MSC促进移植后GVHD受体免疫耐受和重建的机理研究

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.

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。

GVHD是allo-HSCT后的主要并发症和死亡原因。目前，GVHD防治以免疫抑制剂为主，过强的免疫抑制剂可导致肿瘤复发率及感染发生率增加。MSC 是一 种成体干细胞。因具有调节免疫、炎症等功能在防治GVHD领域受到广泛研究。当前报道MSC调控GVHD的机理主要聚焦在MSC对外周免疫池领域的研究。胸腺是T细胞发育和成熟的重要场所，且MSC在胸腺功能发育和再生中发挥重要作用。基于此，我们提出MSC可通过改善胸腺功能调控GVHD受体的免疫耐受和重建来调控GVHD。本研究通过构建GVHD动物模型，将MSC输注到GVHD受鼠体内，观察小鼠的生存和GVHD严重程度等；探讨MSC调控胸腺再生，促进移植后免疫重建的机理；并观察MSC对GVHD患者治疗的有效性与安全性。结果发现：MSC可明显改善GVHD受鼠的生存及临床病理评分。对aGVHD的治疗疗效明显优于cGVHD。且MSC显著改善GVHD受鼠胸腺的再生和输出功能，促进移植后中枢和外周免疫池T细胞亚群的重建，诱导Treg增殖。通过本研究在动物模型揭示MSC调控GVHD机理，MSC通过影响胸腺促进GVHD受体的免疫耐受和重建。