Effect of Exogenously Applied Endothelial Cells in Thymic Regeneration After Hematopoietic Stem Cell Transplantation

造血干细胞移植后免疫系统的恢复是避免严重感染并发症和癌症复发的关键过程。胸腺损伤后，如化疗、放疗或移植物抗宿主病，胸腺再生是恢复免疫功能所必需的。宿主实验室最近证明，胸腺内皮细胞可以被分离、体外扩增(ExECthy)，当静脉注射到接受亚致命全身照射的小鼠体内时，可以促进胸腺恢复。该项目的主要目标是研究过继移植作为一种新的治疗方法，以改善造血细胞移植(HCT)受者的胸腺和免疫再生。从捐赠者、接受者或第三种小鼠品系中分离出来的器官将被注射到接受过同基因或异基因干细胞移植的小鼠体内。将评估这种转移对胸腺再生以及外周T细胞重建、T细胞功能和T细胞受体多样性的影响。同时，还将研究切除在胸腺血管系统中的整合以及加强这一过程的方法。过继给予切除代表了一种促进患者胸腺功能更新的新的细胞疗法。因此，拟议项目的结果将作为开发具有临床意义的免疫再生策略的起点。

Recovery of the immune system after hematopoietic stem cell transplantation is a key process to avoid severe infectious complications and a cancer relapse. Thymic regeneration after an injury, such as chemotherapy, irradiation or graft versus host disease is necessary for regaining the immune competence. The host laboratory recently demonstrated that thymic endothelial cells can be isolated, expanded ex vivo (exECthy) and, when administered intravenously into mice receiving a sub-lethal total body irradiation, enhance thymic recovery. The major goal of the proposed project is to study the adoptive transfer of exECthy as a novel therapeutic approach to improve thymic and immune regeneration in recipients of hematopoietic cell transplantation (HCT). The exECThy isolated from the donor, recipient or a third mouse strain will be injected into mice that have received a syngeneic or allogeneic stem cell transplantation. The effect of this transfer on thymic regeneration, as well as peripheral T-cell reconstitution, T-cell function and T-cell receptor diversity will be evaluated. At the same time, the integration of exECThy in the thymus vasculature and ways to enhance this process will be studied. Adoptive administration of exECThy represents a novel cellular therapy promoting thymic function renewal in patients. Therefore, the results of the proposed project will serve as a starting point for the development of a clinically relevant immune-regenerative strategy.