S. M. Fazle Akbar

Absence of CD83-positive mature and activated dendritic cells at cancer nodules from patients with hepatocellular carcinoma: relevance to hepatocarcinogenesis

Mature and activated dendritic cells (CD83-positive DCs) are essential for the recruitment and survival of activated tumor-specific lymphocytes during carcinogenesis. The frequencies of CD83 positive DCs were almost same in peripheral blood from patients with hepatocellular carcinoma (HCC) and cirrhosis of liver (LC). However, the numbers of CD83 positive DCs in liver tissues were significant lower in HCC compared with LC (6.6+/-10.9 vs. 33.3+/-24 DCs/specimen, P<0.05). Most importantly, there were no CD83-positive DCs at cancer nodules in HCC. A role of infiltration of activated DCs in liver during hepatocarcinogenesis is shown.

Placebo-controlled trial of vaccination with hepatitis B virus surface antigen in hepatitis B virus transgenic mice

BACKGROUND/AIMS Treatment of hepatitis B virus carriers by vaccine containing hepatitis B surface antigen with Pre-S protein and HBsAg/ anti-HBs complex has been reported and these studies have constituted a new and promising concept for the treatment of HBV-carriers. The present communication, a placebo-controlled trial of vaccination in HBV-transgenic mice, was designed to examine the impact of vaccination using a high dose of HBsAg for a duration of 12 months to achieve further insights about the dose, duration and effectiveness of vaccine therapy. Another aim of this study was to analyse the mechanism underlying the antiviral and immunomodulatory potentiality of vaccine therapy in HBV-transgenic mice. METHODS HBV-transgenic mice positive for HBV DNA, hepatitis B surface antigen and hepatitis B e antigen in sera received either HBV-vaccine containing HBsAg in complete Freunds adjuvant (CFA), intraperitoneally, once a month for 12 consecutive months (vaccine recipients), or only CFA, intraperitoneally once in a month for 12 consecutive months (placebo recipients). Thirty-two vaccine-recipient and 16 placebo-recipient HBV-transgenic mice were injected, checked and followed on a monthly basis for the entire duration of 12 months. RESULTS Of the 32 transgenic mice from the vaccine-recipient group, 25 became completely negative for HBsAg and 30 for HBeAg. Five mice developed anti-HBs in sera after the observation period of 12 months. Semiquantitative estimation of HBV DNA by polymerase chain reaction showed that vaccination resulted in a decrease of HBV DNA in sera. Placebo-recipient transgenic mice did not show any significant change in the titres of HBV markers after receiving 12 monthly injections of CFA. Interleukin-2 could be detected in sera from vaccine-recipient transgenic mice, but not in placebo-recipient transgenic mice. CONCLUSIONS Vaccination with a high dose of HBsAg in adjuvant over a long period had a significant antiviral as well as immunomodulatory potential in HBV-transgenic mice. This inspires optimism that vaccine alone or in combination with antiviral agents can be used successfully for the treatment of human HBV-carriers.

Macrophage migration inhibitory factor in hepatocellular carcinoma and liver cirrhosis; relevance to pathogenesis ☆

The levels of macrophage migration inhibitory factor (MIF), a proinflammatory and carcinogenic cytokine, were significantly higher in the sera from patients with hepatocellular carcinoma (HCC; 25.6+/-15.3 ng/ml, n=55) and liver cirrhosis (LC; 18.9+/-10.7 ng/ml, n=26) compared with sera from patients with gastrointestinal cancer (6.8+/-7.5 ng/ml, n=29) and normal controls (5.6+/-1.2 ng/ml, n=45; P<0.01). Hepatocytes from patients with LC and HCC, but not from chronic hepatitis, expressed very high levels of MIF. A possible association between overexpression of MIF and hepatocarcinogenesis is suggested.

Existence of TT Virus DNA in Extracellular Body Fluids from Normal Healthy Japanese Subjects

Although recent studies indicate a high prevalence (12–92%) of TT virus (TTV) DNA in sera of healthy Japanese individuals, there is a paucity of information regarding the route of transmission of this virus. Analyzing the nucleotide sequences of the existing polymerase chain reaction (PCR) primers of TTV DNA, we developed a set of noble primers (HM-1) and looked for the prevalence of TTV DNA in sera from 39 normal healthy Japanese individuals using PCR. The existence of TTV DNA was also checked in saliva, urine, sweat, stool, and tears from 11 and in semen from 10 serum TTV-positive normal subjects. TTV DNA was detected in sera from 23 of 39 (59.0%) normal subjects. TTV DNA was also detected in saliva, stool, semen and tears from all cases with TTV-DNA-positive serum, but not in body fluids from subjects with TTV-DNA-negative serum. TTV DNA remained undetected in urine and sweat from all cases. Data from these experiments showing the existence of TTV DNA in different body fluids suggest that the high rates of prevalence of TTV among normal healthy subjects might be due to a possible fecal-oral, droplet, or sexual route of transmission of TTV.

Mechanism and therapeutic potential of DNA-based immunization against the envelope proteins of hepatitis B virus in normal and transgenic mice

Two plasmid DNA vectors, pCAGGS(S) encoding the genes of the major envelope protein of hepatitis B virus (HBV), and pCAGGS(S + preS2) encoding the genes of the middle envelope protein were used to study the mechanism and therapeutic potential of DNA‐based immunization. Injection of these plasmids into the regenerating bilateral tibialis anterior muscle (TA) of normal C57BL/6 mice induced hepatitis B surface antigen (HBsAg)‐specific humoral and cellular immune responses. Seventy‐two hours after injection of pCAGGS(S), infiltrating cells including antigen‐presenting dendritic cells (DC) were localized around the injection site and HBsAg was expressed by both muscle cells and infiltrating cells. Spleen DC from the mice were exposed to HBsAg for up to 32 weeks after a single injection of pCAGGS(S), because these DC induced the proliferation of HBsAg‐specific memory lymphocytes in culture without exogenous HBsAg. A single injection of pCAGGS(S) or pCAGGS(S + preS2) resulted in the clearance of HBsAg in 28 out of 30 HBV‐transgenic (Tg) mice. In contrast, more than 7 monthly injections of an HBsAg‐based vaccine were required for the clearance of HBsAg in 6 out of 29 HBV‐Tg mice. Infiltrating DC at the DNA vaccine injection site may have a role in initiating HBsAg‐specific immune response, whereas the persistence of HBsAg exposed spleen DC may contribute to long‐lasting immunity. This study also suggested that DNA‐based vaccines may be a potent tool for treating chronic HBV carriers.

Three patients with autoimmune cholangiopathy treated with prednisolone

Abstract: We describe three patients with autoimmune cholangiopathy, i.e., anti-mitochondrial antibody-negative and anti-nuclear antibody-positive primary biliary cirrhosis, who were treated with prednisolone. Serum anti-mitochondrial antibody and anti-pyruvate dehydrogenase-E2 component antibody were determined by immunofluorescence of frozen sections and enzyme-linked immunosorbent assay, respectively. Immunoblotting using mitochondria prepared from rat liver was performed to analyze anti-mitochondrial antibody in detail. Serum from one patient reacted with a 48-kilodalton protein, but sera from the other two patients failed to react with the mitochondrial proteins. There was a marked improvement in liver function test results after prednisolone treatment. Before treatment, liver biopsy in all three patients showed histological features of primary biliary cirrhosis with hepatocellular necrosis. Repeat biopsy during treatment showed marked amelioration of hepatocellular damage in all three patients, although bile duct involvement persisted in two patients. These findings suggest that prednisolone is an effective treatment for hepatocellular damage in patients with autoimmune cholangiopathy, but has little impact on the bile duct involvement.

The Seroepidemiology of Hepatitis A and B in a Japanese Town

Sera collected from 1, 118 healthy children and adults aged between four years and 90 years during the period 1989 to 1990, were tested for serological markers of hepatitis A virus (HAV) [antibody to HAV(anti-HAV)] and hepatitis B virus (HBV) [hepatitis B surface antigen (HBsAg) and antibody to hepatitis B surface antigen (anti-HBsAb)]. The overall prevalence rates of anti-HAV, HBsAg, and anti-HBV were 20.2%, 0.36%, and 5.1%, respectively. No body was found to be positive for anti-HAV below 30 years of age but more than 70% of the adults aged 50 years or over were positive for anti-HAV. The level of exposure of HAV infection is declining in Japan and paradoxically at the same time a vast majority of people are becoming susceptible to more severe illness. The fall in prevalence of HBsAg possibly represents the positive impact of ongoing vaccination programs and other preventive measures against HBV.

Seroepidemiolgy of hepatitis viruses of chronic liver diseases in Bangladesh: high prevalence of HCV among blood donors and healthy person

Abstract Forty eight (9.7%) and 27 (5.5%) of 495 apparent healthy persons and 15 (18.8%) and five (6.2%) of 80 blood donors from Dhaka, Bangladesh were found to be infected with hepatitis B virus (HBV), and hepatitis C virus (HCV), respectively. Five apparent healthy persons and two blood donors were infected with both HBV and HCV. Genotyping in 20 anti-HCV positive sera revealed that 13 (65%) had genotype 1b and the rest, seven (35%) had genotype 2a. These data suggest that several million people of Bangladesh being unaware of their infective conditions has been carrying hepatitis viruses that may lead to chronic liver diseases such as liver cirrhosis and hepatocellular carcinoma. As HCV genotype 1b was prevalent among HCV-carriers in Bangladesh, interferon should be used cautiously for type C hepatitis until facilities for quantification or genotyping of HCV become possible.

Drug-induced hepatitis with severe cholestasis due to voglibose

Abstract A case of drug-induced hepatitis with severe cholestasis caused by voglibose, a new agent for treating noninsulin-dependent diabetes mellitus, is described. The patient presented with icterus and pruritis. Voglibose was administered for 3 months before abnormal liver function was detected. The lymphocyte blast transformation test was positive for voglibose (stimulation index = 536%). One month after the onset of icterus, the patient also developed cholangitis due to methicillin-resistant Staphylococcus aureus , and the serum total bilirubin level increased to above 40 mg/dl. He was treated with plasma exchange, but eventually died. Voglibose is only absorbed slightly after oral administration, and there have been no reports of hepatitis due to this drug. This is the first fatal case of voglibose-induced hepatitis combined with methicillin-resistant Staphylococcus aureus cholangitis.

Lymphoid dendritic cells in the liver of patients with primary biliary cirrhosis and its mouse model

Abstract An immunohistochemical survey of lymphoid dendritic cells (LDC), the most efficient antigen-presenting cells, was performed in human primary biliary cirrhosis (PBC) and in a mouse model of PBC, in order to clarify their relevance to the disease. Infiltration of interdigitating DC (IDC), a kind of LDC, into portal areas was observed throughout the progress of human PBC, but was most prominent at the beginning of the disease. The IDC expressed HLA DR and co-stimulatory molecules, B7-1 and B7-2. Likewise, N418 positive mouse LDC were found to be localized in portal areas in senescent female C57BL/6NCrj mice that spontaneously develop PBC-like liver disease. LDC were frequently observed close to the bile duct epithelia. In contrast, accumulation of LDC in portal areas was not observed in young female mice of the same strain or senescent mice of other strains which do not develop the disease. Double staining studies clarified that the LDC express MHC class II and B7-1 and B7-2, and electron microscopy studies further revealed that LDC make contact with lymphocytes. Taking these findings into account, it is conceivable that LDC infiltrate into the liver, present some unknown antigens on their surfaces, and sensitize T-cells which may eventually induce bile duct injury in PBC.