The induction of tolerance may be a promising target of strategies aimed at preventing harmful allergic diseases. Low zone tolerance (LZT), induced by epicutaneous application of low doses of contact allergens, inhibits the development of T_C1-mediated contact hypersensitivity (CHS).

We evaluated the effect of systemic (oral, intravenous) administration of low amounts of haptens on specific immune reactions and tolerance induction.

By using the mouse model of LZT, we analyzed immune reactions in vivo (skin inflammation) and T-cell responses in vitro after oral, intravenous, or epicutaneous application of low amounts of the contact allergen 2,4,6-trinitro-1-chlorobenzene (TNCB).

Subimmunogenic doses of TNCB applied orally and intravenously induced a significant tolerance reaction in vivo comparable to epicutaneously tolerized mice, indicating that LZT is a systemically mediated tolerance reaction. In vitro analysis in all models of LZT revealed the generation of IL-10 secreting, regulatory CD4⁺ T cells that were absolutely required for the development of hapten-specific CD8⁺ T_C2 cells. Adoptive transfer experiments identified CD8⁺ T_C2 cells as effector T cells of LZT inhibiting the development of CHS-promoting T_C1 cells and consequently the manifestation of CHS. These suppressor CD8⁺ T_C2 cells were found as well in skin-draining as in mesenteric lymph nodes and in the spleen of tolerized animals independent of the route of tolerization.

These data indicate that systemic uptake and presentation of small amounts of haptens (eg, contact allergens, drugs, metals) induce the development of LZT and thus prevent inappropriate activation of the immune system and protect from allergic diseases.

These findings will be of particular importance because tolerance induction by protocols applying subimmunogenic, low amounts of haptens may be used as tools for immunotherapy in allergic and autoimmune diseases.