Tolerance to Nickel: Oral Nickel Administration Induces a High Frequency of Anergic T Cells with Persistent Suppressor Activity

Abstract

We adapted our mouse model of allergic contact hypersensitivity to nickel for the study of tolerance. Sensitization in this model is achieved by the administration of nickel ions with H2O2; nickel ions alone are unable to prime 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, preventing the induction of hypersensitivity for at least 20 wk; long term desensitization of nickel-sensitized mice, however, required continuous NiCl2 administration. 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 the recipients. The LNC of such donors were anergic, because upon in vivo sensitization 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 102 bulk T cells, consisting of both CD4+ and CD8+ cells, were able to specifically transfer tolerance to nickel. A hypothesis is provided to account for this extraordinarily high frequency of nickel-reactive, suppressive T cells; it takes into account that nickel ions fail to act as classical haptens, but form versatile, unstable metal-protein and metal-peptide complexes. Furthermore, a powerful amplification mechanism, such as infectious tolerance, must operate which allows but a few donor T cells to tolerize the recipient.

Infectious Nickel Tolerance: A Reciprocal Interplay of Tolerogenic APCs and T Suppressor Cells That Is Driven by Immunization

“…The splenic T cells possessing this ability were anergic in the presence of nickel ions and consisted of both CD4 ϩ and CD8 ϩ T cells. To explain how a minute number of anergic donor T cells could suppress the numerous nickel-reactive T cells in naive recipients, we postulated that infectious tolerance could be involved (17). In the present investigation, genetic cell markers were used to demonstrate that infectious tolerance is indeed the amplification mechanism accounting for the spread of nickel unresponsiveness in vivo.…”

“…Congenic Ly5.1 ϩ (CD45.1 ϩ ) C57BL/6J mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice were kept in accordance with the animal husbandry as described in the previous papers (16,17). They were 6 -8 wk of age at the onset of experiments.…”

“…Mice were immunized as described previously (16,17). In the case of nickel, they were injected intradermally into both flanks (50 l each) with either 10 mM NiCl 2 in sterile, pyrogen-free saline (negative control) or 10 mM NiCl 2 in saline containing 1% H 2 O 2 .…”

Nickel allergy and orthodontics, a review and report of two cases

“…Clinical examination after allergies. [38][39][40][41][42] Nevertheless when clinical three days of removal of the archwires In both cases the diagnosis of nickel signs or symptoms presumed to be due demonstrated that lip competence had returned. The patient's lips no longer appeared swollen and the clinical 'anaes thetic-like' symptoms did not return.…”

Nickel induces secretion of IFN-γ by splenic natural killer cells

“…Since the ELISPOT assay was performed by 24-h stimulation with NiSO4 and naive T cells usually require at least a few days for immune response, it was expected that only memory nickel-reactive T cells could respond to nickel ions and secrete cytokines. We measured the numbers of IL-2-, IL-4-, and IFN-γ-secreting cells since T cells participating in the immune response to nickel could be either Th1 or Th2 cells (Artik et al, 2001;Sebastiani et al, 2002). Total splenic cells were isolated and then 1 × 10 5 cells were cultured in each well of ELISPOT plates with complete RPMI 1640 media and varying concentrations of NiSO4 for 24 h. Contrary to our expectation, a high frequency of nickel-reactive cytokine-secreting cells were detected upon NiSO4 stimulation in non-sensitized mice (Figure 1).…”