Low zone tolerance induced by systemic application of allergens inhibits Tc1-mediated skin inflammation.

BACKGROUND: 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(C)1-mediated contact hypersensitivity (CHS). OBJECTIVE: We evaluated the effect of systemic (oral, intravenous) administration of low amounts of haptens on specific immune reactions and tolerance induction. METHODS: 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). RESULTS: 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(C)2 cells. Adoptive transfer experiments identified CD8+ T(C)2 cells as effector T cells of LZT inhibiting the development of CHS-promoting T(C)1 cells and consequently the manifestation of CHS. These suppressor CD8+ T(C)2 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. CONCLUSION: 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. CLINICAL IMPLICATIONS: 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.

B cells are not required for T cell priming in low zone tolerance to contact allergens and contact hypersensitivity.

Low zone tolerance (LZT) to contact allergens is induced by epicutaneous exposure to haptens in subsensitizing doses resulting in an inhibition of contact hypersensitivity (CHS), which, in contrast, occurs after sensitization with immunogenic doses of allergens. Performing the protocol of tolerance induction resulted in robust LZT to allergens in B cell-deficient mice in vivo, indicating that B cells are not required for the induction and effector phase of LZT. However, CHS reactions in vivo were restricted in B cell-deficient mice as compared to wild-type (WT) mice. In contrast, analysis of hapten-specific T cell activation in vitro revealed a strong proliferative response of T cells derived from both WT and B cell-deficient sensitized mice. Similar to WT animals, T cells obtained from tolerized B cell-deficient mice produced a Tc2 cytokine pattern of LZT with high levels of IL-4 and IL-10, whereas sensitization of B cell-deficient mice resulted in the typical Tc1 cytokine profile of CHS. Adoptive transfer of CD8+ effector T cells from tolerized or sensitized B cell-deficient mice induced significant LZT or CHS reactions, respectively, in WT recipients, demonstrating that the development of hapten-specific effector CD8+ T cells of LZT and CHS is independent of B cells.