GVHD炎性因子内环境对MSC功能可塑性影响的研究

Graft-versus-host disease (GVHD) is a major complication and cause of death following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mesenchymal stromal cell (MSC) is a form of multipotent adult stem cell. It is studied widely in the prevention and treatment of GVHD due to its immunomodulation and inflammatory regulating effects. This might be attributed to different local inflammatory microenvironment of MSC in the host and the plasticity of MSC in inflammatory modulation-pro-inflammation and anti-inflammation. Recently, some studies have found that there are large discrepancies of efficacy among different GVHD recipients and targeted organs receiving MSC treatments. But the mechanisms still need further study. Based on the disparity between the pathogenic mechanism of aGVHD and cGVHD, as well as the plasticity of MSC in inflammatory modulation, we propose the hypothesis that inflammatory environment influences the modulatory functions of MSC in the recipients with GVHD. To confirm this hypothesis, the disparity of cytokine/chemokine in different GVHD targeted organs and a/cGVHD will be explored in animal models and recipients of GVHD. And further study on the effect of MSC in different inflammatory environment will be carried out. These studies will reveal the mechanisms of MSC plasticity in different inflammatory environment, and provide 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作为一种成体干细胞，因具有免疫和炎性调节作用在防治GVHD领域受到广泛研究。MSC的免疫和炎性调节作用受其所处的炎性环境影响，其功能表现为可塑性：增强和抑制作用。临床应用表明MSC对不同类型、靶器官的GVHD疗效存在较大差异，但确切机理尚不清楚。本研究基于不同类型GVHD炎性内环境的差异性和MSC功能的可塑性提出：GVHD炎性因子内环境的差异性影响MSC的功能，从而导致MSC对不同类型、靶器官GVHD疗效的反应性差异假说。为验证此假说，在动物模型和GVHD病人中研究：不同GVHD靶器官、a/cGVHD环境中炎性/趋化因子的差异；MSC在不同GVHD炎性环境下功能的差异性等。通过这些研究验证我们的假说，揭示GVHD炎性内环境对MSC功能的影响及机理，为优化MSC防治GVHD的治疗提供理论依据。

移植物抗宿主病（GVHD）是异基因造血干细胞移植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。间充质细胞（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。MSC的免疫和炎性调节作用受其所处的炎性环境影响，其功能表现为增强或抑制作用的可塑性。临床应用表明MSC对不同类型、不同靶器官的GVHD疗效存在较大差异，但确切机理尚不清楚。本研究基于不同类型GVHD炎性内环境的差异性和MSC功能的可塑性提出：GVHD炎性因子内环境的差异性影响MSC的功能，从而导致MSC对不同类型、靶器官GVHD疗效的反应性差异假说。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；观察MSC对GVHD患者治疗的有效性与安全性。结果发现：1、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。2、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。本课题组在动物模型和GVHD患者中研究不同GVHD靶器官、a/cGVHD环境中炎性/趋化因子的差异，探讨MSC在不同GVHD炎性环境下功能的差异性。通过这些研究验证我们的假说，揭示GVHD炎性内环境对MSC功能的影响及机理，为优化MSC防治GVHD的治疗提供理论依据。