Both donor and recipient adhesion molecules play a crucial role in inducing rejection of rat xenogeneic islets in mice.
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Biomedical subjects
Publications and source records attributed to Y Ohta.
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Germinal centers (GC) are the sites of antigen-driven B cell switch recombination, V(D)J gene hypermutation, and selection to generate high-afinity CD38+ memory B cells. A marked expansion of GC associated with hypergammaglobulinemia followed by complete disruption of normal splenic architecture and a striking drop in immunoglobulin levels are prominent features of the murine retrovirus-induced immunodeficiency syndrome, MAIDS. B cell lymphomas are frequent in long-term infected mice. Normal GC formation is critically dependent on a number of genes including the transcription factor, Bcl6. Deregulated expression of BCL6 protein has been implicated in the development of human and mouse B cell lymphomas. Another nuclear protein, SWAP-70, has been identified as a subunit of the protein complex, SWAP, that recombines switch regions in vitro. To develop a fuller understanding of B cell biology in MAIDS, we examined the characteristics of BCL6, SWAP-70, CD38, and peanut agglutinin (PNA)-staining cells during the course of the disease. The levels of both nuclear proteins increased rapidly until 6-8 weeks after infection. During this time frame, BCL6 was expressed at highest levels in the usually rare CD4+ Thyl- T cell subset as well as in B cells. At later times. BCL6 levels dropped to undetectable levels while SWAP-70 levels continued to increase. Changes in the levels of either protein could not be ascribed to transcriptional regulation. PNA-reactive cells decreased in concert with BCL6 while CD38 staining increased with SWAP-70. These results demonstrate that progression of MAIDS results in the massive accumulation of B cells with the morphology of secretory cells that behave like post-GC cells for expression of BCL6 and CD38, and for PNA-staining but with abnormally high-level expression of SWAP-70.
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Withdrawal of sex hormones by gonadectomy results in rapid involution of mouse reproductive organs. To study the regression mechanism in the uterus and vagina after ovariectomy, histologic and biochemical changes were examined. Apoptotic cells were detected by in situ 3'-DNA nick end labeling method and electron microscopy, while the number of cells showing incorporation of bromo-deoxyuridine (BrdU) decreased in the uterus and vagina after ovariectomy. DNA fragmentation in the uterus was observed even at estrus and the degree of fragmentation increased after ovariectomy. DNA fragmentation in the vagina occurred 1-5 days after ovariectomy. Semi-quantitative RT-PCR revealed that expression of Fas-ligand and tumor necrosis factor-alpha (TNF-alpha) mRNA in the uterus and vagina was increased by ovariectomy. These results suggest that apoptotic cell death is induced by ovariectomy through the mediation of both Fas and TNF-alpha in the mouse uterus and vagina; however, uterine and vaginal cells in CBA lpr(cg)/lpr(cg) mice lacking functional Fas showed apoptosis, indicating that Fas is not the sole regulator of apoptosis in female reproductive organs in mice.
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The effects of dietary arachidonic acid-rich oil (AAoil) on lipids and arachidonate metabolites in the liver and plasma were evaluated in ethanol-treated rats. Rats were fed a purified diet containing 10% weight of lard or AAoil for 14 days. Ethanol was administered by gavage at a single daily dose of 3 g/kg body weight. Comparing with the lard group, a decrease was observed in liver fatty vacuoles in the AAoil group. Plasma 6-keto-prostaglandin (PG) F1 alpha and thromboxane (TX) B(2)levels and the 6-keto-PGF1 alpha/TXB(2)ratio increased significantly in the AAoil group. Liver 6-keto-PGF1 alpha also increased but not leukotriene B(4)in the AAoil group. In the phospholipid fraction of liver tissue, plasma and red blood cells, arachidonic acid (20:4n-6) and docosatetraenoic acid (22:4n-6) increased and oleic acid (18:1n-9) and linoleic acid (18:2n-6) decreased significantly in the AAoil group compared with the lard group. These observations suggest that AAoil supplementation reduces liver injury of ethanol-treated rats, although longer observation will be necessary for confirmation.
An Electron Spin Resonance measurement was conducted on black dust deposited in autopsied human lungs. Free radicals were detected in all specimens examined, and the spectra indicated the presence of two types of radicals, both of which are apparently singlet lines. The amount of the respective component differed from sample to sample. The component with the narrower width, 2.7 G, and the smaller g factor, 2.0025, is attributable to carbon radicals associated with the combustion of hydrocarbons, and especially its relevance to the experience of smoking was inferred. The other component, with a width of about 10 G and g factor fo 2.0037, was found to be more common among the specimens. The assignment of the latter component is not very clear, but an oxygen-related radical is a possible candidate.
We report a case of metastatic pulmonary calcification that showed hyperintense signal on T1-weighted MRI. This uncommon MR appearance of calcification is similar to the MR characteristics of calcification in the brain due to abnormal calcium metabolism.
We present a case with acute radiation-induced hepatic injury using chondroitin sulfate iron colloid (CSIS)-enhanced MRI. Uptake of CSIC was decreased in the irradiated portion of the liver. CSIC-enhanced MRI is useful for obtaining information on the function of the reticuloendothelial system and demarcates between irradiated and nonirradiated zones.
In this study, in addition to studying the efficacy and safety of the once-daily administration of 100-mg capsules of fluconazole over an 8-week administration period with six patients with hyperkeratotic-type tinea pedis, we also measured the serum and horny layer concentrations of fluconazole to study the mobility into the horny layer in diseased areas of the sole skin. The final overall efficacy and overall safety were both 100% (six out of six), and no side-effects, including abnormal laboratory changes, were observed in any of the patients. The drug mobility study revealed that in the horny layer of the skin a steady state was reached after 4 weeks of administration, with the mean concentration being 12.8 micrograms g-1. This concentration was a high concentration that was no less than 13 times the geometric mean MIC (0.972 microgram ml-1) for fresh clinical isolates of Trichophyton rubrum. Based on the above results, fluconazole is considered to be highly useful for treating various kinds of dermatomycosis, including hyperkeratotic-type tinea pedis.
The serum immunoglobulin G (IgG) subclasses were determined in 41 patients with liver cirrhosis (LC) and in 15 normal controls. In 19 cases of LC and in 6 normal controls, the IgG subclasses were also determined in lymphocyte culture supernatants. The determinations were performed by enzyme immunoassay. It was found that the absolute mean IgG1 and IgG3 levels were increased in all LC due to various causes. The mean IgG1 increase was most pronounced in post-hepatitic LC, and the mean percentage of IgG1 to total IgG was also increased in this type of LC in comparison with the normal controls and the other types of LC. The IgG3 fraction was significantly increased in primary biliary cirrhosis (PBC). In alcoholic LC, all IgG subclasses were increased significantly in comparison with normal controls. In lymphocyte culture supernatants from PBC patients, the mean IgG1 and IgG3 levels were increased in supernatants from unstimulated cultures, and the mean IgG1, IgG3, and IgG4 were increased after pokeweed mitogen (PWM) stimulation. In post-hepatitic LC, the mean IgG4 level was increased in both unstimulated culture supernatants and after PWM stimulation. In alcoholic LC, the mean IgG4 level was increased in unstimulated culture supernatants, whereas the mean IgG1 level was increased after PWM stimulation. These findings showed that LC of differing aetiologies exhibited different profiles of IgG subclasses. This may be related to the different aetiological agents and the pathogenesis of the different types of LC.
To clarify the prevalence of concurrent infection with hepatitis C virus (HCV), hepatitis B virus (HBV) and human T cell leukaemia virus (HTLV), we measured HCV antibody in the population of a district endemic for HBV and HTLV infection. Blood samples were collected in June 1990 from 579 inhabitants of four islands of Uwa Bay in the southwest of Ehime Prefecture in Japan. Anti-HCV antibody against C100-3 protein was detected using an enzyme-linked immunosorbent assay kit (Ortho Diagnostics). Thirteen of the 579 inhabitants (2.2%) were positive for anti-HCV, and this prevalence rate was not significantly different from the frequency of anti-HCV in Tokyo blood donors. A total of 11% (64 of 579) of the subjects were positive for HBsAg and 3.3% (19 of 579) were positive for anti-HTLV. These frequencies of HBsAg and anti-HTLV positivity were distinctly higher than the respective means of Japanese. All anti-HCV positive individuals were negative for HBsAg and anti-HTLV, while 54% (7 of 13) had increased alanine aminotransferase levels. These data suggest that the prevalence of HCV infection is not high even in an area endemic for HBV and HTLV infection.
Serum immunoglobulin G (IgG) subclasses of hepatitis B core antibody (anti-HBc) in 54 patients with different types of hepatitis B surface antigen positive (HBsAg+) liver diseases (asymptomatic carrier (ASC), acute hepatitis (AH), chronic hepatitis (CH) and liver cirrhosis (LC)) and 18 normal controls were estimated by enzyme-linked immunosorbent assay (ELISA) using subclass specific anti-human mouse monoclonal antibodies. In 11 cases, the estimations were carried out at both exacerbation and remission stages of chronic active hepatitis (CAH). In 4 cases of CAH, serial observations of anti-HBc IgG subclasses were made according to the clinical course. In 5 cases of CAH, the estimations were carried out at the HBe antigen positive (HBeAg+) stage and after sero-conversion to anti-HBe positive (anti-HBe+) stage. In ASC the main anti-HBc IgG subclasses were restricted to one subclass--anti-HBc IgG1. In AH on the other hand, all the subclasses were represented. In CH all the subclasses were detected under different diagnostic conditions but anti-HBc IgG1 was the main subclass. In LC the mean concentration of anti-HBc IgG3 was higher than the concentration of anti-HBc IgG1. In exacerbation stages of CAH, the different anti-HBc IgG subclasses had higher concentrations than in remission stages. The concentrations of different anti-HBc IgG subclasses fell just after seroconversion from HBeAg+ stage to anti-HBe+ stage. These data suggest that the estimation of anti-HBc IgG subclasses may be helpful in establishing the diagnosis of different types and stages of HBsAg+ liver diseases.
Anti-hepatitis C virus (HCV) immunoglobulin M antibody titres were measured by an enzyme-linked immunosorbent assay method in 16 patients with non-A, non-B acute hepatitis (NANB AH), 13 with non-A, non-B fulminant hepatitis (NANB FH) and nine with type C chronic hepatitis. Anti-HCV IgM was positive in one of the 16 patients with NANB AH, six of the 13 with NANB FH, and five of the nine with type C chronic hepatitis. Anti-HCV IgG was positive in eight of the 16 patients with NANB AH and eight of the 13 with NANB FH. Either anti-HCV IgM or anti-HCV IgG were positive in 10 of the 13 patients with NANB FH. All of the five anti-HCV IgM positive patients with type C chronic hepatitis were undergoing an exacerbation of the diseases, while all of the anti-HCV IgM negative patients were in a remission stage which had lasted for more than 6 months. The findings of this study suggest that anti-HCV IgM is useful for the early diagnosis of type C FH and may be a useful marker of diseases activity in type C chronic hepatitis.
To investigate the decrease in natural killer (NK) activity in chronic liver disease, interleukin-2 receptor beta chain (IL-2R beta) expression was assessed by peripheral blood lymphocytes (PBL) using flow cytometry and an IL-2R beta chain-specific mouse monoclonal antibody. The percentage of IL-2R beta chain-positive PBL was significantly decreased in patients with chronic viral hepatitis, liver cirrhosis and hepatocellular carcinoma in comparison with normal controls (P less than 0.01). Among chronic viral hepatitis patients, it was significantly less in those with chronic active hepatitis than in those with chronic persistent hepatitis (P less than 0.05). Two-colour flow cytometry revealed that the IL-2R beta chain was mainly expressed by CD8+ or CD16+ cells in both the controls and the liver disease patients. CD8dull+ cells (NK cells) constituted more than 60% of the CD8+ cells expressing the IL-2R beta chain. Expression of the IL-2R beta chain with CD8 or CD16 was also significantly decreased in chronic liver disease patients compared with controls. In chronic viral hepatitis, there was a significant correlation between NK activity and the percentage of IL-2R beta+ PBL (P less than 0.001, r = 0.916), as well as between NK activity and the percentage of PBL co-expressing both the IL-2R beta chain and CD16 (P less than 0.001, r = 0.850). These findings suggest that decreased expression of the IL-2R beta chain by PBL may result in diminished NK activity in chronic liver disease.
Three patients with submassive hepatic necrosis developed acute liver failure during the severe reactivation of chronic hepatitis B. The activity of hepatitis B virus (HBV) DNA polymerase increased in all three patients immediately before the onset of hepatic failure. Liver biopsy specimens obtained before and after the episode of submassive hepatic necrosis showed progression to advanced liver cirrhosis. The nucleotide sequences of the precore and core regions of HBV-DNA were investigated in two of the three patients and in another two patients with piecemeal and bridging necrosis. The nucleotide and amino acid sequences of the HBV-DNA core region changed after reactivation in the the two patients with submassive hepatic necrosis, while the sequences in the other two patients with piecemeal necrosis remained unchanged before and after reactivation. These results suggest that the antigenicity of the HBV-DNA core region may have been changed before and after severe reactivation. Due to mutation at the core region, a different type of epitope would be expressed on the hepatocytes after submassive hepatic necrosis, which would not be a target for the cytotoxic T cell. This was evident by the continuation of the normal serum GPT for 5 and 9 years, respectively.
The biliary lesions that developed spontaneously in senescent female C57BL/6NCrj mice were investigated. Degeneration of the bile duct epithelium was observed in 12 of 13 mice (92%), destruction of bile duct epithelial cells was seen in six of 13 mice (46%) and chronic non-suppurative destructive cholangitis was found in three of 13 mice (23%). The biliary lesions were characterized by prominent round cell infiltrates in the portal areas. Extra-hepatic lesions such as sialoadenitis were observed in six mice (46%) and pancreatis in seven (53%). IgM class antipyruvate dehydrogenase antibody was positive in one of three C57BL/6NCrj mice not given anti-Lyt 2 antibody and in three of six C57BL/6NCrj mice injected with anti-Lyt 2 antibody. These lesions were not observed in male C57BL/6NCrj mice, young female C57BL/6NCrj mice, or ICR mice. However, by transferring the splenic cells of senescent female C57BL/6NCrj mice to 6 week old females, the biliary lesions could be transferred at the rate of 6/9. The lymphocytes infiltrating in the bile ducts were CD8 positive lymphocytes. Moreover, in the ultrastructural immunocytochemical analysis of lymphocytes infiltrating bile duct epithelia, CD8 positive lymphocytes often formed broad contacts with the epithelial cells. The biliary lesions developing spontaneously in these mice are similar to those found in human primary biliary cirrhosis.
Ovarian involvement as an initial manifestation of lymphoma, without detectable extraovarian disease, is a rare occurrence. The diagnosis of ovarian lymphoma is almost invariably unsuspected until the tumor has been examined histologically. A 25-year-old null gravid woman presented with abdominal distension. Presence of abnormal lymphoid cells in pleural effusion led to presurgical assumption that the pelvic mass noted on computerized tomography examination might be an ovarian lymphoma. We performed left salpingo-oophorectomy. Clinical, histologic, and molecular examination revealed Burkitt's lymphoma of the ovary with c-myc gene rearrangement and mRNA expression of multiple cytokines. She received dose-intensified combination chemotherapy. She is alive and free of disease 30 months after the diagnosis. Immunophenotype and molecular findings allowed reliable discrimination of Burkitt's lymphoma from diffuse large B-cell lymphoma and other lymphomas. If an ovarian tumor is solid and suspected to be of lymphoid origin, we suggest that it is necessary to obtain samples for genetic examination at surgery. This strategy often provides important information to establish therapeutic regimen and predict patient prognosis.