Weiner H L
Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham & Women's Hospital, 77 Avenue Louis Pasteur, HIM 730, Boston, MA 02115-5817, USA.
Microbes Infect. 2001 Sep;3(11):947-54. doi: 10.1016/s1286-4579(01)01456-3.
Oral tolerance is a long recognized method to induce peripheral immune tolerance. Oral tolerance has been used successfully to treat animal models of autoimmune diseases and is being tested in human diseases. Low doses of oral antigen induce active suppression, whereas high doses induce clonal anergy and deletion. Oral antigen preferentially generates a Th2(IL-4/IL-10)- or a Th3(TGF-beta)-type response. Th3-type cells are a unique T-cell subset which primarily secrete TGF-beta, provide help for IgA and have suppressive properties for Th1 and other immune cells. Th3-type cells appear distinct from the Th2 cells as CD4(+) TGF-beta-secreting cells with suppressive properties in the gut have been generated from IL-4-deficient animals. In vitro differentiation of Th3-type cells from Th0 precursors from TCR transgenic mice is enhanced by culture with TGF-beta, IL-4, IL-10 and anti-IL-12. Because regulatory T cells generated by oral antigen are triggered in an antigen-specific fashion but suppress in an antigen-nonspecific fashion, they mediate bystander suppression when they encounter the fed autoantigen at the target organ. Thus, mucosal tolerance can be used to treat inflammatory processes that are not autoimmune in nature. Mucosal antigen has also been used to treat animal models of stroke and of Alzheimer's disease. Induction of low-dose oral tolerance is enhanced by oral administration of IL-4 and IL-10. Coupling antigen to CTB or administration of Flt-3 ligand enhances oral tolerance. Anti-B7.2 but not anti-B7.1 blocks low-dose, but not high-dose oral tolerance. High-dose oral tolerance is blocked by anti-CTLA-4. CD25(+) CD4(+) regulatory T-cell function also appears to be related to TFG-beta.
口服耐受是一种早已被认可的诱导外周免疫耐受的方法。口服耐受已成功用于治疗自身免疫性疾病的动物模型，并且正在人类疾病中进行试验。低剂量口服抗原诱导主动抑制，而高剂量则诱导克隆无能和缺失。口服抗原优先产生Th2（IL-4/IL-10）型或Th3（TGF-β）型反应。Th3型细胞是一种独特的T细胞亚群，主要分泌TGF-β，为IgA提供辅助，并对Th1和其他免疫细胞具有抑制特性。Th3型细胞似乎与Th2细胞不同，因为在肠道中具有抑制特性的分泌CD4(+) TGF-β的细胞已从IL-4缺陷动物中产生。用TGF-β、IL-4、IL-10和抗IL-12培养可增强TCR转基因小鼠Th0前体细胞在体外向Th3型细胞的分化。由于口服抗原产生的调节性T细胞以抗原特异性方式被触发，但以抗原非特异性方式发挥抑制作用，当它们在靶器官遇到摄入的自身抗原时，它们介导旁观者抑制。因此，黏膜耐受可用于治疗非自身免疫性的炎症过程。黏膜抗原也已用于治疗中风和阿尔茨海默病的动物模型。口服IL-4和IL-10可增强低剂量口服耐受的诱导。将抗原与霍乱毒素B亚单位偶联或给予Flt-3配体可增强口服耐受。抗B7.2而非抗B7.1可阻断低剂量但不能阻断高剂量口服耐受。抗CTLA-4可阻断高剂量口服耐受。CD25(+) CD4(+)调节性T细胞功能似乎也与TGF-β有关。
