MSC促进移植后GVHD受体免疫耐受和重建的机理研究

项目名称： MSC促进移植后GVHD受体免疫耐受和重建的机理研究

项目编号： No.81470349

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘启发

作者单位： 南方医科大学

项目金额： 70万元

中文摘要： GVHD是 allo-HSCT后主要并发症和死亡原因，MSC是一种成体干细胞，因它的免疫调节作用在防治GVHD受到广泛研究。新近一些研究表明MSC抑制GVHD同时不增加感染和肿瘤复发，这可能归于MSC免疫调节的双重性-免疫抑制和免疫增强，但确切机理需深入研究。我们前期研究提示MSC能促进GVHD受体长期免疫耐受和免疫重建，接受MSC治疗病人胸腺输出功能增强。本研究基于MSC在胸腺功能发育和再生中作用、胸腺是T细胞发育与成熟的重要场所和我们前期研究结果提出：MSC通过影响胸腺而促进免疫耐受和重建假说。为验证此假说，在动物模型和GVHD病人中研究：MSC抗胸腺GVHD作用、MSC对TEC再生与胸腺功能影响；胸腺组织结构与胸腺微环境可溶性分子变化；外周TCR库重建等。通过这些研究验证我们的假说、揭示MSC促进GVHD受体免疫耐受和重建的机理，为MSC防治GVHD的技术平台建立提供理论依据。

中文关键词： 间充质干细胞；移植物抗宿主病；胸腺上皮细胞；免疫调控；异基因造血干细胞移植

英文摘要： Graft-versus-host disease (GVHD) is a major complication and cause of death following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mesenchymal stem cell (MSC) is a form of multipotent adult stem cell.It is studied widely in the prevention and treatment of GVHD because of its capacity of immunomodulation effects. Recently, some studies have demonstrated that MSC does not increase the risks of infections and tumour relapse for preventing and treating GVHD. This might be attributed to the bidirection immunomodulation of MSC- immunosuppression and immunoenhancement, but the mechanisms still need further study. Our previous studies found that MSC could induce long-term immune tolerance and promote immune reconstruction in recipients with GVHD, and the recipients undergoing MSC treatment exhibited a higher thymic output compared with the recipients without MSC treatment. Basing on that MSC plays an important role in thymus development and regeneration, as well as thymus is the primary lymphoid organ responsible for the generation and mature of T cells and our previous studies, we proposed the hypothesis that MSC promotes immune tolerance and reconstruction by influencing thymus. To verify this hypothesis, we will explore the effect of MSC on thymic GVHD and the regeneration of thymic epithelial cells (TECs), thymic microenviroment, thymic function, as well as the reconstruction of peripheral T-cell receptor (TCR) repertoire in animal model and recipients of GVHD. These studies will bring to light the mechanisms of MSC inducing immune tolerance and promoting immune reconstuction in the recipients with GVHD, and supply theoretical basis for MSC in preventing and treating GVHD.

英文关键词： mesenchymal stromal cell(MSC);graft versus host disease(GVHD);thymic epithelial cell(TEC);immunomodulation;allogeneic hematopoietic stem cell transplantation(allo-HSCT)