Two Immunotoxicity Ring Studies According to OECD TG 407—Comparison of Data on Cyclosporin A and Hexachlorobenzene

Schulte, Agnes; Althoff, J.; Ewe, Sigrid; Richter‐Reichhelm, H.‐B.

doi:10.1006/rtph.2002.1568

Cited by 44 publications

(30 citation statements)

References 11 publications

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“…Furthermore, HCB increased gene expression of CD52 or B7 antigen, a marker present on antigen-presenting cells, such as B cells and monocytes. This is in line with previous studies that have shown a stronger increase of monocytes and granulocytes in blood after HCB exposure, resulting in relatively fewer lymphocytes (Schulte et al 2002;Vos et al 1979). In kidney we observed an increased expression of OX 45 (homolog to CD2), a membrane protein involved in the binding to LFA-3, important in adhesion of T cells to other cell types and in T-cell activation.…”

Section: T and B Cells And Major Histocompatibility Complex II Expressupporting

confidence: 93%

Toxicogenomics of Subchronic Hexachlorobenzene Exposure in Brown Norway Rats

Ezendam¹,

Staedtler²,

Pennings³

et al. 2004

Environ. Health Perspect.

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) for performing the radioimmunoassay to determine antiacetylcholine receptor antibodies, and we thank B. Baumann (RIVM, Bilthoven, the Netherlands) for measuring the dioxin-like contamination of HCB.The authors declare they have no competing financial interests.Received 13 Hexachlorobenzene (HCB) is a persistent environmental pollutant with toxic effects in man and rat. Reported adverse effects are hepatic porphyria, neurotoxicity, and adverse effects on the reproductive and immune system. To obtain more insight into HCB-induced mechanisms of toxicity, we studied gene expression levels using DNA microarrays. For 4 weeks, Brown Norway rats were fed a diet supplemented with 0, 150, or 450 mg HCB/kg. Spleen, mesenteric lymph nodes (MLN), thymus, blood, liver, and kidney were collected and analyzed using the Affymetrix rat RGU-34A GeneChip microarray. Most significant (p < 0.001) changes, compared to the control group, occurred in spleen, followed by liver, kidney, blood, and MLN, but only a few genes were affected in thymus. This was to be expected, as the thymus is not a target organ of HCB. Transcriptome profiles confirmed known effects of HCB such as stimulatory effects on the immune system and induction of enzymes involved in drug metabolism, porphyria, and the reproductive system. In line with previous histopathological findings were increased transcript levels of markers for granulocytes and macrophages. New findings include the upregulation of genes encoding proinflammatory cytokines, antioxidants, acute phase proteins, mast cell markers, complements, chemokines, and cell adhesion molecules. Generally, gene expression data provide evidence that HCB induces a systemic inflammatory response, accompanied by oxidative stress and an acute phase response. In conclusion, this study confirms previously observed (immuno)toxicological effects of HCB but also reveals several new and mechanistically relevant gene products. Thus, transcriptome profiles can be used as markers for several of the processes that occur after HCB exposure.

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Section: T and B Cells And Major Histocompatibility Complex II Expressupporting

confidence: 93%

Toxicogenomics of Subchronic Hexachlorobenzene Exposure in Brown Norway Rats

Ezendam¹,

Staedtler²,

Pennings³

et al. 2004

Environ. Health Perspect.

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“…Similar results of unaffected body weight were observed in several rodent studies with CsA [27][28][29][30]56]. However, in other studies, reduction in body weight was observed, varying between laboratories and varying with sex [29,31,39].…”

Section: Effects On Growth Organ Weights and Histopathologysupporting

confidence: 86%

“…CsA-treatment showed only minor effects on NK cell activity of PBMC isolated from minipigs, which is in line with the lack of effect on NK cell activity in a placebo controlled study in human subjects with insulin-dependent diabetes mellitus type I [38]. In several observations made in rodents treated with CsA, either no effect [27,31,39,40] or a tendency to increased NK activity was observed [29,30,41]. Interestingly, in studies of Blot et al [27], it was observed that in splenic cells of mice but not of rats NK cell activity was dosedependently decreased upon exposure to comparable dose levels of CsA even though the blood concentrations of CsA were higher in the rat than in the mouse.…”

Section: Nk Cell Activity Assaysupporting

confidence: 77%

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A Sub Acute Immunotoxicity Study in G?ttingen Minipigs? with the Immunosuppressive Compounds Cyclosporin A and Dexamethasone

2013

Clin Exp Pharmacol

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Introduction: There is a growing interest in the minipig as a non-rodent species in the safety assessment of (bio) pharmaceuticals and (agro) chemicals. For (bio) pharmaceuticals the need to evaluate the potential adverse effects on the immune system is an increasingly important aspect of safety evaluation. In the present study, cyclosporin A and Dexamethasone were used as model compounds to examine whether the regulatory endpoints requested for immunotoxicity testing can be tested in the Göttingen minipig.

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“…For example, in a randomized clinical trial (Kropf, Hommel, Schmidt, Brickwedel, and Jepsen, 2000), two new extracorporeal circulation sets were compared with a standard set for the three primary endpoints thrombocyte count, thrombocyte activity ADP and thrombocyte activity TRAP. Or in an immuno-toxicological inter-laboratory study (Schulte, Althoff, Ewe, and Richter-Reichhelm, 2002), immuno-toxicity endpoints were considered for a comparison of three dose levels with a zero dose control. The experimental goal is not only to clarify, which treatment groups differ, but also on which endpoints.…”

Section: Introductionmentioning

confidence: 99%

A Dunnett-Type Procedure for Multiple Endpoints

Hasler¹,

Hothorn²

2011

The International Journal of Biostatistics

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This paper describes a method for comparisons of several treatments with a control, simultaneously for multiple endpoints. These endpoints are assumed to be normally distributed with different scales and variances. An approximate multivariate t-distribution is used to obtain quantiles for test decisions, multiplicity-adjusted p-values, and simultaneous confidence intervals. Simulation results show that this approach controls the family-wise error type I over both the comparisons and the endpoints in an admissible range. The approach will be applied to a randomized clinical trial comparing two new sets of extracorporeal circulations with a standard for three primary endpoints. A related R package is available.

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Two Immunotoxicity Ring Studies According to OECD TG 407—Comparison of Data on Cyclosporin A and Hexachlorobenzene

Cited by 44 publications

References 11 publications

Toxicogenomics of Subchronic Hexachlorobenzene Exposure in Brown Norway Rats

Toxicogenomics of Subchronic Hexachlorobenzene Exposure in Brown Norway Rats

A Sub Acute Immunotoxicity Study in G?ttingen Minipigs? with the Immunosuppressive Compounds Cyclosporin A and Dexamethasone

A Dunnett-Type Procedure for Multiple Endpoints

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