间充质干细胞抑制预致敏移植受者中抗体介导免疫排斥的机制研究

Organ transplantation is the therapy of choice for end-stage organ failure or congenital organ abnormalities, and offers an excellent opportunity for allowing patients to resume their normal lifestyles. Antibody-mediated rejection (AMR) is emerging as the leading cause of allograft rejection and graft loss in presensitized patients, however novel immunotherapies directly against AMR are still lacking. Bone marrow-derived mesenchymal stem cells (MSCs) are considered a promising therapeutic tool in clinical transplantation. The molecular mechanisms whereby MSCs mediate their immunomodulatory functions in vivo remain to be elucidated. Our preliminary data demonstrated for the first time - to our knowledge - that MSCs were capable of prolonging heart allograft survival, and in combination with rapamycin, effectively prevented AMR and achieved long-term graft survival in presensitized recipients. In this proposed study, we will use SPECT/CT imaging and cellular/molecular biology techniques to track MSC migration and localization, and to determine that MSCs (a) are inhibitors of B-cell activation and (b) are capable of inducing cardiac allograft prolongation and potentiating tolerance through: (i) attenuation of B-cell maturation and differentiation, (ii) direct conversion of B cells to regulatory B cells (Bregs) that are essential for the induction of regulatory T cells (Tregs). We will also demonstrate that the interaction between the PD-1 ligand (B7-H1) on MSCs and its receptor PD-1 on immune cells (T and B cells) is crucial in this process. Through this series of proposed experiments, we hope to expand our understanding of the mechanisms underlying the ability of MSCs to inhibit AMR and ultimately induce indefinite cardiac allograft survival in presensitized transplant recipients. This study aims to demonstrate the multi-potency of MSCs as an inhibitor of both B cell and T cell activation, which would clearly emphasize their significant clinical potential.

抗体介导免疫排斥反应(AMR)是造成预致敏器官移植受者中移植物丢失的主要原因，但目前尚无有效抑制AMR的治疗方案。骨髓间充质干细胞(MSC)治疗在器官移植领域中的应用展现可喜前景但其机理尚待阐明。基于申请人有关MSC可抑制预致敏小鼠中移植心脏AMR发生并与常规免疫抑制剂联用成功诱导移植物长期存活的首次前期发现，本项目采用影像及分子/细胞生物学技术，研究MSC对预致敏小鼠心脏移植受体中T和B细胞的相关免疫调控机制，阐明MSC在抑制B细胞活化及促进调节性T和B细胞增殖中的作用机理，同时论证MSC上B7-H1基因表达(与免疫细胞上PD-1相互作用)是促进MSC体内迁移和分布并发挥免疫抑制功能的必要条件，从而探讨MSC阻止预致敏受者中移植物AMR发生和诱导抗原特异性免疫耐受形成的作用机制。此项研究为进一步优化MSC治疗及其临床应用，以最终实现预致敏患者中移植器官免疫耐受的目标提供理论及实践依据。

抗体介导免疫排斥反应(AMR)是造成器官移植受者中移植物丢失的主要原因，也是影响移植器官长期存活的主要障碍。但目前尚无有效抑制AMR的治疗方案。骨髓间充质干细胞(MSC)治疗在器官移植领域中的应用展现可喜前景但其机理尚待阐明。基于申请人有关MSC可抑制心脏移植小鼠中AMR发生并与常规免疫抑制剂联用成功诱导移植物长期存活的前期发现，本项目采用分子和细胞生物学及影像学技术，对MSC抑制小鼠心脏移植物AMR发生并诱导抗原特异性免疫耐受形成的相关免疫调控机制进行了系列研究。研究结果发现MSC在抑制B细胞活化、增殖、成熟和功能中起着关键性作用。MSC可明显抑制心脏移植受体内抗原特异性抗体的产生，并可促进具有免疫抑制功能的耐受性树突状细胞以及调节性T和B细胞的产生。同时，结果证实MSC上B7-H1基因的显著表达是促进MSC体内迁移和分布并发挥免疫抑制功能的必要条件，在诱导心脏移植物长期存活中发挥着重要作用。同时利用转基因小鼠建立的动物模型，进一步说明了MSC联合常规免疫抑制剂所诱导的调节性B细胞是促进调节性T细胞产生的重要条件。此项研究为进一步优化MSC治疗及其临床应用，以最终实现患者移植器官免疫耐受的目标提供理论及实践依据。