生分解性ポリマービーヅを用いた経口免疫法の開発と経口免疫寛容の解析への応用

长期以来，口服抗原免疫一直被认为是预防或延缓与自身和非自身抗原的不良免疫反应相关的疾病的发生的一种方法。虽然口服抗原提供了一种诱导全身耐受的便捷方法，但其治疗潜力受到严重限制，因为它需要反复喂食大量抗原，而且当使用自身抗原时，它可能会恶化正在进行的自身免疫性疾病。我们先前已经证明，口服含有抗原的聚-D，L-乳酸微球，根据其直径选择性地分布到Peyer‘s斑块(PP)和系统淋巴组织中，然后在较长时间内释放抗原。我们报道，用直径合适的PDLLA微球(含2 mg OVA)单次灌胃，与100 mg水溶性OVA一样有效地抑制OVA特异性的Ig G和DTH反应。这与抗原刺激的PP T细胞产生大量的干扰素-g和少量增加卵清蛋白特异性的分泌型IgA有关。相反，注射另一种合适直径的抗原包裹体可以增强卵清蛋白特异性的免疫球蛋白G反应，而不显著增加卵清蛋白特异性的分泌型免疫球蛋白A。因此，通过利用适当直径的微球作为疫苗载体，我们能够通过口服单一低剂量的抗原选择性地诱导全身耐受和致敏。

Oral immunization of antigens has long been recognized as a method to prevent or delay the onset of the diseases associated with untoward immune responses to self and non-self antigens. Although oral administration of antigens offers a convenient way to induce systemictolerance, its therapeutic potential has been seriously limited by the fact that it requires repeated feeding of a large amount of antigens and that it may deteriorate ongoing autoimmune diseases when autoantigens are employed. We have previously shown that orally administered poly-D,L-lactic accid (PDLLA) microspheres containing an antigen were selectively distributed to Peyer's patches (PP) and systemic-lymphoid tissues according to their diameter and then releses the antigen over a long period of time. We reported that a single dose of intragastric imunization with a PDLLA microsphere of appropropriate diameter size containing 2 mg of OVA was as effective as 100 mg of water soluble OVA to suppress OVA-specific IgG ad DTH response. This was associated with a large incresae of IFN-g production by PP T cells stimulated with an antigen and a small increase in secretory IgA specific to OVA. In contrast, administration of an antigen encapsulatead in another appropriate diameter size led to an enhanced OVA-specific IgG response and no significant increase in OVA-specific secretory IgA. Thus, by utilizing microspheres of an appropriate diameter as a vaccination vehicle, we were able to selectively induce both systemic tolerance and sensitization by oral ingestion of single low dose of an antigen.