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

抗原的口服免疫长期以来被认为是预防或延迟与对自身和非自身抗原的不良免疫应答相关的疾病的发作的方法。虽然口服抗原提供了一种方便的诱导系统耐受的方法，但其治疗潜力受到严重限制，因为它需要重复喂养大量抗原，并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。我们以前已经表明，口服给药的聚-D，L-乳酸（PDLLA）微球含有抗原选择性地分布到派尔集合淋巴结（PP）和全身淋巴组织根据其直径，然后释放抗原在一个很长的时间。我们报道了用含有2 mg OVA的适当直径的PDLLA微球单剂量胃内免疫抑制OVA特异性IgG和DTH反应的有效性与100 mg水溶性OVA相当。这与用抗原刺激的PP T细胞的IFN-g产生的大量增加和对OVA特异性的分泌伊加的少量增加有关。相反，给予另一种适当直径的抗原包被物导致增强的OVA特异性IgG应答，而OVA特异性分泌伊加没有显著增加。因此，通过利用适当直径的微球作为疫苗接种媒介物，我们能够通过口服单次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.