Abstract：
Antigen-specific immune tolerance, which possesses great potential in preventing or curing type 1 diabetes mellitus (T1DM), can be induced by oral vaccination with T1DM-related autoantigens. However, direct administration of autoantigens via oral route exhibits a low tolerance-inducing effect as a result of the digestion of protein antigens in the gastrointestinal tract (GIT) and therefore, a large dosage of autoantigens may be needed. In this study, bacterium-like particles (BLPs) made from food-grade lactic acid bacteria were used to deliver the intracellular domain of the insulinoma-associated protein 2 (IA-2ic). For this purpose, BLPs-IA-2ic vaccine in which IA-2ic bound to the surface of BLPs was constructed. BLPs enhanced the stability of the delivered IA-2ic based on the stability analysis in vitro. Oral administration of BLPs-IA-2ic significantly reduced T1DM incidence in NOD mice. The mice fed BLPs-IA-2ic exhibited a significant reduction in insulitis and preserved the ability to secrete insulin. Immunologic analysis showed that oral vaccination with BLPs-IA-2ic induced antigen-specific T cell tolerance. The results revealed that the successful induction of immune tolerance was dependent on the immune deviation (in favor of T helper 2 responses) and CD4+CD25+FoxP3+ regulatory T cells. Hence, oral vaccination with BLPs-IA-2ic shows potential for application in preventing T1DM.
摘要：
抗原特异性免疫耐受，在预防或治疗1型糖尿病（T1DM）方面具有巨大潜力，可通过口服接种T1DM相关自身抗原诱导。然而,通过口服途径直接给药自身抗原表现出低的耐受性诱导作用，这是由于蛋白质抗原在胃肠道（GIT）中的消化，因此，可能需要大剂量的自身抗原。在这项研究中,由食品级乳酸菌制成的细菌样颗粒(BLP)用于递送胰岛素瘤相关蛋白2(IA-2ic)的胞内结构域.为此,构建了其中IA-2ic结合到BLPs表面的BLPs-IA-2ic疫苗。基于体外稳定性分析,BLP增强递送的IA-2ic的稳定性。口服BLP-IA-2ic显著降低NOD小鼠的T1DM发病率。饲喂BLP-IA-2ic的小鼠表现出胰岛炎的显着减少，并保留了分泌胰岛素的能力。免疫学分析表明，口服BLP-IA-2ic疫苗可诱导抗原特异性T细胞耐受。结果表明，成功诱导免疫耐受取决于免疫偏差（有利于T辅助细胞2应答）和CD4+CD25+FoxP3+调节性T细胞。因此，口服BLP-IA-2ic疫苗在预防T1DM方面具有潜在的应用价值.
