly from bacterial antigens, or indirectly through chemically-modified bacterial antigens. Dissection of the mechanisms involved will lead not only to understanding the immunogenetic basis of PBC, but likely its pathogenic etiology.

Short‐term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct‐acting anti‐viral treatment

With the development of direct‐acting anti‐virals (DAAs), almost all patients with chronic hepatitis C virus (HCV) infection can achieve sustained viral response (SVR).

Effectiveness and safety of daclatasvir plus asunaprevir for HCV genotype 1b patients aged 75 and over with or without cirrhosis

The aim of this study was to evaluate the efficacy and safety of 24‐week daclatasvir (NS5A inhibitor) plus asunaprevir (NS3/4 A protease inhibitor) treatment for elderly patients with hepatitis C virus (HCV) genotype 1b infection.

Comparative effectiveness and safety study of triple therapy with simeprevir or telaprevir for non-cirrhotic patients with chronic hepatitis C virus genotype 1b infection.

The addition of hepatitis C virus (HCV) NS3/4A protease inhibitors to pegylated‐interferon alpha (PEG‐IFNα) and ribavirin (triple therapy) has greatly improved treatment outcome. The aim of this study was to compare the effectiveness and safety of simeprevir‐based or telaprevir‐based triple therapy for non‐cirrhotic patients in real‐world clinical practice.