Biomedical subjects

R Bleumink

Publications and source records attributed to R Bleumink.

6 recordsLinked to original sources

PubMed2002

Predictive testing for autoimmunity.

Many chemicals, in particular drugs, cause systemic allergy or autoimmune-like disorders. Due to complex pathogenesis and strong dependence on genetic make-up, these immunotoxicological effects are usually missed in standard toxicity testing. Besides, animal studies that demonstrate chemically induced systemic allergy or autoimmune-like disorders are scarce. Here, animal models are presented that would fit into a predictive two-tiered strategy, designed to allow screening for immunostimulatory potential in the first tier, and more elaborate testing for allergenic or autoimmunogenic potential of selected chemicals in the second tier. The popliteal lymph node assay (PLNA), with or without reporter antigens, would fit in the first tier, and relevant route of exposure protocols with selected strains of mice or rats may be further developed to compose the second tier. To date, the relevant route of exposure models mentioned here (with 'normal' inbred mice and/or Brown Norway rats) has been tested with only a few chemicals, and the PLNA, although tested with over 100 chemicals, is not validated as yet. Conceivably, a major challenge in immunotoxicology is to incorporate the present knowledge on chemical-induced systemic allergy and autoimmunity in further development and validation of predictive models and strategies.

Animals↗

PubMed1999

Distinct immunomodulation by autoimmunogenic xenobiotics in susceptible and resistant mice.

HgCl(2) and diphenylhydantoin (DPH) are prototype chemicals associated with diverse (auto)immune effects in genetically susceptible individuals. Both chemicals activate T cells, and the balance of Th1 versus Th2 activation may influence the clinical outcome of exposure. It is unknown which chemically created neoantigens are responsible for Th activation. We therefore investigated the effect of DPH and HgCl(2) on specific responses to TNP-ovalbumin, in mouse strains with varying sensitivity for the adverse effects. HgCl(2) was found to enhance Th2-driven antibody responses in susceptible B10.s, but protective type 1 responses in resistant B10.d2 mice. This was chemical-specific, as DPH enhanced type 2 responses in both strains. DBA/2 mice were relatively unresponsive to HgCl(2), whereas DPH stimulated type 1 responses in these mice. Interestingly, prior exposure to HgCl(2), but not DPH, facilitated IC deposition in B10.s mice only. Thus, we demonstrate that, depending on MHC-II and background genes, HgCl(2) and DPH preferentially adjuvate type 1 or type 2 responses. In case of HgCl(2), the type of response corresponds with susceptibility to antibody-mediated autoimmunity induced by this chemical. In addition, we demonstrate that, within one strain, different autoimmunogenic chemicals can enhance distinct responses to the same antigen.

Adjuvants, Immunologic↗

PubMed1998

Selective immunomodulation by the autoimmunity-inducing xenobiotics streptozotocin and HgCl2.

Exposure to certain drugs and environmental chemicals can provoke the onset of autoimmune disease in susceptible individuals by releasing (self) epitopes for which tolerance has not been established, while simultaneously providing the necessary adjuvant activity. The resulting response type is influenced by the genotype of exposed individuals and relates to susceptibility to the adverse immune effects of the chemicals. Here, we assessed the modulatory role of the chemical compounds themselves. A single injection of streptozotocin (STZ) increased the number of CD8+ cells, macrophages, apoptotic cells, and IFN-gamma-producing T helper and T cytotoxic cells, whereas the number of CD4+ cells and B cells was reduced in the draining lymph node. Coinjection with the reporter antigen TNP-OVA resulted in primary and secondary production of TNP-specific antibodies that were predominantly of IgG2a and IgG2b isotype, whereas STZ did not enhance priming for delayed-type hypersensitivity (DTH) responses to TNP-OVA. Injection of HgCl2 on the other hand, reduced the number of IFN-gamma-producing cells, induced accumulation of B cells and CD4+ and CD8+ T cells, enhanced IgG1 and IgE production to TNP-OVA, and primed for secondary IgG1 and IgE production as well as for DTH reactions. Together these results indicate that a single injection of STZ stimulates type-1 responses, whereas HgCl2 enhanced mixed type-1 and -2 responses in BALB/c mice. These response types match the (auto)immune effects elicited to unknown (auto)antigens following multiple injections of these chemicals.

Adjuvants, Immunologic↗

PubMed1996

Local popliteal lymph node reactions to hexachlorobenzene and pentachlorobenzene: comparison with systemic effects.

The effects of the presumed autoimmunogenic chemical hexachlorobenzene (HCB), and the closely related non-autoimmunogenic pentachlorobenzene (PCB) in the local popliteal lymph node assay (PLNA) were investigated. To that end 1-5 mg of HCB, equimolar amounts of PCB or the vehicle only, were injected into the hind footpads of rats or mice, and the reaction in the draining lymph node was evaluated on days 7 and 21 after injection. PLN were isolated, weighed, and cell suspensions were prepared to determine PLN cell numbers, and antibody production of PLN cells with an ELISPOT assay or a line immunoassay. The extent of the lymphoproliferative effect was examined by detection of proliferating cells with the BrdU method, and by measurement of paracortex and follicle areas, by combined immunohistochemistry and morphometry of PLN cryosections. We demonstrate here that HCB elevated PLN weights and cell numbers of the rat PLN, by day 7 after injection, but no elevation of antibody production in the PLN. Moreover, HCB caused an enlargement of both the PLN paracortical and follicular areas, and an elevation of proliferating paracortical T cells. None of the HCB-induced effects were found on day 21. HCB caused the same effects in the mouse PLNA, but they tended to sustain at least until day 21. Hardly any of the HCB-induced changes were found when PCB was injected. Previously, we have shown that oral exposure of Wistar rats to HCB elevated the number of splenic T cells and B cells, but also the serum levels of (auto-)antibodies and the production of these antibodies in the spleen, which is thus only partly in accordance with the results of the local reaction to HCB described in this study. This seeming contradiction is discussed.

Animals↗

PubMed1995

The thymus atrophy-inducing organotin compound DBTC inhibits the binding of thymocytes to thymic epithelial cells.

In this study, it is examined whether the organotin compound di-n-butyltindichloride (DBTC), which has been shown to inhibit immature thymocyte proliferation, is able to disturb the binding between thymocytes and thymic epithelial cells (TEC). To that end, an enzyme-linked binding assay was developed in which the amount of binding of Thy-1+ (mAb ER4)-thymocytes to the rat-derived TEC-line IT45R1 (IT45R1-TEC) could be detected. It was found that preincubation of thymocytes with 3-5 microM DBTC for 30 min inhibited the binding by 50-60% during a 1 h adhesion period. By extending the preincubation period to 1 h and the adhesion period to 22 h, 0.1 microM DBTC was already sufficient to reduce the binding with 60-80%. Further characterization of the binding revealed that splenic lymphocytes were unable to bind to the MHC class II-negative IT45R1-TEC. Since dextran sulfate inhibited the binding as well, sulfated polysaccharide-binding molecules such as Thy-1 and CD2 are likely to be involved in the binding. Electron microscopy showed filament-containing microvilli at the site of interaction. The results are discussed in relation to the mechanism of DBTC-induced thymus atrophy.

Animals↗

PubMed1990

The effect of beclobric acid and clofibric acid on peroxisomal beta-oxidation and peroxisome proliferation in primary cultures of rat, monkey and human hepatocytes.

The peroxisome-proliferating effects of clofibric acid and beclobric acid were studied in primary cultures of hepatocytes derived from rat, monkey (Macaca fascicularis) and human liver. Determination of peroxisomal fatty acid beta-oxidation and morphometrical analysis of the peroxisomal compartment were performed after incubation of 1-day-old hepatocyte cultures for 3 days with either compound. In rat liver cell cultures both compounds gave a 10-fold increase in peroxisomal beta-oxidation, a 3-fold increase in the relative number of peroxisomes and a 1.5-fold increase in the mean size of peroxisomes. Beclobric acid gave its maximal effect at a concentration of 10 microM, which is at least one order of magnitude lower than the maximum-effect concentration of clofibric acid. At concentrations greater than 300 microM beclobric acid was cytotoxic. No stimulation of peroxisomal fatty acid beta-oxidation was found in either monkey or human hepatocyte cultures. Morphometrical analysis also showed no increase in the peroxisomal compartment in cultures derived from these species, as indicated by the lack of increase in both relative number and size of peroxisomes. In all three species tested beclobric acid was equally cytotoxic for hepatocytes in vitro. These results are of relevance for the interpretation of the peroxisome-proliferating effects of clofibrate and similar compounds in rats. Since peroxisome proliferation may be correlated to increased hepatic tumour incidences in the rat, the absence of peroxisome proliferation in primates suggests the absence of tumourogenic activity by hypolipidemic compounds in these species.

Adult↗