IDO (indoleamine 2,3-dioxygenase)tryptophan吲哚胺2.3-双加氧酶1MTIDOkynurenineKynurenicacidanthranilic acid3-hydroxykynurenine3-HAincreasedIDOquinoninatedecreasedtryptophantryptophanmetabolitesGCN2activationIDO表达与功能调控*DC产生IDODC被抑制increased→IDO ↓unchangedtRNA*SOCS1-IFN-X信号转导分子STAT1★→IFN-Y诱生IDO的cell cycle arrestTregapoptosis效应↓T cell anergyinduction?cell cycle arrest*SOCS3表达+→IDO活性↑
tryptophan kynurenine Kynurenic acid anthranilic acid 3-hydroxykynurenine 3-HA quinoninate IDO 1MT increased unchanged tRNA decreased tryptophan increased tryptophan metabolites GCN2 activation cell cycle arrest T cell anergy apoptosis cell cycle arrest Treg induction? IDO IDO (indoleamine 2,3-dioxygenase) (吲哚胺2,3-双加氧酶) IDO表达与功能调控 * DC产生IDO↑DC被抑制 IDO↓ * SOCS1IFN-γ信号转导分 子STAT1↓IFN-γ诱生IDO的 效应↓ * SOCS3表达↓IDO活性↑
PositiveregulationCpGIEN-ONegativeregulationIFN-YDC1L-12NKHHH2TH2HTregKTH17IDO（色氨酸代谢限速酶）→微环境色氨酸耗竭→>T细胞增殖和应答产生色氨酸代谢中间产物一→细胞毒性或调亡直接或间接（→>HO-1表达↑）抑制HMGB1释放及功能直接/间接诱生Treg
IDO（色氨酸代谢限速酶） 微环境色氨酸耗竭T细胞增殖和应答↓ 产生色氨酸代谢中间产物细胞毒性或凋亡 直接或间接（HO-1表达↑）抑制HMGB1释放及功能 直接/间接诱生Treg
IDO-expressingTreg与 IDODCTreg→DC产生IDO↑1→抑制作用87-1TregIDOorB7-2CTLA4interactionIDOwithB7-1orB7-2activatesactivatesIDoIDOTregCTLA4expression→色氨酸分解产物↑→诱导Foxp3表达→Treg分化与诱生 ↑Treg
Treg →DC产生IDO↑ ↑ →抑制作用 Treg IDO Treg与IDO IDO →色氨酸↓分解产物↑ →诱导Foxp3表达 →Treg分化与诱生↑
Themechanisms of IDO mediated TcellsuppressionIDO+IDO-expressingTregexpreesedDCbyDCsHO-1HMGB1B7-1orB7-2CTLA4interactionIDOWithB7-1orB7-2activatesactivatesIDOTregCTLA4inflammatoryresponseexpressiongraftrejectionlAiDTreg
The mechanisms of IDO mediated T cell suppression Treg IDO expreesed by DCs HMGB1 HO-1 inflammatory response graft rejection/AID↓
IDO相关的免疫病理DiseaseEffects of IDOHuman CancerHelp Tumoral immune escapeHIV InfectionSuppress immune responsesAIDInduce EAE, RA and AsthmaFetal RejectionInduce ToleranceColitisReduce InflammationAllo-graftInduce Tolerance*调控IDO表达一保护组织移植物一诱导移植耐受IDO基因导入胰岛一→延长同种胰腺细胞存活时间**IDO抑制剂→逆转同种（鼠）肝移植耐受→排斥反应Steadystatedendritic cells withforcedIDO expression induceskinallografttolerancebyupregulationof regulatoryTcells.Transpl Immunol.2oo8Jan;18(3):208-19.Epub2007Sep10.Gene deliveryof indoleamine 2,3-dioxygenase prolongs cardiacallograft survivalbyshapingthetypesofT-cellresponses.JGeneMed.2oo8May2
IDO相关的免疫病理 ————————————————————————————— Disease Effects of IDO ————————————————————————————— Human Cancer Help Tumoral immune escape HIV Infection Suppress immune responses AID Induce EAE，RA and Asthma Fetal Rejection Induce Tolerance Colitis Reduce Inflammation Allo-graft Induce Tolerance ———————————————————————————— * 调控IDO表达保护组织移植物诱导移植耐受 * IDO基因导入胰岛延长同种胰腺细胞存活时间 * IDO抑制剂逆转同种(鼠）肝移植耐受排斥反应 ————————————————————————————— Steady state dendritic cells with forced IDO expression induce skin allograft tolerance by upregulation of regulatory T cells.Transpl Immunol. 2008 Jan;18(3):208-19. Epub 2007 Sep 10. Gene delivery of indoleamine 2,3-dioxygenase prolongs cardiac allograft survival by shaping the types of T-cell responses. J Gene Med. 2008 May 2