Biomedical subjects

T Scholl

Publications and source records attributed to T Scholl.

29 records · Page 2Linked to original sources

PubMed1995

Cooperativity between the J and S elements of class II major histocompatibility complex genes as enhancers in normal and class II-negative patient and mutant B cell lines.

The class II major histocompatibility complex genes all contain in their proximal promoters three cis-elements called S, X, and Y that are conserved in both sequence and position, and a fourth element, J, conserved in sequence but not in position. J, X, and Y and, to some extent, S, have been shown to be functionally important in regulation of expression of these genes. In the present study, a protein factor that binds cooperatively to the S plus J elements of the promoter of the class II major histocompatibility complex gene DPA has been detected. Moreover, functional cooperativity between S and J in activation of the enhancerless -40 interferon-beta (-40 IFN-beta) promoter has been demonstrated. Finally, the latter assay appears to subdivide complementation group A of class II negative human B cell lines that includes both mutants generated in vitro and cells from patients with the bare lymphocyte syndrome (type II). In three of these cell lines, the enhancerless -40 IFN-beta promoter containing the S plus J elements was functionally active, while in the others it was inactive.

B-Lymphocytes↗

PubMed1994

A factor that regulates the class II major histocompatibility complex gene DPA is a member of a subfamily of zinc finger proteins that includes a Drosophila developmental control protein.

A novel DNA sequence element termed the J element involved in the regulated expression of class II major histocompatibility complex genes was recently described. To study this element and its role in class II gene regulation further, a cDNA library was screened with oligonucleotide probes containing both the S element and the nearby J element of the human DPA gene. Several DNA clones were obtained by this procedure, one of which, clone 18, is reported and characterized here. It encodes a protein predicted to contain 688 amino acid residues, including 11 zinc finger motifs of the C2H2 type in the C-terminal region, that are Krüppel-like in the conservation of the H/C link sequence connecting them. The 160 N-terminal amino acids in the nonfinger region of clone 18 are highly homologous with similar regions of several other human, mouse, and Drosophila sequences, defining a subfamily of Krüppel-like zinc finger proteins termed TAB (tramtrack [ttk]-associated box) here. One of the Drosophila sequences, ttk, is a developmental control gene, while a second does not contain a zinc finger region but encodes a structure important in oocyte development. An acidic activation domain is located between the N-terminal conserved region of clone 18 and its zinc fingers. This protein appears to require both the S and J elements, which are separated by 10 bp for optimal binding. Antisense cDNA to clone 18 inhibited the expression of a reporter construct containing the DPA promoter, indicating its functional importance in the expression of this class II gene.

Amino Acid Sequence↗

PubMed1993

African swine fever virus specific porcine cytotoxic T cell activity.

African swine fever virus (ASFV) specific, cytotoxic T lymphocyte (CTL) activity has been studied in a protection model in which SLA inbred miniature swine are experimentally inoculated with a naturally occurring, non-fatal ASFV isolate (NHV). Peripheral blood mononuclear cells (PBMC) from such infected swine show significant activity in CTL assays, using cultured ASFV-infected porcine blood derived macrophages as target cells. This CTL activity is elicited from PBMC by in vitro restimulation of effector cells with low doses (multiplicity of infection = 0.1) of the homologous virus isolate for 48 to 72 h. For SLAc/c effectors, this CTL activity appears to be SLA class I restricted because (1) blocking target cell antigens with monoclonal antibodies (mAb) against SLA class I antigens causes a major reduction in CTL activity; (2) there is preferential lysis of SLA class I matched, ASFV infected targets; and (3) depletion of effector cells with CD8 specific mAb and complement causes a reduction in CTL activity. The CTL activity is ASFV specific for all pigs tested in that infected macrophages are preferentially lysed as compared to normal (non-infected) cultured macrophages or macrophages infected with hog cholera virus (HCV). Lysis of macrophages infected with different ASFV isolates revealed that there is marked lysis of macrophages infected with the virulent L60 isolate but less lysis of macrophages infected with the DR-II and Tengani isolates. In summary, our data show that ASFV specific CTL activity is triggered in swine infected with the NHV ASFV isolate.

African Swine Fever Virus↗

PubMed1992

2-[(2-pyridylmethyl)sulfinyl]-1H-thieno[3,4-d]imidazoles. A novel class of gastric H+/K(+)-ATPase inhibitors.

2-[(2-Pyridylmethyl)sulfinyl]thienoimidazoles were synthesized and investigated as potential inhibitors of gastric H+/K(+)-ATPase. The [3,4-d] isomers of the two possible thienoimidazole series were found to be potent inhibitors of gastric acid secretion in vitro and in vivo. Structure-activity relationships indicate that especially lipophilic alkoxy, benzyloxy, and phenoxy substituents with additional electron-demanding properties in the 4-position of the pyridine moiety combined with an unsubstituted thieno[3,4-d]imidazole lead to highly active compounds with a favorable chemical stability. Various substitution patterns in the thieno[3,4-d]imidazole moiety result in lower biological activity. The heptafluorobutyloxy derivative saviprazole (HOE 731, 5d) was selected for further development and is currently undergoing clinical evaluation. Comprehensive pharmacological studies indicate a pharmacodynamic profile different to omeprazole, the first H+/K(+)-ATPase blocker introduced on the market.

Animals↗

PubMed1992

Hypomethylation of MHC class II Eb gene is associated with expression.

Methylation patterns in the major histocompatibility complex (MHC) class II Eb locus have been analyzed in cell lines representative of different cell types; in particular those with phenotypes found at various stages of B cell development. A series of variant B cell lymphoma lines which serves as a model in which to investigate mechanisms regulating class II gene expression in normal peripheral B cells has been examined. Eb methylation patterns have also been determined in various healthy mouse tissues. The pattern of methylation of the Eb locus varies between different cell lines and tissue types such that hypomethylation is associated with gene expression. There appears to be a methylation pattern which is permissive for class II gene expression and which is characteristic of a variety of cell lines, but is lost in cell lines representing terminally differentiated class II nonexpressing plasma cells. Another methylation pattern has been identified which is found in cloned cell lines selected for expression of very high levels of cell surface class II product. The patterns of methylation associated with MHC class II expression involve changes in methylation sites located within the first intron and several kilobase pairs 5' of the promoter, but no changes were observed in the 3' end of the locus. Moreover, the different methylation patterns do not map to the prominent CpG rich cluster located 5' of the Eb promoter and which remains completely methylated regardless of transcriptional status.

Animals↗

PubMed1991

Gastric acid inhibitory profile of saviprazole (HOE 731) compared to omeprazole.

Saviprazole (HOE 731), a substituted thienoimidazole, caused a dose-dependent inhibition of gastric acid secretion in dogs and rats with ID50 values which were not significantly different from that of omeprazole indicating that both compounds are equally effective. The duration of action in dogs lasted for more than 24 h and was dependent on the state of stimulation. Measurement of serum concentrations of 1 mg/kg saviprazole after intravenous or intraduodenal administration revealed a bioavailability of about 60% in dogs. The elimination half-life was about 30 min following both routes of administration. In rats basal acid secretion was inhibited by saviprazole. In addition stimulation of acid secretion by histamine, desglugastrin, carbachol and isobutylmethylxanthine-forskolin was equally inhibited. This was in agreement with the known mechanism of action, inhibition of the gastric proton pump which is the last step of acid secretion within the parietal cell. Surprisingly, at high dose levels, saviprazole differed from omeprazole. After saviprazole, 1 mg/kg i.v. to dogs, acid output dropped to zero but recovered within 30 min to a level of 90%, whereas omeprazole depressed acid output completely over the whole observation period (4.5 h). Similar results were obtained in pylorus-ligated rats.

Animals↗

PubMed1990

The inhibitory effect of HOE 731 in isolated rabbit gastric glands.

HOE 731, a substituted thienoimidazole derivative, was studied on [14C] aminopyrine uptake and oxygen consumption in isolated rabbit gastric glands. HOE 731 caused a concentration-dependent inhibition of [14C]aminopyrine uptake during histamine and dbcAMP stimulation. The inhibition during dbcAMP stimulation was in accordance with its proton-pump inhibiting properties, which has already been reported. (Herling et al., Gastroenterology 96: A206, 1989). IC50 values were during histamine stimulation 0.8 +/- 0.3 microM and during dbcAMP stimulation 1.3 +/- 0.4 microM. The inhibition was reversible after addition of dithioerythritol and was of a non-competitive type. Omeprazole caused similar inhibitory effects in the same concentration-range. During time-course studies in glands, the inhibitory effect on [14C]aminopyrine uptake of 0.1 microM HOE 731 already appeared after 10 min of incubation but decreased with increasing incubation time, while 0.1 microM omeprazole caused an unchanged inhibition which started after 30 min of incubation. The concentration of 3 microM of HOE 731 and omeprazole caused a comparable constant inhibition. After pre-incubation for 135 min under basal conditions with subsequent stimulation of the glands with dbcAMP, the inhibitory effect of 10 microM HOE 731 also decreased in contrast to omeprazole. During stimulation for 4 hr, the inhibition of both compounds remained constant. In oxygen consumption studies HOE 731, at 100 microM, caused a strong inhibition down to basal values. This inhibitory effect could be prevented totally when 10 mM imidazole was added to neutralize the acidic compartment of the parietal cell during stimulation. It is concluded that HOE 731 needs acid-activation like omeprazole to inhibit the proton pump, but probably due to its chemical differences (stability, pH for conversion of HOE 731 to its active form) it shows a different inhibitory profile (faster transformation into its active moiety with faster onset of a partially reversible inhibition) as compared to omeprazole.

Adenosine Monophosphate↗

PubMed1990

Antiviral activity and pharmacokinetics of HOE 602, an acyclic nucleoside, in animal models.

The acyclic nucleoside derivative HOE 602 (2-amino-9-[1,3-bis(isopropoxy)-2-propoxymethyl]purine) was evaluated for its antiviral activity in cell culture and for its therapeutic efficacy in mice infected with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) or with murine cytomegalovirus (MCMV). HOE 602 was inactive in vitro against a variety of DNA- and RNA-viruses. However it prevented symptoms and mortality in mice systemically infected with HSV-1, HSV-2 or MCMV when administered intraperitoneally or orally at a dosage of 100 mumol/kg twice per day. Pharmacokinetic studies in mice and macaques revealed that HOE 602 was converted via three metabolic steps to ganciclovir, which seemed to be the antivirally active compound. The bioavailability of ganciclovir after oral administration of HOE 602 or ganciclovir was similar in mice, while in rhesus monkeys much higher serum levels of ganciclovir were reached with HOE 602. After intraperitoneal or intravenous administration higher drug levels were obtained with ganciclovir. The excellent therapeutic efficacy in animal models, the high enteral absorption in monkeys, and the favourable physical properties will hopefully lead to an orally active drug against cytomegalovirus and severe herpes infections in man.

Acyclovir↗

PubMed1989

Virus-specific cellular blastogenesis and interleukin-2 production in swine after recovery from African swine fever.

Animals recovered from viral diseases represent an important model to study the host cellular and humoral immune responses to the etiologic agents. This is particularly important for African swine fever virus (ASFV) infections in which antibodies have little or no virus-neutralizing effect. Pigs surviving experimental infection with the naturally occurring low-virulent, nonhemadsorbing ASFV/NH/P68 (NHV) isolate did, however, exhibit virus-specific T-cell activities, as measured by a variety of assays. A strong virus-induced, antigen-specific blastogenic response was observed only with blood mononuclear cells (BMC) from ASF-recovered swine, whereas cells from recovered and naive swine responded similarly to the mitogens concanavalin A and phytohemagglutinin. The ASFV-induced blastogenesis was dependent on virus dose and on the presence of adherent cells. Blood mononuclear cells cultured with antigenically related hemadsorbing ASFV isolates of different virulence characteristics, the highly virulent L60 isolate and moderately virulent DRII isolate, exhibited a similar magnitude of blastogenesis to cells infected with the low-virulent NHV isolate. Virus-infected cells proved to be an efficient inducer of interleukin-2 (IL-2) activity to cells from recovered swine, but not from naive swine, whereas T-cell-specific lectins induced production of similar amounts of IL-2 activity from cells of naive and recovered swine. Correlated with the appearance of virus-induced IL-2 activity in the culture supernatant was the induction of promiscuous killing in cells exposed to prolonged (7 days) virus stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

African Swine Fever↗

PubMed1982

Leukemia and other cancers, anomalies and infections as causes of death in Down's syndrome in the United States during 1976.

All 995 persons with Down's syndrome who died in the United States during 1976 and whose death certificates listed Down's syndrome as the underlying or a contributing cause of death were identified. This allowed the underlying causes of death of 793 affected persons to be analysed and compared to deaths in the whole US population for that year. Mortality ratios provided evidence that the excess risk of leukemia mortality continues into adulthood and that deaths from other hematopoietic malignancies also occur excessively among Down's syndrome adults. Congenital anomalies of all kinds in infancy and congenital defects of the heart in infancy and later were also excessive. Respiratory tract infections and pneumonia showed persistently high ratios. Diabetes was raised only at ages 24 to 34 years. Ischemic heart disease, non-hematopoietic cancers, accidents, suicides and violence were under-represented among the causes of death. Methodological limitations of proportional mortality analysis are discussed.

Abnormalities, Multiple↗

PubMedDate not supplied

Modulation of porcine peripheral blood-derived macrophage functions by in vitro infection with African swine fever virus (ASFV) isolates of different virulence.

Macrophages play an important role in defense against invading pathogens and neoplastic diseases. Their ability to maintain their functional characteristics is also important in the survival of the host. Loss of macrophage function during infection may be important in determining resistance or susceptibility of a host species. In this communication, we describe the effect of ASFV replication, in macrophages in vitro, on the functional characteristics of these cells. Infection with ASFV did not alter the expression of Fc receptors nor their ability to mediate ADCC. However, African swine fever virus was shown to modulate antibody mediated phagocytosis, chemiluminescence and chemotaxis. Similar modulation of certain macrophage functions was observed with ASFV isolates that differed in their virulence. We were therefore, unable to correlate the virulence of ASFV with the ability to alter macrophage function.

African Swine Fever↗