第三方间充质干细胞（MSCs）促进胸腺再生调控移植免疫重建和抗CMV的作用及机制研究

巨细胞病毒（CMV）感染是移植后的致命并发症，治疗手段有限。有研究发现间充质干细胞（MSCs）具刺激胸腺再生和双向调节适应性免疫应答的功能，可协同CMV-CTL发挥抗CMV作用，但机制有待进一步探讨。我们前期在临床观察到MSCs共移植可以降低CMV病毒血症的发生率；研究了MSCs免疫调节和组织修复功能的信号通路。基于前期工作我们提出假说：CMV血清学阴性的第三方MSCs可通过刺激胸腺再生促进移植后免疫重建，发挥稳定的抗CMV效应。为此，本项目拟应用我们已建立的CMV感染疾病模型、MSCs移植的人源化小鼠模型和全景扫描分析等多种免疫学技术，深入研究MSCs在移植后免疫缺陷状态下通过刺激胸腺再生促进整体免疫重建，激发CMV特异性免疫应答的机制，系统评估其在感染小鼠移植模型中的抗CMV作用，并探讨优化治疗策略，为移植后免疫重建的治疗策略提供新思路，也为MSCs抗CMV的临床转化提供科学依据。

CMV infection is the one of the most frequent and lethal infectious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the immunosuppressed state, and treatment options are limited. It has been found that mesenchymal stem cells (MSCs) can promote the thymic regeneration, and moreover, MSCs could be a double-edged sword in regulating antigen-specific immune responses, which may enhance the antiviral effect of CMV-specific cytotoxic T lymphocytes (CMV-CTL) , while the mechanism remains unknown. Our clinical study shows that co-transplantation of MSCs can ameliorate CMV viremia. We have also previously reported the new insights into the signal transduction pathways related to the immunomodulatory and regenerative activity of MSCs. Thus, a hypothesis was proposed that third-party MSCs, derived from cytomegalovirus-seronegative donors, can promote immune reconstitution early after transplantation and exert a stable and durable protective anti-CMV effects. In order to verify this hypothesis, our project intends to explore the role and mechanism of MSCs in modulating immune reconstitution by thymic regeneration post-HSCT and anti-CMV effects using our established technologies and human CMV infection model as well as the dual-humanized mouse model with human mesenchymal stem cell transplantation, and moreover to explore its optimal treatment strategies. This study will provide a new strategy for promoting immune reconstruction after transplantation by thymic regeneration, and be valuable for the clinical application of MSCs for the treatment of CMV infections post-transplantation.