Use of Oral Tolerance to Improve the Disposition of Protein Drugs in the Body

在本研究中，我们提出了一种新的策略，以解决蛋白质药物的免疫学问题，通过诱导口服耐受。通过使用卵清蛋白（OVA）作为模型蛋白质药物，它清楚地表明，在重复静脉给药后，全身免疫反应深刻地影响蛋白质的药代动力学方面。预先口服OVA可通过诱导口服耐受来完全抑制OVA的免疫应答，这表明有可能克服蛋白质药物的免疫学问题。比较口服耐受与免疫抑制剂环孢素A（CsA）抑制全身免疫反应的效力。口服耐受和CsA均有效地抑制了免疫应答，其中OVA的血浆浓度模式与对照实验中的那些几乎相同，尽管CsA处理的大鼠中的抗-OVAIgG水平明显升高。对生物活性蛋白如胰岛素进行了进一步的研究。再次，胰岛素的药理作用下降后，重复给药it. The口服耐受性的诱导口服preingestimation胰岛素显着提高了它的药理作用。总之，我们已经证明了我们的策略，以克服蛋白质药物的免疫问题的实用性。这一策略有望在临床阶段应用于蛋白质药物的有效和安全的治疗。

In this study, we have proposed a new strategy to solve the immunological problems of protein drugs by induction of oral tolerance. By using ovalbumin (OVA) as a model protein drug, it was clearly demonstrated that, after repeating intraveneous administration, systemic immune response profoundly affects the pharmacokinetic aspects of proteins. Oral pre-ingestion of OVA perfectly suppressed the immune response of OVA by inducing oral tolerance, suggesting the possibility to overcome the immunological problems of protein drugs. The potency of oral tolerance to suppress the systemic immune response was compared with that of cyclosporin A (CsA), immune suppressive drug. Both oral tolerance and CsA effectively suppressed the immune response where the plasma concentration pattern of OVA was almost the same with those in control experiments, although anti-OVA IgG levels in CsA treated rats were apparently elevated. Further studies were carried out with the bioactive proteins such as insulin. Again, the pharmacological effect of insulin declined after the repeated administration of it. The induction of oral tolerance by oral preingestion of insulin significantly improved the pharmacological effect of it. In conclusion, we have demonstrated the usefulness of our strategy to overcome the immunological problems of protein drugs. This strategy is expected to be used in the clinical stage for the efficient and safe therapy with the protein drugs.