Xiao B G, Link H
Division of Neurology, Karolinska Institute, Stockholm, Sweden.
Clin Immunol Immunopathol. 1997 Nov;85(2):119-28. doi: 10.1006/clin.1997.4432.
Mucosal administration of autoantigens results in the development of a state of peripheral immunological tolerance. Depending upon the dose of antigen administered, anergy/deletion of antigen-specific T cells (higher doses) and/or selective expansion of cells producing immunosuppressive cytokines (TGF-beta, IL-4, and IL-10) (lower doses) are two major mechanisms in mucosal tolerance induction. Mucosal tolerance is more effective after nasal compared to oral administration of antigens at the same dose. A large series of studies have demonstrated that mucosal tolerance by oral or nasal antigen administration effectively prevents several experimental disease models (EAE, EAMG, EAN, EAU, IDDM, and CIA). Mucosal antigen administration is superior in prevention to treatment of autoimmune diseases. To broaden the effectiveness of mucosal tolerance, a conjunction of tolerogens with cytokines/CTB might enhance suppression of clinical disease. Based on experimental experience with mucosal tolerance, trials in humans are ongoing in MS, RA, and uveitis. However, mucosal tolerance induction is related to the route of antigen administration (oral, nasal, parentetal), type of antigen (whole protein, peptide, altered peptide), and timing with regard to disease onset and may represent a two-edged sword. In particular, the risks of worsening an ongoing autoimmune disease by mucosal antigen administration have been incompletely addressed. Here we give an overview on some recent developments in this field where, however, much more studies are needed to define an ultimate and safe procedure.
自身抗原的黏膜给药可导致外周免疫耐受状态的形成。根据所给药抗原的剂量，抗原特异性T细胞的无反应性/缺失（高剂量）和/或产生免疫抑制细胞因子（转化生长因子-β、白细胞介素-4和白细胞介素-10）的细胞选择性扩增（低剂量）是诱导黏膜耐受的两个主要机制。在相同剂量下，与口服抗原相比，经鼻给药后黏膜耐受更有效。大量研究表明，口服或经鼻给予抗原诱导的黏膜耐受可有效预防多种实验性疾病模型（实验性自身免疫性脑脊髓炎、实验性自身免疫性重症肌无力、实验性变态反应性神经炎、实验性自身免疫性葡萄膜炎、胰岛素依赖型糖尿病和胶原诱导性关节炎）。黏膜抗原给药在预防自身免疫性疾病方面优于治疗。为了扩大黏膜耐受的有效性，将耐受原与细胞因子/霍乱毒素B亚单位联合使用可能会增强对临床疾病的抑制作用。基于黏膜耐受的实验经验，针对多发性硬化症、类风湿关节炎和葡萄膜炎的人体试验正在进行。然而，黏膜耐受的诱导与抗原给药途径（口服、经鼻、胃肠外）、抗原类型（全蛋白、肽、改变的肽）以及疾病发作的时间有关，可能是一把双刃剑。特别是，黏膜抗原给药使正在进行的自身免疫性疾病恶化的风险尚未得到充分解决。在此，我们对该领域的一些最新进展进行综述，然而，还需要更多的研究来确定最终的安全程序。
