骨髓来源的免疫抑制细胞在激素治疗局灶节段性肾小球硬化过程中的作用研究

发布时间：2018-04-29 11:44

本文选题：局灶节段性肾小球硬化 + 糖皮质激素　；参考：《南京大学》2014年硕士论文

【摘要】：糖皮质激素(Glucocorticoids,GC)是广泛应用于治疗肾小球肾炎的一种常见激素类药物,其缓解免疫疾病的机制尚不明确。通过一系列的研究验证,我们发现糖皮质激素在治疗局灶节段性肾小球硬化(Focal Segmental Glomerulosclerosis,FSGS)的过程中通过刺激骨髓来源的免疫抑制细胞(Myeloid derived suppressor cell,MDSC)发挥作用。我们根据临床样本检测结果发现,相比于健康正常人群,在FSGS 患者外周血中出现 CD11b~+HLA-DR-CD14CD15~+ 和 CD11b~+ HLA-DR-CD14~+CD33~+细胞的累积。其中,对糖皮质激素易感的患者,在使用糖皮质激素治疗后,患者体内 CD11b~+HLA-DR-CD14-CD15~+ 和 CD11b~+HLA-DR-CD14~+CD33~+细胞出现更大程度累积;而对糖皮质激素不敏感的患者,经激素治疗后体内却并未检测到这种细胞的进一步累积。此外,我们通过动物疾病模型构建,发现这种细胞在肾脏损伤的小鼠外周血、脾、骨髓中也出现类似的累积现象,同时我们还观察到阿霉素肾损伤诱导的MDSC可以抑制T细胞的增殖并上调细胞因子水平。当我们给肾损伤小鼠施用地塞米松后,小鼠组织损伤情况缓解,外周血、脾、骨髓中的MDSC水平在损伤的基础上进一步升高,说明CD11b~+HLA-DR-CD14-CD15~+和CD11b~+HLA-DR-CD14~+CD33~+细胞很可能参与抵御阿霉素诱导的小鼠初期肾损伤,且地塞米松对损伤的缓解作用也可能与MDSC存在某种联系。为了确认这一点,我们通过体外转导MDSC至小鼠体内,发现MDSC可以在微环境的作用下迁移至脾脏,从而发挥T细胞抑制作用。然而我们发现进行MDSC敲除后,阿霉素诱导的小鼠肾组织损伤程度加深,体内炎症水平上调。随后,我们对活体小鼠进行了 MDSC敲除,发现地塞米松无法在MDSC敲除的基础上缓解阿霉素诱导的肾损伤。以上结果表明,糖皮质激素治疗小鼠FSGS过程中通过刺激MDSC活性而发挥作用,患者血液中的MDSC水平也许可以作为判断糖皮质激素治疗效果的预测信号。
[Abstract]:Glucocorticoid glucocorticoid (GCC) is a common hormone used in the treatment of glomerulonephritis. Through a series of studies, we found that glucocorticoid plays an important role in the treatment of focal Segmental Glomerulosclerosis (FSGSs) by stimulating bone marrow-derived immunosuppressive cells (Myeloid derived suppressor cell line MDSCs) in the treatment of focal segmental glomerulosclerosis. We found that CD11b ~ HLA-DR-CD14 CD15 ~ and CD11b~ HLA-DR-CD14 ~ CD33 ~ accumulated in peripheral blood of FSGS patients compared with healthy controls. After glucocorticoid therapy, CD11bHLA-DR-CD14-CD15 ~ and CD11b~ HLA-DR-CD14 ~ CD33~ cells in patients with high risk of glucocorticoids accumulated to a greater extent, while those insensitive to glucocorticoids showed a greater accumulation. No further accumulation of such cells was detected in the body after hormone therapy. In addition, we found a similar accumulation of these cells in the peripheral blood, spleen and bone marrow of mice with kidney injury. We also observed that MDSC induced by adriamycin induced renal injury could inhibit T cell proliferation and up-regulate cytokine level. When we administered dexamethasone to mice with kidney injury, the tissue damage was alleviated, and the levels of MDSC in peripheral blood, spleen and bone marrow increased further on the basis of injury. These results suggest that CD11b~ HLA-DR-CD14-CD15 ~ and CD11b~ HLA-DR-CD14 ~ CD33~ cells may be involved in resisting the initial renal injury induced by doxorubicin in mice, and that the protective effect of dexamethasone on the damage may be related to MDSC. In order to confirm this, we transduced MDSC into mice in vitro and found that MDSC could migrate to the spleen under the action of microenvironment, thus exerting the inhibitory effect of T cells. However, we found that after MDSC knockout, adriamycin-induced renal tissue injury in mice was increased and inflammation level was upregulated. Then we performed MDSC knockout in live mice and found that dexamethasone could not alleviate the renal injury induced by doxorubicin on the basis of MDSC knockout. These results suggest that glucocorticoid may play a role in the treatment of FSGS by stimulating the activity of MDSC, and the level of MDSC in the blood of the patients may be used as a predictive signal to judge the effect of glucocorticoid therapy.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R692

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