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)作为蛋白质药物的模型，清楚地表明，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。口服预先摄入OVA可通过诱导口服耐受而完全抑制OVA的免疫反应，这表明有可能克服蛋白质药物的免疫学问题。比较口服耐受性与免疫抑制药环孢素A(CsA)对全身免疫反应的抑制作用。口服耐受性和CsA均能有效地抑制免疫反应，其中OVA的血药浓度模式与对照组几乎相同，但CsA组大鼠的抗OVA-Ig G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。再次，胰岛素的药理作用在反复给药后下降。口服胰岛素诱导耐受可显著提高胰岛素的药理作用。总而言之，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效性。这一策略有望应用于临床阶段，为蛋白质类药物的高效安全治疗奠定基础。

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.