Chen Y, Inobe J, Weiner H L
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cell Immunol. 1997 May 25;178(1):62-8. doi: 10.1006/cimm.1997.1119.
Oral administration of antigen induces a systemic hyporesponsiveness termed oral tolerance. High doses of oral antigen lead to deletion or anergy of T-cells whereas low doses induce regulatory T-cells that secrete Th2 cytokines (IL-4/IL-10) and TGF-beta. The initiating events associated with oral tolerance have not been well characterized. We investigated the induction phase of oral tolerance by adoptively transferring ovalbulumin (OVA) p (323-339) TcR specific transgenic (Tg+) T-cells into BALB/c recipients that were then fed either a high (5 mg x 5) or a low (0.1 mg x 5) dose of OVA 323-329 peptide. The frequency of Tg+ T-cells in lymphoid tissues was determined by flow cytometry using an anti-clonotypic monoclonal antibody. In high-dose-fed animals, Tg+ cells increased six- to eightfold in Peyer's patches after one feeding and then progressively decreased to 44% of those in the control by Day 20. In contrast, a biphasic-type response was observed in lymph node and spleen where Tg+ cells decreased after the first feeding, returned to the control level, and then decreased to 36-63% of the control level by Day 20. In low-dose-fed animals, changes in Tg+ T cells were only observed in Peyer's patches after five feedings, where cells increased approximately twofold. T-cell activation as measured by proliferation and IFN-gamma secretion occurred in both low- and high-dose-fed animals after only one feeding and then declined whereas secretion of Th2 cytokines and TGF-beta remained high even 10 days after the last feeding in low-dose-fed animals. Immunization with OVA/CFA demonstrated peripheral tolerance as measured by decreased proliferation and IFN-gamma secretion and was associated with increased production of TGF-beta and IL-10. These results suggest that the inductive phase of oral tolerance is characterized by an activation of antigen-specific T-cells that involves the initial secretion of IFN-gamma followed by prolonged secretion of Th2 cytokines and TGF-beta.
口服抗原可诱导一种称为口服耐受的全身性低反应性。高剂量口服抗原会导致T细胞的缺失或无反应性，而低剂量则诱导分泌Th2细胞因子（IL-4/IL-10）和转化生长因子β的调节性T细胞。与口服耐受相关的起始事件尚未得到充分表征。我们通过将卵清蛋白（OVA）p（323 - 339）T细胞受体特异性转基因（Tg+）T细胞过继转移到BALB/c受体中，然后给这些受体喂食高剂量（5mg×5）或低剂量（0.1mg×5）的OVA 323 - 329肽，来研究口服耐受的诱导阶段。使用抗克隆型单克隆抗体通过流式细胞术测定淋巴组织中Tg+ T细胞的频率。在高剂量喂食的动物中，一次喂食后派尔集合淋巴结中的Tg+细胞增加了六至八倍，然后逐渐减少，到第20天时降至对照组的44%。相比之下，在淋巴结和脾脏中观察到双相型反应，其中Tg+细胞在第一次喂食后减少，恢复到对照水平，然后到第20天时降至对照水平的36 - 63%。在低剂量喂食的动物中，仅在五次喂食后才在派尔集合淋巴结中观察到Tg+ T细胞的变化，细胞增加了约两倍。通过增殖和IFN-γ分泌测量的T细胞活化在高剂量和低剂量喂食的动物中仅一次喂食后就发生，然后下降，而在低剂量喂食的动物中，即使在最后一次喂食后10天，Th2细胞因子和转化生长因子β的分泌仍保持高水平。用OVA/CFA免疫证明了外周耐受，表现为增殖和IFN-γ分泌减少，并与TGF-β和IL-10的产生增加有关。这些结果表明，口服耐受的诱导阶段的特征是抗原特异性T细胞的活化，其涉及IFN-γ的初始分泌，随后是Th2细胞因子和TGF-β的持续分泌。
