Oral tolerance in myelin basic protein T-cell receptor transgenic mice: Suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells
Oral tolerance in myelin basic protein T-cell receptor transgenic mice: Suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells
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DOI：
10.1073/pnas.93.1.388
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发表时间：
1996-01-09
影响因子：
11.1
通讯作者：
Weiner, HL
中科院分区：
文献类型：
--
作者：
Chen, YH;Inobe, J;Weiner, HL
口服给予的抗原诱导称为口服耐受的免疫低反应性状态。不同的机制参与介导口服耐受，这取决于所喂食的剂量。低剂量的抗原产生分泌精氨酸的调节细胞，而高剂量诱导无反应性或缺失，我们使用了T细胞受体（TCR）转基因小鼠，该受体来源于对乙酰化N-髓鞘碱性蛋白（MBP）Ac-1-11的末端肽加I-A（u），以测试调节性T细胞是否可以从与致脑炎Th-1细胞相同的前体细胞产生，以及诱导是否是剂量依赖性的，MBP TCR转基因小鼠主要具有产生白细胞介素2（IL-2）的前体表型的T细胞，几乎没有干扰素γ（IFN-γ）、IL-4或转化生长因子β我们给转基因动物喂食低剂量的（1 mg x 5）或高剂量测试小鼠MBP（25 mg × 1）方案和没有进一步免疫的脾细胞的细胞因子产生，低剂量喂养诱导IL-4、IL-10和TGF-β的显著分泌，而高剂量喂养观察到这些细胞因子的最小分泌。无论剂量如何，在喂养的动物中几乎没有或没有观察到增殖或IL-2/IFN-γ分泌的变化，为了证明由口服抗原产生的精氨酸分泌细胞的体外功能活性，将来自低剂量喂养动物的脾细胞过继转移到幼稚细胞中。（PLJ x SJL）F-1小鼠，然后免疫以发展实验性自身免疫性脑脊髓炎（EAE），当T细胞从MBP喂养的转基因动物中转移时，观察到EAE的显著抑制，但不从未喂养的动物中转移。与口服耐受化相比，s.c.用在完全弗氏佐剂中的MBP免疫转基因动物在体外诱导分泌IFN-γ的Th-1细胞和在体内诱导实验性脑脊髓炎。尽管在转基因动物中有大量的细胞对MBP反应，但在免疫前低剂量喂养MBP也抑制了EAE。这些结果表明，MBP特异性T细胞可以在体内分化为致脑炎性或调节性T细胞，这取决于它们暴露于抗原的竞争。
Orally administered antigens induce a state of immunologic hyporesponsiveness termed oral tolerance, Different mechanisms are involved in mediating oral tolerance depending on the dose fed, Low doses of antigen generate cytokine-secreting regulatory cells, whereas high doses induce anergy or deletion, We used mice transgenic for a T-cell receptor (TCR) derived from an encephalitogenic T cell clone specific for the acetylated N-terminal peptide of myelin basic protein (MBP) Ac-1-11 plus I-A(u) to test whether a regulatory T cell could be generated from the same precursor cell as that of an encephalitogenic Th-1 cell and whether the induction was dose dependent, The MBP TCR transgenic mice primarily have T cells of a precursor phenotype that produce interleukin 2 (IL-2) with little interferon gamma (IFN-gamma),IL-4, or transforming growth factor beta (TGF-beta), We fed transgenic animals a low-dose (1 mg x 5) or high-dose (25 mg x 1) regimen of mouse MBP and without further immunization spleen cells were tested for cytokine production, Low-dose feeding induced prominent secretion of IL-4, IL-10, and TGF-beta, whereas minimal secretion of these cytokines was observed with high-dose feeding, Little or no change was seen in proliferation or IL-2/IFN-gamma secretion in fed animals irrespective of the dose, To demonstrate in vitro functional activity of the cytokine-secreting cells generated by oral antigen, spleen cells from low-dose-fed animals were adoptively transferred into naive (PLJ x SJL)F-1 mice that were then immunized for the development of experimental autoimmune encephalomyelitis (EAE), Marked suppression of EAE was observed when T cells were transferred from MBP-fed transgenic animals but not from animals that were not fed. In contrast to oral tolerization, s.c. immunization of transgenic animals with MBP in complete Freund's adjuvant induced IFN-gamma-secreting Th-1 cells in vitro and experimental encephalomyelitis in vivo. Despite the large number of cells reactive to MBP in the transgenic animals, EAE was also suppressed by low-dose feeding of MBP prior to immunization, These results demonstrate that MBP-specific T cells can differentiate in vivo into encephalitogenic or regulatory T cells depending upon the contest by which they are exposed to antigen.