CORM-3抑制树突状细胞TLRs信号转导的机制及其在肾移植排斥中作用的实验研究

项目名称： CORM-3抑制树突状细胞TLRs信号转导的机制及其在肾移植排斥中作用的实验研究

项目编号： No.30872581

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 生物科学

项目作者： 朱有华

作者单位： 中国人民解放军第二军医大学

项目金额： 30万元

中文摘要： 本课题探讨了CORM-3对树突状细胞生物学特性和功能的影响以及其对抗移植排斥反应的作用和机制。使用CORM-3处理小鼠骨髓来源DC和基于小鼠肾移植模型获取的肾固有DC。结果显示：CORM-3可显著抑制DC表面TLR4、CD80、CD86表达，显著抑制LPS刺激后TNF-α30340;分泌和p38、NF-κ#30340;活化，降低DC刺激T细胞增殖能力。但当TLR4缺陷之后，CORM-3抑制DC TNF-α34920;达作用不再存在。基于已建立的小鼠肾移植模型的体内实验显示，经CORM-3处理的供肾可明显延长移植肾存活时间，降低移植后血清肌酐水平，减轻肾脏病理损伤。此外，CORM-3处理供肾rDC移植后CD80和CD86的表达较对照组降低。因此，CORM-3能够抑制DC的活化和成熟，改善移植肾预后，本课题的研究结果为今后抗移植排斥研究提供新的思路，也为新型器官保存液的研发指出了新的方向。

中文关键词： 肾固有树突状细胞；一氧化碳；排斥反应；肾移植

英文摘要： In this study, we intended to research the inhibitory effect of Carbon monoxide-releasing molecules (CORM-3) on the maturation and activation of renal dendritic cells (rDC) and the underlining mechanisms in renal graft rejection. We treated Bone marrow dendritic cells (BMDC) and rDC with CORM-3 together with or without Lipopolysaccharides (LPS). We found that CORM-3 significantly inhibited the expression of both TLR2 and TLR4 in immature DC in a dose dependent manner. CORM-3 also suppressed the ability of BMDC to stimulate proliferation of allogenic T cells. Compared with iCORM, CORM-3 suppressed the expression of TNF-αn DC after LPS stimulation. However, this inhibitory effect of CORM-3 was abrogated in TLR4-/- mice. We also treated harvested donor BALB/c kidney with CORM-3 in preservation solution before transplant into C57BL/6J mouse. Our data showed that CORM-3 pretreated kidneys had significantly extended survival time as compared with the iCORM pretreated kidneys. Consistently, CORM-3 group had lower levels of creatinine and perserved histological structure in the graft kidney. Meanwhile, CORM-3 suppressed the expression of CD80 and CD86 in rDCs. Our studies suggest that CORM-3 inhibited the maturation and activation of DCs after transplantation,supressed allorejection and therefore improved graft survival. Our study provided a new strategy for treating grafts before transplantation to suppress allograft rejection.

英文关键词： renal dendritic cell; carbon monoxide; reject reaction; kidney transplantation