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

在这项研究中，我们提出了一种新的策略，通过诱导口服耐受来解决蛋白质药物的免疫学问题。通过使用卵清蛋白（OVA）作为模型蛋白药物，清楚地表明，在反复静脉给药后，全身免疫反应深刻地影响了蛋白质的药代动力学方面。口服预摄入OVA可通过诱导口服耐受，很好地抑制OVA的免疫应答，提示有可能克服蛋白类药物的免疫问题。比较口服耐受性与免疫抑制剂环孢素A （cyclosporin A, CsA）对全身免疫反应的抑制作用。口服耐受和CsA均能有效抑制免疫反应，血浆中OVA浓度模式与对照组基本相同，但CsA处理大鼠的抗OVA IgG水平明显升高。对胰岛素等生物活性蛋白进行了进一步的研究。胰岛素的药理作用在反复服用后再次下降。口服预摄胰岛素诱导的口服耐受性显著提高了胰岛素的药理作用。总之，我们已经证明了我们的策略在克服蛋白质药物的免疫学问题方面的有用性。该策略有望应用于临床阶段，与蛋白质药物一起进行有效、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.