Biotechnology advances have provided novel methods for the risk assessment of chemicals. The application of microarray technologies to toxicology, known as toxicogenomics, is becoming an accepted approach for identifying chemicals with potential safety problems. Gene expression profiling is expected to identify the mechanisms that underlie the potential toxicity of chemicals. This technology has also been applied to identify biomarkers of toxicity to predict potential hazardous chemicals. Ultimately, toxicogenomics is expected to aid in risk assessment. The following discussion explores potential applications and features of the Japanese Toxicogenomics Project.

The serology of chronic hepatitis B infection has been established through the use of commercial immunoassays to measure the structural antigens of the hepatitis B virus and their respective antibodies in serum. However, the commercial assays have not been designed to detect serum antibodies in the presence of an excess of circulating antigens. A series of serum samples from 200 HBeAg-positive, chronically infected hepatitis B patients with varying degrees of liver disease were analyzed using novel immunoassays designed to detect antibodies in the presence ofcirculating viral antigens. All patients, regardless of their liver disease, were seronegative for antibodies specific for the envelope antigens or the secreted nucleoprotein antigen (HBeAg) when the commercial assays were used. In contrast, virtually all chronically infected patients with liver disease and 50% of patients without liver disease demonstrated anti-HBe and anti-envelope antibodies when sera were tested in the more sensitive immunoassays. Furthermore, asymptomatic patients could be serologically distinguished from symptomatic patients based on antibody fine specificity, titer, and IgG subclass. This study revealed that the majority of chronically infected hepatitis B patients produce a variety of antibodies for many years, and are not immunologically unresponsive, as suggested by the current assays. (J. Clin. Invest. 1993Invest. . 91:2586Invest. -2595

In order to find out whether high intensity focused ultrasound (HIFU) might be useful against hepatocellular carcinoma, we analyzed the effect of a microbubble agent (Levovist) on the temperature rise and tissue necrosis induced by HIFU. Rabbits were given 7 ml Levovist (300 mg/ml) or saline intravenously. Up to six areas per rabbit liver were exposed to HIFU for 60 s (2.18 MHz, I(SPTA)=400 W/cm(2)). The volume of the tissue coagulated by HIFU was measured 10 min after the start of HIFU. HIFU-induced lesions were larger in the animals given Levovist: (mm(3), Levovist versus saline) 371+/-104 versus 166+/-71 (P<0.001). Temperatures in the animals given Levovist were also higher 60 s after the start of exposure: ( degrees C, Levovist versus saline) 20.3+/-3.5 versus 13.2+/-3.8 (P<0.001). The amount of damage differed greatly, but the pathological changes caused by HIFU with Levovist were the same as those caused by HIFU with saline. Hemorrhagic areas and implosion cysts were seen, and many cells had been disrupted or destroyed. Microbubble agents developed for diagnostic uses could also be used in anticancer therapy.

No abstract

No abstract

No abstract

No abstract

Studies in hepatitis B e antigen (HBeAg)-expressing transgenic mice indicate that self tolerance to two T-cell determinants on the same transgenic self molecule can differ markedly. The dominant T-cell site on HBeAg is tolerogenic, whereas a proportion of T cells recognizing a second T-cell site evade tolerance induction, persist in the periphery, and can be activated in vivo by a single injection of a 12-residue T-cell self peptide. The self-reactive T cells mediate in vivo autoantibody production sufficient to neutralize detection of the autoantigen in serum. Furthermore, autoantibody production can be inhibited by nonself peptides that compete with the self peptide for binding to major histocompatibility complex molecules. This model illustrates that T cells specific for an immunogenic T-cell site on a nonsequestered autoantigen can escape tolerance induction and, more importantly, can mediate autoreactivity in vivo. Furthermore, these results suggest that synthetic T-cell sites may be useful as immunotherapeutic agents for the purpose ofcircumventing nonresponse to HBeAg during persistent hepatitis B virus infection.A central requirement of the immune system is the ability to respond to the universe of nonself antigens while maintaining a lack of immune responsiveness to self components. Mechanisms demonstrated to account for the maintenance ofT-cell self tolerance include: clonal deletion (1-3) and clonal anergy (4-6) of autoreactive T cells. A prediction of a clonal deletion model oftolerance is that the affinity ofthe T cell for its ligand will influence the deletion process such that T cells with low affinity for self antigen may escape deletion (7). Recent studies in several neonatal tolerance (8, 9) and transgenic (Tg) (10-13) models are consistent with this prediction. Residues 120-140 of the hepatitis B e antigen (HBeAg) make up the predominant T-cell recognition sites for the B1O.S [e-(120-131)] and B10 [e-(129-140)] murine strains (14). Neonatal injection of e-(120-140) into B1O.S mice resulted in complete T-cell tolerance to the e-(120-131) determinant and to the entire native HBeAg. In contrast, e-(120-140) was immunogenic but not tolerogenic in the B10 strain. Injection of e-(120-140) into (B10 x B1O.S)F1 neonatal mice tolerized e-(120-131)-specific I-As-restricted T cells but not e-(129-140)-specific