工程化嵌合蛋白FasL修饰供体脾细胞输注为基础的治疗方案通过影响CD8+CD122+PD1+新型调节性T细胞诱导预致敏模型移植免疫耐受研究

预致敏受者体内存在的记忆性细胞是诱导移植免疫耐受的重要障碍。本课题组应用体外工程化蛋白修饰技术—ProtEx，使膜型嵌合蛋白Fas配体（mSA-FasL）短暂表达在器官、组织和细胞表面，成功诱导了多种器官初次移植免疫耐受。本课题在此基础上，将mSA-FasL修饰供体脾细胞输注联合阻断OX40/OX40L通路方案应用到预致敏小鼠心脏移植模型中，获得了良好治疗效果。我们前期发现：mSA-FasL诱导产生的CD8+CD122+PD1+新型调节性T细胞在移植后早期及移植物长期存活过程中可能发挥了重要免疫调节作用。本研究拟从mSA-FasL影响CD8+CD122+PD1+新型调节性T细胞产生的比例/数量变化，该群细胞抑制排斥反应的效果和作用机制等方面进行深入探讨。本研究为治疗预致敏排斥提供了一个新颖、有效的方案，并初步阐明相关机制，丰富了免疫学理论。

Memory cells in the pre-sensitize receipts are currently thought to be a major barrier to tolerance induction in transplantation. We developed a novel protein display technology called ProtEx, to transiently display a chimeric form of FasL on the surface of organs, tissues and cells, which proved to be efficient to induce tolerance in several primary transplant models. Based on these data, we obtained a very good result by displaying SA-FasL on the surface of donor splenocytes, combing blocking OX40/OX40L pathway in the pre-sensitize mice heart transplant model. In our previous data, we found mSA-FasL induced novel CD8+CD122+PD1+ regular T cell, and this group of cells play a critical role in the early stage of transplantation and in the long-term survival of grafts. Major mechanistic studies include the percentages/quantity, effect of rejection inhibiting and mechanism of CD8+CD122+PD1+T cells in immune regulation. The results from this project will clarify the mechanisms, enrich the theory of immunology, and also provide a novel, safe, and applicable approach for the prevention of pre-sensitize rejection.