Seidel-Guyenot Wolfgang, Perschon Sylwia, Dechant Natascha, Alt Ruth, Knop Jürgen, Steinbrink Kerstin
Department of Dermatology, University of Mainz, Germany.
J Allergy Clin Immunol. 2006 May;117(5):1170-7. doi: 10.1016/j.jaci.2006.01.014. Epub 2006 Apr 3.
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).
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(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.
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.
诱导免疫耐受可能是预防有害过敏性疾病策略的一个有前景的目标。经皮应用低剂量接触性变应原诱导的低带耐受（LZT）可抑制T（C）1介导的接触性超敏反应（CHS）的发生。
我们评估了全身（口服、静脉注射）给予少量半抗原对特异性免疫反应和耐受诱导的影响。
通过使用LZT小鼠模型，我们分析了口服、静脉注射或经皮应用少量接触性变应原2,4,6-三硝基-1-氯苯（TNCB）后体内的免疫反应（皮肤炎症）和体外的T细胞反应。
口服和静脉注射亚免疫原剂量的TNCB在体内诱导了与经皮耐受小鼠相当的显著耐受反应，表明LZT是一种全身介导的耐受反应。在所有LZT模型的体外分析中均发现产生了分泌IL-10的调节性CD4+ T细胞，这些细胞是半抗原特异性CD8+ T（C）2细胞发育所绝对必需的。过继转移实验确定CD8+ T（C）2细胞是LZT的效应T细胞，可抑制促进CHS的T（C）1细胞的发育，从而抑制CHS的表现。在耐受动物的皮肤引流淋巴结、肠系膜淋巴结和脾脏中均发现了这些抑制性CD8+ T（C）2细胞，且与耐受途径无关。
这些数据表明，全身摄取和呈递少量半抗原（如接触性变应原、药物、金属）可诱导LZT的发生，从而防止免疫系统的不适当激活并预防过敏性疾病。
这些发现将具有特别重要的意义，因为应用亚免疫原性、少量半抗原的方案诱导耐受可能用作过敏性和自身免疫性疾病免疫治疗的工具。
