Oral tolerance.
Oral tolerance.
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DOI：
10.1111/j.1600-065x.2011.01017.x
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发表时间：
2011-05
影响因子：
8.7
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Weiner HL;da Cunha AP;Quintana F;Wu H
肠道相关淋巴组织是体内最大的免疫器官，也是我们接触抗原的主要途径。耐受诱导是肠道中默认的免疫途径，诱导的耐受类型与饲喂抗原的剂量有关：无反应/缺失（高剂量）或调节性 T 细胞 (Treg) 诱导（低剂量）。肠道上皮细胞和肠道菌群对肠道树突状细胞 (DC) 的调节本身对肠道免疫具有重大影响，可诱导 CD103+ 视黄酸依赖性 DC，从而诱导 Tregs。许多Tregs在粘膜表面被诱导。 Th3 型 Tregs 是转化生长因子-β 依赖性的，并在其表面表达潜伏相关肽 (LAP)，并在口服耐受的背景下被发现。 Tr1 型 Tregs（白细胞介素 10 依赖性）由鼻抗原诱导，叉头盒蛋白 3+ iTreg 由口服抗原和口服芳烃受体配体诱导。口腔或鼻腔抗原通过诱导 Tregs 改善动物模型中的自身免疫和炎症性疾病。此外，抗 CD3 单克隆抗体在粘膜表面具有活性，口服或鼻腔抗 CD3 单克隆抗体可诱导 LAP+ Tregs 抑制动物模型（实验性自身免疫性脑炎、1 型和 2 型糖尿病、狼疮、关节炎、动脉粥样硬化），并且正在人体中进行测试。尽管有大量关于通过粘膜耐受治疗动物模型的文献，并且在人类中取得了一些积极的结果，但这种方法尚未转化为临床。成功的转化需要定义有反应的患者群体，验证生物标志物来测量免疫效应，并使用联合疗法和免疫佐剂来增强 Treg 诱导。正在研究的治疗自身免疫的主要途径是诱导 Tregs，而粘膜耐受是实现这一目标的无毒生理方法。
The gut-associated lymphoid tissue is the largest immune organ in the body and is the primary route by which we are exposed to antigens. Tolerance induction is the default immune pathway in the gut, and the type of tolerance induced relates to the dose of antigen fed: anergy/deletion (high dose) or regulatory T-cell (Treg) induction (low dose). Conditioning of gut dendritic cells (DCs) by gut epithelial cells and the gut flora, which itself has a major influence on gut immunity, induces CD103+ retinoic acid-dependent DC that induces Tregs. A number of Tregs are induced at mucosal surfaces. Th3 type Tregs are transforming growth factor-β dependent and express latency-associated peptide (LAP) on their surface and were discovered in the context of oral tolerance. Tr1 type Tregs (interleukin-10 dependent) are induced by nasal antigen and forkhead box protein 3+ iTregs are induced by oral antigen and by oral administration of aryl hydrocarbon receptor ligands. Oral or nasal antigen ameliorates autoimmune and inflammatory diseases in animal models by inducing Tregs. Furthermore, anti-CD3 monoclonal antibody is active at mucosal surfaces and oral or nasal anti-CD3 monoclonal antibody induces LAP+ Tregs that suppresses animal models (experimental autoimmune encephalitis, type 1 and type 2 diabetes, lupus, arthritis, atherosclerosis) and is being tested in humans. Although there is a large literature on treatment of animal models by mucosal tolerance and some positive results in humans, this approach has yet to be translated to the clinic. The successful translation will require defining responsive patient populations, validating biomarkers to measure immunologic effects, and using combination therapy and immune adjuvants to enhance Treg induction. A major avenue being investigated for the treatment of autoimmunity is the induction of Tregs and mucosal tolerance represents a non-toxic, physiologic approach to reach this goal.