Dose dependence of oral tolerance to nickel

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+αEβ7+ 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.