供者T细胞致骨髓niche中Nestin+MSC异常在chronicGVHD发生发展中的作用及机理

Abnormality of bone marrow niche plays an important role in the development of GVHD. Nestin+MSC is an important component of bone marrow niche. Our previous research showed that MSC derived from bone marrow had therapeutic effect on chronic GVHD by restoring B cell homeostasis. The number of endosteal Nestin+MSC decreased in the chronic GVHD mouse models. However, it is unkown whether donor T cells cause the damage of Nestin+MSC. What kind of T cells mediated the damage of Nestin+MSC and the mechanism has not been elucidated. Based on these finding, we propose that the damage of Nestin+MSC caused by donor T cells lead to the abnormality of bone marrow niche、imbalance of B cell homeostasis and so on. These changes induce or aggravate the development of chronic GVHD. To test this hypothesis, we will explore the destruction and mechanism of Nestin+MSC in bone marrow niche by donor T cells; the changes of soluble cytokines and recipient cell antigen expression in the abnormal bone marrow niche; and the effects of abnormal bone marrow niche on B cell homeostasis and so on. These studies will reveal the role and mechanism of Nestin+MSC abnormality caused by donor T cells in the development of chronic GVHD. These studies will also provide the theoretical basis for preventing and treating chronic GVHD.

骨髓niche异常在GVHD中起重要作用，Nestin+MSC是niche的重要组成。我们前期研究发现骨髓来源MSC对cGVHD有效是通过调节B细胞稳态；cGVHD小鼠骨内膜附近Nestin+MSC减少。但Nestin+MSC破坏或异常的原因是否与供者T细胞相关,何种T细胞介导该异常及介导机制尚未阐明。基于这些我们提出：移植后供者T细胞破坏niche中Nestin+MSC，致骨髓niche功能异常、B细胞稳态失平衡等诱发或加重cGVHD发生与发展的假说。为验证假说，本项目在动物模型、体外和cGVHD病人中研究：供者T细胞对骨髓niche中Nestin+MSC的破坏及机理；骨髓niche的异常及其对B细胞稳态等影响。通过这项研究揭示供者T细胞破坏骨髓niche中Nestin+MSC，致骨髓niche功能异常、B细胞稳态失平衡等在cGVHD发生与发展中的作用及机理，为cGVHD防治提供理论依据

骨髓niche异常在GVHD中起重要作用，Nestin+MSC是niche的重要组成。我们前期研究发现骨髓来源MSC对cGVHD有效是通过调节B细胞稳态；cGVHD小鼠骨内膜附近Nestin+MSC减少。但Nestin+MSC破坏或异常的原因是否与供者T细胞相关,何种T细胞介导该异常及介导机制尚未阐明。我们的研究发现：异体反应性/自体反应性T细胞大量增殖且杀伤功能等明显增加，并向Th1和Tc1分化。扩增及功能异常的T细胞介导了骨髓niche中血管的破坏及Nestin+MSC的扩增。扩增的Nestin+MSC其成纤维化能力、成骨能力明显增加而成脂能力明显下降。且扩增的Nestin+MS与异常骨niche中CD169+巨噬细胞相互作用，Nestin+MSC中异常的TGF-β/Smad信号通路以及B细胞稳态的失平衡加重了cGVHD的发生发展。