Suzan Artik

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 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

Previously, we reported that tolerance to nickel, induced by oral administration of Ni2+ ions, can be adoptively transferred to naive mice with only 102 splenic T cells. Here we show that 102 T cell-depleted spleen cells (i.e., APCs) from orally tolerized donors can also transfer nickel tolerance. This cannot be explained by simple passive transfer of the tolerogen. The APCs from orally tolerized donors displayed a reduced allostimulatory capacity, a tolerogenic phenotype, and an increased expression of CD38 on B cells. In fact, it was B cells among the APCs that carried the thrust of tolerogenicity. Through serial adoptive transfers with Ly5.1+ donors and two successive sets of Ly5.2+ recipients, we demonstrated that nickel tolerance was infectiously spread from donor to host cells. After the transfer of either T cells or APCs from orally tolerized donors, the spread of tolerance to the opposite cell type of the recipients (i.e., APCs and T cells, respectively) required recipient immunization with NiCl2/H2O2. For the spread of tolerance from a given donor cell type, T cell or APC, to the homologous host cell type, the respective opposite cell type in the host was required as intermediate. We conclude that T suppressor cells and tolerogenic APCs induced by oral administration of nickel are part of a positive feedback loop that can enhance and maintain tolerance when activated by Ag associated with a danger signal. Under these conditions, APCs and T suppressor effector cells infectiously spread the tolerance to naive T cells and APCs, respectively.

Complementary therapy for atopic eczema and other allergic skin diseases.

ABSTRACT: u2002Atopic eczema is one of the most common chronic inflammatory skin diseases, with a prevalence of at least 10% in children and 0.5–1% in adults. The disease shows a drastically increasing tendency. This article provides an overview of the pathophysiology, pathomechanisms, prevention, and treatment of atopic eczema. We present a therapeutic concept that integrates all aspects of the complex pathophysiology that is a prerequisite for individualized and successful treatment. This is based on intervention in the pathophysiology of atopic eczema and elimination of exogenous provocation factors. Particular attention is given to unconventional therapy options such as phytotherapy, which are attracting patients in many countries, and possible effects, side effects, and interactions with other drugs are discussed.

Toleranzinduktion gegen Nickel: Vom Tiermodell zum Menschen

ZusammenfassungNickel ist das häufigste Kontaktallergen des Menschen. Dennoch waren bis vor kurzem viele Fragen insbesondere bezüglich der Toleranzmechanismen gegenüber Nickel nicht geklärt. Neben humanen Ex-vivo-, Interventions- und Beobachtungsstudien hat die Etablierung eines reproduzierbaren Mausmodells nun dazu beigetragen, diese Mechanismen besser zu analysieren. Erst das genauere Verständnis der Pathogenese der Nickelallergie und Toleranz gegenüber Nickel durch Untersuchungen im Tiermodell sowie in humanen Studien wird dazu beitragen, eine gezielte Prävention bzw. Therapie der Nickelallergie zu entwickeln. Wir beabsichtigen, mit dieser Arbeit einen Überblick über die im Tiermodell und im Menschen erhobenen Erkenntnisse zur Nickelallergie und vor allem zur oralen Toleranzinduktion gegenüber Nickel zu geben.AbstractNickel is the most common contact allergen in humans. Until recently, many questions concerning tolerance mechanisms to nickel were unresolved. Besides human ex vivo, intervention and observation studies, the establishment of a reproducible mouse model has contributed to the analysis of these mechanisms. A more detailed understanding of the pathogenesis of nickel allergy and tolerance towards nickel by investigations in an animal model and in human studies is a prerequisite for developing specific prevention and therapy of nickel allergy. With this article, we provide a review of the investigations concerning nickel allergy and give perspectives towards oral tolerance induction to nickel in the animal model and in humans.

Toleranzinduktion gegen Nickel

ZusammenfassungNickel ist das häufigste Kontaktallergen des Menschen. Dennoch waren bis vor kurzem viele Fragen insbesondere bezüglich der Toleranzmechanismen gegenüber Nickel nicht geklärt. Neben humanen Ex-vivo-, Interventions- und Beobachtungsstudien hat die Etablierung eines reproduzierbaren Mausmodells nun dazu beigetragen, diese Mechanismen besser zu analysieren. Erst das genauere Verständnis der Pathogenese der Nickelallergie und Toleranz gegenüber Nickel durch Untersuchungen im Tiermodell sowie in humanen Studien wird dazu beitragen, eine gezielte Prävention bzw. Therapie der Nickelallergie zu entwickeln. Wir beabsichtigen, mit dieser Arbeit einen Überblick über die im Tiermodell und im Menschen erhobenen Erkenntnisse zur Nickelallergie und vor allem zur oralen Toleranzinduktion gegenüber Nickel zu geben.AbstractNickel is the most common contact allergen in humans. Until recently, many questions concerning tolerance mechanisms to nickel were unresolved. Besides human ex vivo, intervention and observation studies, the establishment of a reproducible mouse model has contributed to the analysis of these mechanisms. A more detailed understanding of the pathogenesis of nickel allergy and tolerance towards nickel by investigations in an animal model and in human studies is a prerequisite for developing specific prevention and therapy of nickel allergy. With this article, we provide a review of the investigations concerning nickel allergy and give perspectives towards oral tolerance induction to nickel in the animal model and in humans.