CD40及CTLA4模拟小分子肽诱导免疫耐受的实验研究

目的 最新实验数据显示了CD28－B7和CD40－CD154共刺激信号通路在T细胞活化与效应过程中起重要作用。治疗策略关键在于干扰这些通路，诱导移植物宿主产生免疫耐受。方法 我们运用生物信息学和多肽合成技术模拟CTLA4和CD40小分子肽，以阻断这些信号通路。通过MLC，IL－2测定及同源小鼠皮肤皮肤移植实验，检测了不同剂量的两种小分子短肽在体内和体外对免疫反应的影响。结果 所有治疗组的巴细胞增殖降低，IL－2表达低下。在不同水平与时间段，皮肤移植物存活时间显著延长。结论 成功模拟CTLA4和CD40小分子肽，该小分子肽能有效地阻断调节T细胞活化的CD28－B7和CD40－CD154分子连接，是潜在的具有临床应用价值的免疫抑制剂。

An experimental study on CD40 and CTLA4 simulating peptides inducing immune tolerance

Objective Recent experimental data indicate that the costimulatory signal pathways of CD28 B7 and CD40 CD154 offer essential roles for T cell activation and effecting.Therapeutic strategy focuses on interrupting these pathways for tolerance induction in transplant recipients.Methods We designed two novel peptides by simulating the partial active region of CTLA4 and CD40 molecules with bioinformatics technique and peptide synthesis in order to block these signal pathways.In this study we determine how the immune response develops under the influence of the two peptides both in vitro and in vivo.The experiments of human mixed lymphocyte culture(MLC),IL 2 Elisa assay and skin allotransplantation in mice were performed with different doses.Results All treatment groups along with lower proliferation of lymphocytes and poor IL 2 product prolong the skin graft survival obviously in different levels and times.Conclusion We for the first time synthesized the CTLA4 and CD40 peptides successfully.And these peptides could block the important signals effectively between CD28 B7 and CD40 CD154 molecular ligation that modulates T cell activation.These two novel peptides are potentially being immunosuppressive agents on tolerance induction for clinical use.