Tolerance to nickel: Oral nickel administration induces a high frequency of anergic T cells with persistent suppressor activity

We adapted our mouse model of allergic contact hypersensitivity to nickel f or the study of tolerance. Sensitization in this model is achieved by the a dministration of nickel ions with H2O2; nickel ions alone are unable to pri me naive T cells, but can restimulate primed ones. A 4-wk course of oral or i.p. administration of 10 mM NiCl2 to naive mice induced tolerance, preven ting the induction of hypersensitivity for at least 20 wk; long term desens itization of nickel-sensitized mice, however, required continuous NiCl2 adm inistration. When splenic T cells of orally tolerized donors, even after a treatment-free interval of 20 wk, were transferred to naive recipients, as with lymph node cells (LNC), they specifically prevented sensitization of t he recipients. The LNC of such donors were anergic, because upon in vivo se nsitization with NiCl2 in H2O2 and in vitro restimulation with NiCl2, they failed to show the enhanced proliferation and IL-2 production as seen with LNC of mice not tolerized before sensitization. As few as 10(2) bulk T cell s, consisting of both CD4(+) and CD8(+) cells, were able to specifically tr ansfer tolerance to nickel. A hypothesis is provided to account for this ex traordinarily high frequency of nickel-reactive, suppressive T cells; it ta kes into account that nickel ions fail to act as classical haptens, but for m versatile, unstable metal-protein and metal-peptide complexes. Furthermor e, a powerful amplification mechanism, such as infectious tolerance, must o perate which allows but a few donor T cells to tolerize the recipient.