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ToxSci Advance Access published online on December 2, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh034
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received July 16, 2003; accepted November 4, 2003
© 2003 Society of Toxicology

Immunotoxicology

Hexachlorobenzene-Induced Immunopathology in Brown Norway Rats Is Partly Mediated by T Cells

Janine Ezendam 1*, Ine Hassing 2, Rob Bleumink 2, Joseph G. Vos 3, and Raymond Pieters 2

1 Institute for Risk Assessment Sciences (IRAS), Immunotoxicology, Utrecht University, P.O. Box 80.176, 3508 TD Utrecht, Netherlands; National Institute for Public Health and the Environment, Laboratory for Toxicology, Pathology and Genetics, Bilthoven, P.O. Box 1 3720 BA, Netherlands; Faculty of Veterinary Medicine, Department of Pathobiology, Utrecht University, P.O. Box 80.150, 3508 TD Utrecht, Netherlands
2 Institute for Risk Assessment Sciences (IRAS), Immunotoxicology, Utrecht University, P.O. Box 80.176, 3508 TD Utrecht, Netherlands
3 National Institute for Public Health and the Environment, Laboratory for Toxicology, Pathology and Genetics, Bilthoven, P.O. Box 1 3720 BA, Netherlands; Faculty of Veterinary Medicine, Department of Pathobiology, Utrecht University, P.O. Box 80.150, 3508 TD Utrecht, Netherlands

* To whom correspondence should be addressed. E-mail: J.Ezendam{at}iras.uu.nl.


  Abstract

Hexachlorobenzene (HCB) is a persistent environmental pollutant with (auto)immune effects in man and rat. The Brown Norway (BN) rat is very susceptible to HCB-induced immunopathology and oral exposure causes inflammatory skin and lung lesions, splenomegaly, lymph node (LN) enlargement and increased serum levels of IgE and anti-ssDNA IgM. The role of T cells in HCB-induced immunopathology is unclear and to elucidate this Cyclosporin A (CsA) was used. BN rats were exposed to either a control diet or a diet supplemented with 450 mg/kg HCB for 21 days. CsA treatment started 2 days prior to HCB exposure and rats were injected daily with 20 mg/kg body weight CsA. Treatment with CsA prevented the HCB-induced immunopathology significantly. The onset of skin lesions was delayed and the severity was also strongly decreased. Furthermore, CsA prevented the HCB-induced increase in spleen weight partly and the increase in auricular LN weight completely. The increase in serum IgE and IgM against ssDNA levels was prevented completely. Macrophage infiltrations into the spleen and lung still occurred but infiltrations of eosinophilic granulocytes into the lung were prevented. Restimulation of spleen cells with the T cell mitogen ConA and the macrophage activator LPS clearly showed that CsA inhibited T cell activation, but not macrophage activation. Together, our results show that both T cells and macrophages play a prominent role in HCB-induced immunopathology.

Key Words: Hexachlorobenzene, T cells, macrophages, immunostimulation, Cyclosporin A, Brown Norway rat .


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