Kagnoff M F
Laboratory of Mucosal Immunology, University of California, San Diego, La Jolla 92093-0623, USA.
Baillieres Clin Rheumatol. 1996 Feb;10(1):41-54. doi: 10.1016/s0950-3579(96)80005-7.
Decreased systemic immune responsiveness to a specific antigen following exposure to that antigen by the enteric route is termed 'oral tolerance.' Oral tolerance is revealed when attempts are made to parenterally immunize the host to the same antigen that was previously administered orally or intragastrically. A similar phenomenon is also seen following antigen exposure via the nasal mucosa and a related phenomenon is seen following antigen exposure in the upper respiratory tract. There has been a marked renewal of interest in the mechanisms that underlie oral tolerance because of its potential role for preventing and treating autoimmune and inflammatory diseases and IgE-mediated allergic disorders. The specific factors that determine whether or not the host develops mucosal tolerance to an antigen administered by the mucosal route are also of substantial importance for those involved in mucosal vaccine development. Furthermore, putative abnormalities in the ability of the host to develop mucosal tolerance may play a pathogenetic role in certain autoimmune and allergic diseases and disorders. Several well-defined immunological mechanisms mediate oral tolerance. These include the induction, following mucosal antigen exposure, of regulatory populations of T-cells that can down-regulate specific immune responses (e.g. DTH) via the production of specific cytokines (e.g. TGF-beta 1, IL-10 and IL-4). In addition, clonal anergy, clonal deletion and antibody-mediated suppression can be shown to play a role in the induction and maintenance of mucosal tolerance in several experimental systems. In animal studies, the onset of collagen-induced, adjuvant-induced, antigen-induced and pristane-induced arthritis has been delayed and the severity of ongoing disease diminished following feeding collagen type II. Mucosal tolerance has been clearly demonstrated in humans and clinical studies have been undertaken to treat rheumatoid arthritis using a similar approach. Results of initial clinical studies in rheumatoid arthritis indicated a modest improvement and further studies are ongoing in this and other autoimmune diseases (e.g. multiple sclerosis, autoimmune uveitis and insulin-dependent diabetes). This approach, if successful, could offer a new and novel therapeutic modality for preventing autoimmune and allergic disorders, and modulating ongoing disease.
经肠道途径接触特定抗原后，全身对该抗原的免疫反应性降低，这被称为“口服耐受”。当试图通过非肠道途径使宿主免疫先前经口服或胃内给予的相同抗原时，口服耐受就会显现出来。通过鼻黏膜接触抗原后也会出现类似现象，在上呼吸道接触抗原后会出现相关现象。由于口服耐受在预防和治疗自身免疫性疾病、炎症性疾病以及IgE介导的过敏性疾病方面的潜在作用，人们对其潜在机制的兴趣显著复苏。对于参与黏膜疫苗研发的人员来说，决定宿主是否对经黏膜途径给予的抗原产生黏膜耐受的特定因素也至关重要。此外，宿主产生黏膜耐受能力的假定异常可能在某些自身免疫性和过敏性疾病及病症中发挥致病作用。几种明确的免疫机制介导口服耐受。这些机制包括黏膜抗原接触后诱导产生调节性T细胞群体，这些细胞可通过产生特定细胞因子（如转化生长因子-β1、白细胞介素-10和白细胞介素-4）来下调特定免疫反应（如迟发型超敏反应）。此外，在多个实验系统中，克隆无能、克隆缺失和抗体介导的抑制作用在黏膜耐受的诱导和维持中也发挥作用。在动物研究中，喂食II型胶原蛋白后，胶原诱导性、佐剂诱导性、抗原诱导性和 pristane 诱导性关节炎的发病延迟，且现有疾病的严重程度减轻。黏膜耐受在人类中已得到明确证实，并且已经开展了临床研究，采用类似方法治疗类风湿关节炎。类风湿关节炎初步临床研究结果表明有一定程度的改善，目前正在对这种疾病和其他自身免疫性疾病（如多发性硬化症、自身免疫性葡萄膜炎和胰岛素依赖型糖尿病）进行进一步研究。如果这种方法取得成功，可能会为预防自身免疫性和过敏性疾病以及调节现有疾病提供一种全新的治疗方式。
