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H Schellekens

Publications and source records attributed to H Schellekens.

At least 73 records · Page 4Linked to original sources
PubMed1987

Mechanism of escape of exoerythrocytic forms (EEF) of malaria parasites from the inhibitory effects of interferon-gamma.

We have studied the mechanism of inhibition by interferon-gamma (IFN-gamma) of the development of exoerythrocytic forms (EEF) of Plasmodium berghei in the livers of rats. At the time corresponding to the maximum development of EEF (44 hr after injection of sporozoites), the livers of the IFN-gamma-treated rats contained less parasite DNA as compared with controls. Twenty-four to 72 hr later, the livers of both groups of animals were free of parasites; that is, IFN-gamma treatment does not delay the development of the EEF. The decrease in parasite DNA observed in the IFN-gamma-treated rats was due to a diminution in the number, but not the size, of EEF. It appears, therefore, that treatment with the lymphokine either destroys the parasites or does not affect their replication. To study the mechanism of resistance to IFN-gamma of a small population of EEF, we subjected the parasites to four cycles of selection by IFN-gamma. The parasites from the "selected" and "nonselected" populations were equally susceptible to inhibition by IFN-gamma, indicating that the escape from IFN-gamma activity is not inherited.

Animals↗
PubMed1987

Protective immunisation against hepatitis B with an internal antigen of the virus.

Preparations of hepatitis B virus (HBV) core antigen (HBcAg) synthesised in Escherichia coli have been shown previously to confer partial immunity against infection by the virus [Murray, Bruce, Hinnen, Wingfield, van Eerd, de Reus, and Schellekens: EMBO Journal 3:645-650, 1984]. In a further experiment reported here, immunisation of chimpanzees with a similar preparation of HBcAg that had been treated with sodium dodecyl sulphate in order to expose e antigen epitopes was found to protect one animal completely and another quite substantially upon challenge with the virus. The results are used to support the argument for trials in humans of a vaccine against HBV based upon or containing HBcAg and its e antigen derivative, and in discussion of a more general role for internal antigens in generating immunity against viral infection.

Animals↗
PubMed1987

Impact of class II major histocompatibility complex antigen expression on the immunogenic potential of isolated rat vascular endothelial cells.

We have investigated the immunogenic potential of rat heart vascular endothelial cells by their ability to induce an accelerated rejection of a relevant heart allograft, and related the immunogenic potential to the expression of class II major histocompatibility complex (MHC) antigens on the endothelial cell surface. Only 12% of freshly isolated rat vascular endothelial cells express class II antigens in serum-free medium, and the level of expression is low as judged by immunoperoxidase staining and/or the ability of endothelial cells to bind staphylococci to the cell surface after treatment with monoclonal antibodies to the class II molecule. On the other hand, 99% of the endothelial cells under the same conditions express class I, and the level of expression is high. The class II antigen expression of vascular endothelial cells can be upregulated to more than 98% by recombinant gamma-interferon in vitro--and, concomitantly, the level of expression becomes high, even on the cell surface. Treatment with gamma-interferon did not substantially alter the level of class I expression. The endothelial cells expressing class II antigens weakly, are also weakly immunogenic in vivo: 10(7) endothelial cells are required to reduce the graft survival by 50% of that of the unprimed host. On the contrary, the endothelial cells of the same lineage induced to express class II antigens by gamma-interferon in vitro are highly immunogenic in vivo, as immunogenic as freshly-isolated spleen dendritic cells: only 10(4) endothelial cells are required to induce a 50% reduction of graft survival. These observations demonstrate for the first time that rat vascular endothelial cells are immunogenic in a primary transplantation response in vivo--and, moreover, that the immunogenic capacity of the endothelial cells is directly proportional to the extent of class II MHC antigen expression on the cell surface.

Animals↗
PubMed1987

The protection of chimpanzees against hepatitis B viral infection using a recombinant yeast-derived hepatitis B surface antigen.

In order to determine the efficacy of the SmithKline Biologicals recombinant DNA yeast-derived hepatitis B vaccine in inducing protection against hepatitis B infection, two chimpanzees were injected intramuscularly with 20 micrograms according to a 0-, 1-, and 2-month schedule. After the second dose, the vaccinated animals already showed a significant antibody response. One month after the last injection, the animals were challenged with hepatitis B virus. The vaccinated animals were protected while the two unvaccinated controls showed all signs of hepatitis B infection. One year after vaccination, antibodies remained high and were comparable with levels produced by plasma-derived vaccines.

Animals↗
PubMed1986

Antagonistic effects of gamma interferon and steroids on tissue antigenicity.

A single injection of 10(5) U/kg of recombinant rat IFN-gamma increases the amount of tissue dendritic cells up to sixfold, and concomitantly induces the (capillary) endothelial cells to express class II MHC antigens. Both responses peak on the third day after IFN-gamma injection, and the antigen expression returns to basic levels on day 7. Simultaneous administration of 1 mg/kg/d of methylprednisolone entirely abolishes both responses. These observations demonstrate, for the first time, that IFN-gamma and steroids have antagonistic effects on class II MHC antigen presentation in tissue, and suggest that one immunosuppressive mechanism of glucocorticosteroids in organ transplantation is downregulation of graft antigenicity.

Animals↗
PubMed1986

Inhibition of development of exoerythrocytic forms of malaria parasites by gamma-interferon.

A specific DNA probe was used to study the effect of recombinant rat, mouse, and human gamma-interferon (gamma-IFN) on the course of sporozoite-induced malaria infections. In mice and rats infected with sporozoites of Plasmodium berghei, mouse and rat gamma-IFN's strongly inhibited the development of the exoerythrocytic forms in the liver liver cells of the hosts, but not the development of the erythrocytic stages. The degree of inhibition of the exoerythrocytic forms was proportional to the dose of gamma-IFN administered, but was independent of the number of sporozoites used for challenge. A 30 percent reduction in the development of exoerythrocytic forms in rat liver was achieved when 150 units (about 15 nanograms of protein) of rat gamma-IFN were injected a few hours before sporozoite challenge; the reduction was 90 percent or more with higher doses of gamma-IFN. The effect was less pronounced if the gamma-IFN was administered 18 hours before or a few hours after challenge. Human gamma-IFN also diminished the parasitemia in chimpanzees infected with sporozoites of the human malaria parasite Plasmodium vivax. The target of gamma-IFN activity may be the infected hepatocytes themselves, as shown by in vitro experiments in which small doses of the human lymphokine inhibited the development of exoerythrocytic forms of Plasmodium berghei in a human hepatoma cell line. These results suggest that immunologically induced interferon may be involved in controlling malaria infection under natural conditions.

Animals↗
PubMed1986

Identification and transmission of hepatitis B virus-related variants.

We have identified long-incubation viral agents that share epitopes with hepatitis B virus (HBV). During chimpanzee infectivity studies, these agents may be recognized in the liver since they possess complementary nucleic acid sequences with HBV DNA; the genomic size was found to be 3.2 kilobases, identical to that of HBV. Liver injury was produced and there was antigen expression in hepatocytes. Chimpanzees were not protected by prior immunization with hepatitis B surface antigen; conversely, they were still susceptible to HBV after recovery from infection with such agents. These findings suggest that these hepatitis B virus-related variants appear to be immunologically distinct from HBV.

Animals↗
PubMed1986

Concomitant enhancement of a cytoskeleton-associated 76,000-dalton protein and inhibition of fluid-phase pinocytosis by interferon-alpha in Fujinami sarcoma virus-transformed rat 3Y1 cells.

Addition of rat interferon-alpha (IFN-alpha) to Fujinami sarcoma virus-transformed rat 3Y1 cells progressively inhibited fluid-phase pinocytosis [10% inhibition at 3 h; maximal (60%) inhibition by 12 h]. Electrophoretic analysis of the cytoskeletal fraction from cultures exposed to IFN for 24 h revealed a novel 76,000-dalton protein (CKp76). The kinetics of its appearance paralleled the inhibition of fluid-phase pinocytosis. CKp76 was not detected in cultures pretreated with actinomycin D, or prelabeled with [35S]methionine, prior to IFN addition. However, the presence of cycloheximide during incubation with IFN had no effect on the synthesis of CKp76 after removal of both agents. These results suggest that the appearance of CKp76 was due to enhanced transcription of its gene in response to IFN. Subcellular fractionation revealed the presence of induced CKp76 in the nuclear pellet. From these results it is possible that CKp76 may be responsible at leat in part for the effects of IFN on fluid-phase pinocytosis.

Animals↗
PubMed1986

The purification and characterization of rat gamma interferon by use of two monoclonal antibodies.

Two mouse monoclonal antibodies, designated DB-1 and DB-2, were isolated and used for the purification and characterization of recombinant rat interferon gamma (rRIF-gamma) derived from Chinese hamster ovary (CHO) cells. The two antibodies belong to different classes (DB-1 is an IgG1 and DB-2 an IgA) and display similar epitope specificities as shown in competition binding experiments. Both antibodies, raised against rRIF-gamma, exhibited high affinity for rat and mouse gamma interferon and efficiently neutralized the antiviral activity of both animal interferon species. Affinity chromatography analysis showed that a column with immobilized DB-1 was capable of complete binding of rat and mouse gamma interferon, both natural and recombinant DNA-derived. As visualized by SDS-polyacrylamide gel electrophoresis and Western blot analysis, the purified rRIF-gamma preparation consisted of at least seven molecular forms with Mr values ranging between 14 000 and 25 000, with a relative abundance of a 18 000 Mr protein. Gel permeation chromatography of crude rRIF-gamma gave coincident peaks of rRIF-gamma proteins (all different forms) and interferon activity corresponding to a Mr value of 45 000. The results suggest that the molecular heterogeneity was due to differential glycosylation and was not the consequence of a proteolytic degradation process.

Animals↗
PubMed1986

Growth inhibition and eicosanoid metabolism in the R3230AC mammary adenocarcinoma by interferon.

The mode of action of rat interferon (IFN) on growth of the R3230AC mammary adenocarcinoma was studied in vivo in Fischer female rats. A dose of 1 X 10(4) units of rat IFN given thrice weekly inhibited the growth of the transplanted mammary tumors. Of the five eicosanoids measured in the tumor, the content of four arachidonate products, prostaglandin (PG) E2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane (TX) B2, was higher in mammary tumors from IFN-treated rats than the control rats. PGE2 was the major eicosanoid. In vitro PG synthesis (PGE1, PGE2, and PGF2 alpha) was lower in tumor microsomes prepared from IFN-treated tumors. These data suggest that the tumor content of four arachidonate products in the IFN-treated tumors was related to the in vivo effects of rat IFN. Indomethacin, a cyclooxygenase inhibitor, also inhibited tumor growth. Furthermore, when indomethacin was administered daily in combination with rat IFN, the tumor-inhibiting effect of rat IFN was reduced. These observations suggest that the effects of eicosanoids appear to be biphasic in this tumor model. Inhibition of arachidonic acid metabolism resulted in tumor growth inhibition, a finding consistent with the view that eicosanoid production is required for tumor enhancement. Conversely, in the experiments with rat IFN, retardation of tumor growth is associated with a greater amount of arachidonic acid metabolism, and indomethacin prevents this effect. Eicosanoids appear to be required for tumor-inhibiting effects of rat IFN, and yet inhibition in vivo of eicosanoid synthesis also resulted in retardation of tumor growth. Although the precise mechanism of action in each situation is unclear, these apparently contradicting results are consistent with the biphasic actions of eicosanoids reported in some normal tissues and transformed tumor cell lines.

Adenocarcinoma↗