间充质干细胞免疫调节功能及其机制的研究

发布时间：2018-01-11 05:22

本文关键词：间充质干细胞免疫调节功能及其机制的研究　出处：《中国协和医科大学》2007年博士论文　论文类型：学位论文

【摘要】： 间充质干细胞具有低免疫原性和免疫调节功能，在治疗免疫疾病方面具有广阔的应用前景，但是疾病状态下间充质干细胞(Mesenchymal stem cell，MSC)的免疫调节功能是否正常还较少有人研究，MSC的免疫调节机制也还存在着很大的争议。在文章的第一部分，我们首先研究了骨髓异常增生综合征难治性贫血(myelodysplastic syndromes refractory anemia，MDS—RA)患者骨髓来源的MSC是否存在正常的免疫调节作用，实验结果发现MDS—RA的BMSC(Bone marrow derived MSC)抑制T细胞增殖和活化能力均减弱，但是抑制活化的T细胞凋亡的作用反而增强，这可能和MDS—RA患者BMSC分泌的TGF—β(Transforming growth factor)1，3，FasL(Fas ligand)等因子减少有关，我们推测在疾病状态下的BMSC也可能是不正常的，所以不适于做自体MSC移植。由于正常脂肪较正常骨髓组织容易获取，更适于大规模生产做临床治疗的药物，所以在文章的第二部分我们比较了AMSC(adipose derived MSC)和BMSC的免疫调节作用，发现AMSC和BMSC在抑制T细胞增殖，活化，调节T辅助细胞亚群的比例方面有相似的作用，但BMSC可以抑制活化的T细胞凋亡，而AMSC没有这种作用。在文章的第三部分，我们进一步研究了MSC免疫调节的机制，发现MSC表达Nanog，同时Nanog通过调节TGF—β和Dkk—1(Dickkopf-1)的分泌间接参与MSC的免疫调节。在文章的第四部分，我们利用小鼠模型，研究了MSC在体内免疫调节存在的时间以及需要使用的剂量，发现MSC在体内的作用具有剂量依赖性，，同时这种免疫调节作用在2周时最强，1个月是逐渐减弱，2个月基本消失。
[Abstract]:Mesenchymal stem cells have low immunogenicity and immunomodulatory function, so they have a broad application prospect in the treatment of immune diseases. However, whether the immune regulatory function of mesenchymal stem cells is normal under the condition of disease is still not studied. The immunomodulation mechanism of MSC is also controversial. In the first part of the article. We first studied myelodysplastic syndromes refractory anemia in refractory anemia patients with myelodysplastic syndrome. Whether MSC from bone marrow of MDS-RAA patients has normal immunomodulatory effect. The results showed that MDS-RA 's BMSC(Bone marrow derived inhibited the proliferation and activation of T cells. However, the inhibitory effect of activated T cell apoptosis was enhanced. This may be associated with TGF- 尾 transforming growth factor-1 secreted by BMSC in patients with MDS-RA. We speculate that BMSC may be abnormal in the condition of disease, so it is not suitable for autologous MSC transplantation. Because normal fat is easier to obtain than normal bone marrow tissue, it is more suitable for mass production of drugs for clinical treatment. So in the second part of this article, we compare the immunomodulatory effects of AMSC(adipose derived MSCI with BMSC. It was found that AMSC and BMSC had similar effects in inhibiting T cell proliferation, activating and regulating the proportion of T helper cell subsets, but BMSC could inhibit the apoptosis of activated T cells. AMSC does not. In the third part of the paper, we further studied the mechanism of MSC immunomodulation, and found that MSC expressed Nanog. At the same time, Nanog indirectly participates in the immunomodulation of MSC by regulating the secretion of TGF- 尾 and Dkk-1Dickkopf-1. In the 4th part of the paper, we used the mouse model to study the time and dosage of MSC in vivo immunomodulation. We found that the effect of MSC in vivo is dose-dependent. At the same time, the immunomodulation effect was the strongest at 2 weeks, gradually weakened at 1 month, and disappeared at 2 months.
【学位授予单位】：中国协和医科大学
【学位级别】：博士
【学位授予年份】：2007
【分类号】：R392

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