Institute of Biomedicine, Department of Microbiology and Immunology, and University of Gothenburg Vaccine Research Institute, Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
Scand J Immunol. 2010 Jan;71(1):1-11. doi: 10.1111/j.1365-3083.2009.02321.x.
Induction of peripheral immunological tolerance by mucosal administration of selected antigens (Ags) ('oral tolerance') is an attractive, yet medically little developed, approach to prevent or treat selected autoimmune or allergic disorders. A highly effective way to maximize oral tolerance induction for immunotherapeutic purposes is to administer the relevant Ag together with, and preferably linked to the non-toxic B subunit protein of cholera toxin (CTB). Oral, nasal or sublingual administration of such Ag/CTB conjugates or gene fusion proteins have been found to induce tolerance with superior efficiency compared with administration of Ag alone, including the suppression of various autoimmune disorders and allergies in animal models. In a proof-of-concept clinical trial in patients with Behcet's disease, this was extended with highly promising results to prevent relapse of autoimmune uveitis. Tolerization by mucosal Ag/CTB administration results in a strong increase in Ag-specific regulatory CD4(+) T cells, apparently via two separate pathways: one using B cells as APCs and leading to a strong expansion of Foxp3(+) Treg cells which can both suppress and mediate apoptotic depletion of effector T cells, and one being B cell-independent and associated with development of Foxp3(-) regulatory T cells that express membrane latency-associated peptide and transforming growth factor (TGF-beta) and/or IL-10. The ability of CTB to dramatically increase mucosal Ag uptake and presentation by different APCs through binding to GM1 ganglioside (which makes most B cells effective APCs irrespective of their Ag specificity), together with CTB-mediated stimulation of TGF-beta and IL-10 production and inhibition of IL-6 formation may explain the dramatic potentiation of oral tolerance by mucosal Ags presented with CTB.
经黏膜给予选择的抗原（Ags）（“口服耐受”）诱导外周免疫耐受是一种有吸引力但在医学上尚未得到充分发展的方法，可用于预防或治疗某些自身免疫或过敏疾病。为了最大程度地提高口服耐受诱导的免疫治疗效果，一种非常有效的方法是将相关 Ag 与霍乱毒素（CTB）的无毒 B 亚单位蛋白一起给予，并且最好与之结合。已经发现，经口、鼻或舌下给予此类 Ag/CTB 缀合物或基因融合蛋白可诱导比单独给予 Ag 更高效率的耐受，包括在动物模型中抑制各种自身免疫疾病和过敏。在一项针对 Behcet 病患者的概念验证临床试验中，这一结果得到了极具前景的扩展，可预防自身免疫性葡萄膜炎的复发。黏膜 Ag/CTB 给药导致 Ag 特异性调节性 CD4(+)T 细胞强烈增加，显然通过两种独立的途径：一种使用 B 细胞作为 APC，并导致 Foxp3(+)Treg 细胞的强烈扩增，这些细胞既可以抑制又可以介导效应 T 细胞的凋亡耗竭，另一种途径是 B 细胞非依赖性的，与 Foxp3(-)调节性 T 细胞的发育相关，后者表达膜潜伏期相关肽和转化生长因子（TGF-β）和/或 IL-10。CTB 通过与 GM1 神经节苷脂结合，极大地增加不同 APC 对黏膜 Ag 的摄取和呈递的能力（这使得大多数 B 细胞成为有效的 APC，而与它们的 Ag 特异性无关），再加上 CTB 介导的 TGF-β和 IL-10 产生的刺激以及 IL-6 形成的抑制，可能解释了黏膜 Ag 与 CTB 结合后口服耐受的显著增强。
