研究树突状细胞诱导免疫耐受的作用和机理。方法 :将可溶性TNF α受体 (sTNFR p5 5 )基因修饰骨髓来源的非成熟型DC ,观察基因修饰DC的表型特征和功能变化 ,并研究其诱导免疫耐受的效果及机制。结果 :腺病毒sTNFR p5 5基因转染DC后 ,其表型及IL 12分泌与非成熟型DC相比无明显的变化 ;但LPS刺激后 ,sTNFR基因修饰可明显抑制LPS刺激对DC的表型及IL 12分泌的上调作用。sTNFR基因修饰的DC与同种T细胞的MLR明显减弱 ,并可体外诱导同种抗原特异性T细胞低反应性。将基因修饰的DC免疫受者后 ,移植的同系肿瘤的生长较非成熟型DC和LacZ DC免疫的受者明显加快 (P <0 .0 0 1)。结论 :sTNFR基因修饰非成熟型DC后 ,可抑制外源性LPS刺激的促成熟作用 ,维持DC的非成熟状态 ,并增强其致耐受活性 ;免疫小鼠后 ,可以诱导机体产生针对抗原的特异性免疫耐受。

Objective: To investigate the tolerogeneic properties of the gene modified dendritic cells. Methods: Bone marrow cells derived immature dendritic cells were transferred with AdmsTNFR or AdmLacZ. The phenotype and cytokine releasing of it were analyzed. Then, the tolerogeneic properties of the gene modified dendritic cells were investigated. Results: After modification with sTNFR gene, the phenotypes and IL 12 seeretics of DC have no significant changes as compare to those of unmodified DCs. But after stimulated with exogenous LPS, the phenotype of the unmodified DCs was significantly changed toward maturation and IL 12 release was mardedly up regulated, while sTNFR modification helped the DCs to resist the stimulative effects of LPS. The proliferation of allogeneic T cells co cultured with sTNFR modified DCs in MLR was strikingly depressed. T cells hyporesponsiveness could be induce when co cultured with sTNFR modified DCs in second MLR. In a tumor isograft transplant model, the growth of E.G7(OVA) was greatly promoted in the recipients immunized with OVA loaded sTNFR gene modified DCs. Conclusion: sTNFR modification blocks the effects of LPS on DC maturation, and augments the tolerogeneic properties of these cells. sTNFR modified DCs can induce alloantigen specific immune tolerance in mice.

国家自然科学基金 ( 39870 80 9)