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International Immunology Advance Access published online on August 13, 2007
International Immunology, doi:10.1093/intimm/dxm066
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Dose dependence of oral tolerance to nickel

Xianzhu Wu1,3, Karin Roelofs-Haarhuis1, Jianhong Zhang1, Michael Nowak1,4, Laura Layland1,2, Erich Jermann1 and Ernst Gleichmann1

1 Institut für Umweltmedizinische Forschung at Heinrich Heine University gGmbH, Düsseldorf, Auf'm Hennekamp 50, D-40225 Düsseldorf, Germany
2 Institute for Medical Microbiology, Immunology and Hygiene at Technical University of Munich, Germany
3 Present address: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
4 Present address: Beth Israel Deaconess Medical Center, Hematology/Oncology division, Harvard Medical School, Boston MA, 02215, USA

Correspondence to: Correspondence to: E. Gleichmann; E-mail: ernst.gleichmann{at}uni-duesseldorf.de

The dose dependence of oral nickel tolerance was analyzed by comparing three different subsets of C57BL/6 mice: Nivery low mice were reared in a nickel-reduced environment, Nilow and Nihigh mice were reared in a stainless steel-containing environment and the latter received oral NiCl2 (10 mM). In spleen and feces, Nivery low mice exhibit significantly lower nickel concentrations than Nilow and Nihigh mice. In contrast to Nivery low mice that can be sensitized with a single intradermal administration of NiCl2 alone, Nilow mice can only be sensitized in the presence of an adjuvant and Nihigh mice cannot be sensitized at all. This dose-dependent resistance to nickel sensitization (i.e. Nihigh > Nilow > Nivery low) correlates with differences in the number and type of nickel-specific T regulatory (Treg) cells. Adoptive transfer studies into Nivery low recipients showed that Nivery low mice completely lack specific Treg cells whereas Nilow and Nihigh mice harbor them, albeit their numbers and/or suppressive strength are much higher in Nihigh than Nilow mice. The principal Treg subset in Nilow mice consists of CD4+CD25+ cells, among which CD4+CD25+{alpha}Eß7+ cells are the most effective. In Nihigh mice, CD4+CD25+ Treg cells co-exist with an ensemble of CD8+ Treg and CD4+CD25– suppressor–inducer cells.

Keywords: allergy, nickel, regulatory T cells, tolerance/suppression

Transmitting editor: S. Romagnani

Received 27 September 2006, accepted 17 April 2007.


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