Li Yunyuan, Tredget Edward E, Ghahary Aziz
Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
Hum Immunol. 2004 Feb;65(2):114-23. doi: 10.1016/j.humimm.2003.11.004.
Indoleamine 2,3-dioxygenase (IDO) has been indicated to prevent the fetus from maternal T-cell rejection. A longer survival of IDO genetically modified islets transplanted into NOD mouse kidney capsules has also been demonstrated. As IDO mediated mechanism of graft protection has not been elucidated, in our study we hypothesize that the expression of IDO may prevent immune rejection by suppressing the major histocompatibility complex (MHC) class I antigen. To test this hypothesis, an IDO adenoviral vector was constructed and the effect of IDO on MHC class I expression was evaluated on recombinant adenoviral transfected keratinocytes. Following a successful construction of IDO expressing adenoviral vector, the catabolic activity of IDO enzyme was evaluated by measuring the levels of its product, kynurenine in keratinocyte conditioned medium. The results indicated a higher level of kynurenine in IDO expressing cells relative to those of control cells. The results of MHC class I experiments revealed a significant downregulation of cell membrane associated MHC class I antigen in IDO genetically modified keratinocytes relative to that of either nontransfected or empty vector transfected cells. Further experiments demonstrated that an addition of tryptophan or IDO inhibitor markedly restored the expression of MHC class I on IDO transfected keratinocytes. The findings of this study suggest that downregulation of MHC class I expression by IDO might be one of the mechanisms through which IDO mediates local immunosuppression.
吲哚胺2,3-双加氧酶（IDO）已被证实可防止胎儿受到母体T细胞的排斥。研究还表明，将经IDO基因修饰的胰岛移植到NOD小鼠肾被膜中，其存活时间会延长。由于IDO介导的移植物保护机制尚未阐明，在我们的研究中，我们假设IDO的表达可能通过抑制主要组织相容性复合体（MHC）I类抗原，从而防止免疫排斥。为了验证这一假设，构建了一种IDO腺病毒载体，并在重组腺病毒转染的角质形成细胞上评估了IDO对MHC I类表达的影响。成功构建表达IDO的腺病毒载体后，通过测量角质形成细胞条件培养基中其产物犬尿氨酸的水平，评估了IDO酶的分解代谢活性。结果表明，与对照细胞相比，表达IDO的细胞中犬尿氨酸水平更高。MHC I类实验结果显示，与未转染或空载体转染的细胞相比，经IDO基因修饰的角质形成细胞中与细胞膜相关的MHC I类抗原显著下调。进一步的实验表明，添加色氨酸或IDO抑制剂可显著恢复IDO转染角质形成细胞上MHC I类的表达。本研究结果表明，IDO介导的MHC I类表达下调可能是IDO介导局部免疫抑制的机制之一。
