Hafler D A, Kent S C, Pietrusewicz M J, Khoury S J, Weiner H L, Fukaura H
Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Ann N Y Acad Sci. 1997 Dec 19;835:120-31. doi: 10.1111/j.1749-6632.1997.tb48623.x.
Oral administration of antigen is a long-recognized method of inducing systemic immune tolerance. In animals with experimental autoimmune disease, a major mechanism of oral tolerance involves the induction of regulatory T cells that mediate active suppression by secreting the cytokine TGF-beta 1. Multiple sclerosis (MS) is a presumed T cell-mediated Th1 type autoimmune disease. In this paper we investigated, in patients with MS, whether oral myelin treatment (myelin containing both MBP and PLP) induced antigen-specific MBP- or PLP-reactive T cells that were either Th2-like (secreted IL-4 or TGF-beta 1), or alternatively whether Th1 type sensitization occurred as measured by IFN-gamma secretion. Specifically, 4,860 short-term T cell lines were generated to either MBP, PLP or TT from 34 relapsing-remitting patients with MS; 17 were orally treated with bovine myelin daily for a minimum of two years as compared to 17 non-treated patients. We found a marked increase in the relative frequencies of both MBP- and PLP-specific TGF-beta 1 secreting T cell lines in the myelin-treated MS patients as compared to non-treated MS patients (MBP, p < 0.001; PLP, p < 0.003). In contrast, no changes in the frequency of MBP- or PLP-specific IFN-gamma or TT-specific TGF-beta 1 secreting T cells were observed. These results suggest that the oral administration of antigens generates antigen-specific TGF-beta 1 secreting T cells of presumed mucosal origin that may represent a distinct cytokine-secreting lineage of T cells (Th3). Since, in animal models, antigen-specific TGF-beta 1 secreting cells localize to the target organ and then suppress inflammation in the local microenvironment, oral tolerization with self-antigens may provide a therapeutic approach for the treatment of cell-mediated autoimmune disease which does not depend upon knowledge of the antigen specificity of the original T cell clone triggering the autoimmune cascade.
口服抗原是一种早已被认可的诱导全身免疫耐受的方法。在患有实验性自身免疫病的动物中，口服耐受的一个主要机制涉及诱导调节性T细胞，这些调节性T细胞通过分泌细胞因子转化生长因子β1（TGF-β1）来介导主动抑制。多发性硬化症（MS）被认为是一种T细胞介导的Th1型自身免疫病。在本文中，我们研究了在MS患者中，口服髓磷脂治疗（含有髓鞘碱性蛋白（MBP）和蛋白脂蛋白（PLP）的髓磷脂）是否会诱导出抗原特异性的MBP或PLP反应性T细胞，这些T细胞要么类似Th2细胞（分泌白细胞介素-4（IL-4）或TGF-β1），或者通过干扰素-γ（IFN-γ）分泌来衡量是否发生了Th1型致敏。具体而言，从34例复发缓解型MS患者中产生了4860个针对MBP、PLP或破伤风类毒素（TT）的短期T细胞系；17例患者每天口服牛髓磷脂至少两年，与之相比的是17例未接受治疗的患者。我们发现，与未接受治疗的MS患者相比，接受髓磷脂治疗的MS患者中，MBP特异性和PLP特异性分泌TGF-β1的T细胞系的相对频率显著增加（MBP，p < 0.001；PLP，p < 0.003）。相比之下，未观察到MBP或PLP特异性分泌IFN-γ的T细胞或TT特异性分泌TGF-β1的T细胞的频率有变化。这些结果表明，口服抗原会产生推测为黏膜来源的抗原特异性分泌TGF-β1的T细胞，这些T细胞可能代表一种独特的分泌细胞因子的T细胞谱系（Th3）。由于在动物模型中，抗原特异性分泌TGF-β1的细胞定位于靶器官，然后在局部微环境中抑制炎症，因此用自身抗原进行口服耐受可能为治疗细胞介导的自身免疫病提供一种治疗方法，这种方法不依赖于引发自身免疫级联反应的原始T细胞克隆的抗原特异性知识。
