吲哚胺-2,3-双加氧酶及其在肿瘤方面免疫调节的研究进展

吲哚胺-2,3-双加氧酶是催化色氨酸沿犬尿氨酸分解代谢的限速酶,在哺乳动物组织和细胞中广泛表达.色氨酸耗竭及其代谢产物是调节免疫抑制和免疫耐受的重要机制,在多种生理和病理状态中发挥重要的作用.因此,吲哚胺-2,3-双加氧酶在器官移植、自身免疫性疾病和肿瘤等方面的治疗也成了研究的热点.     

吲哚胺2,3-双加氧酶参与调控寄生虫与宿主免疫互作关系的研究进展

吲哚胺2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)是一种重要的免疫调节酶,主要通过耗竭色氨酸(tryp-tophan,Trp)和产生多种代谢产物来调节免疫效应.近年来,对IDO免疫功能的研究大多局限在肿瘤、自身免疫性疾病等领域,而在寄生虫病中的研究相对较少,尤其是寄生虫与宿主免疫互...     

吲哚胺-2,3双加氧酶在支气管哮喘和过敏症中的作用

变态反应(过敏症)是指机体对某些抗原初次应答后,再次接触相同抗原刺激时,产生以机体生理功能紊乱或组织损伤为主的一种特异性免疫应答.吲哚胺-2,3双加氧酶(indoleamine 2,3 dioxygenase,IDO)既是细胞内催化色氨酸分子沿犬尿酸途径进行分解代谢的限速酶,也是一种重要的免疫调节酶.越来越多的研究表明,免疫耐受机制缺陷在变应性疾病中扮演着重要的角色,而抗原递呈细胞(APC)如树突状细胞(DC)表达的IDO可通过多种机制诱导机体产生免疫耐受.因此,通过增加DC表达IDO而诱导免疫耐受,有望成为治疗支气管哮喘、变应性鼻炎和特应性皮炎的新靶点.     

吲哚胺2,3双加氧酶在病毒感染中的作用

吲哚胺2,3双加氧酶(indoleamine 2,3-dioxygenase,IDO)是色氨酸犬尿氨酸代谢途径的限速酶.IDO在抗病毒免疫中起重要作用,他能介导IFN-γ病毒及有免疫调节和致免疫耐受功能.本文就其在抗病毒免疫方面作一综述.     

吲哚胺-2,3双加氧酶、白细胞介素-10及白细胞介素-17变化与慢性阻塞性肺疾病的相关性

目的探讨慢性阻塞性肺疾病(COPD)稳定期患者血中吲哚胺-2,3双加氧酶(IDO)、白细胞介素(IL)-10及IL-17变化及其临床意义。方法检测33例COPD稳定期患者及21例健康对照组外周血中IDO mRNA、IL-17及IL-10水平。结果与健康对照组相比,COPD稳定期患者IDO mRNA及IL-10下降(P0.05),IL-17升高(P0.05)。结论 COPD稳定期患者中IDO减少,诱导IL-17分泌增加,IL-10分泌减少,IDO的减少可能参与了COPD慢性炎症的发生发展,提高机体树突细胞IDO的分泌有望为COPD的治疗开辟新的思路。     

细粒棘球蚴抗原诱导树突状细胞表达吲哚胺2,3-双加氧酶的动态观察

目的动态检测细粒棘球蚴不同抗原体外诱导树突状细胞表达吲哚胺2,3-双加氧酶(IDO)。方法在体外实验的条件下,获得C57BL/6小鼠骨髓来源的树突状细胞(BMDCs),分别应用15μg/ml重组抗原B(rAgB)、5mg/ml小鼠囊型包虫囊液(MHF)、1 000U/ml IFN-γ(阳性对照)刺激BMDCs,在6、18、24、48、60h采用实时荧光定量RT-PCR动态监测IDO、IL-10mRNA相对表达情况;在不同时间点收集各组DCs,应用Western blot检测IDO蛋白的表达。结果 FQ-RT-PCR显示,rAgB处理组IDO mRNA在24h时上调26.8倍,IL-10mRNA在48h时上调65.1倍,MHF处理组干预24h时IDO mRNA、IL-10mRNA表达分别上调12.6倍和3.9倍。Western blot显示IDO的表达可被rAgB、MHF上调,rAgB处理组在24h时出现IDO条带,MHF处理组于48h出现MHF条带。结论 rAgB、MHF均可上调DCs表面IDO的表达,并在一定时间内rAgB上调IDO表达的能力强于MHF。推测在CE的慢性感染过程中,IDO作为调节宿主反应的分子开关可能在Th2型反应中发挥着主导作用,棘球蚴致机体免疫逃避中可能参与抑制炎症反应。     

吲哚胺2,3-二氧化酶在病毒性肝炎中的研究进展

病毒性肝炎具有强传染性、高流行性,其传播途径复杂、发病率高、对人体危害性大,已成为社会普遍关注的一类重要的传染性疾病。随着科学社会的进步,目前对于肝炎的治疗有一定的进展,主要应用干扰素、核苷类、基因疗法等抗病毒药物,但这些治疗适用范围局限,副作用大,易产生病毒变异和耐药现象,使病情反复,治疗出现"瓶颈"。近几年,吲哚胺2,3-二氧化酶(indoleamine 2,3-dioxygenase,IDO)在病毒性肝炎中的作用日益受到关注,其与肝炎患者免疫耐受、病毒的复制、肝细胞的损伤程度密切相关。这将为病毒性肝炎的治疗提供新的思路。本文针对IDO在病毒性肝炎中的进展作一概述。     

吲哚胺2,3-二加氧酶抑制剂对慢性脑低灌注大鼠认知功能损害的行为学改善

目的观察使用吲哚胺2,3-二加氧酶(IDO)抑制剂后慢性脑低灌注大鼠认知功能损害的行为学改善,及血犬尿氨酸(KYN)、犬尿喹啉酸(KYNA)水平的变化。方法雄性Wistar大鼠30只,随机分为假手术组,对照组和IDO抑制剂组,各10只,后2组采用改良的永久性双侧颈总动脉结扎术制作慢性脑低灌注大鼠模型。Morris水迷宫检测大鼠空间学习与记忆能力变化,高效液相色谱-荧光检测法检测血KYN、KYNA的水平,免疫组织化学检测大鼠海马CA1区IFN-γ、TNF-α表达。结果与假手术组比较,对照组IFN-γ、TNF-α表达明显升高(P<0.05);与对照组比较,IDO抑制剂组大鼠第4、5天逃避潜伏期缩短,平台象限游泳距离百分比增加,KYN[(15.33±0.90)μmol/L vs(1.69±0.94)μmol/L]及KYNA[(39.51±3.81)μmol/L vs(25.66±6.80)μmol/L]水平明显降低(P<0.05),但IFN-γ、TNF-α表达无显著差异(P>0.05)。结论 IDO抑制剂不影响炎性因子表达,但可减少血KYN及KYNA表达,可改善慢性脑低灌注所致的认知功能损害的空间学习及记忆能力。     

狼疮肾炎患者肾组织中吲哚胺2,3-双加氧酶的表达及意义

目的检测Ⅳ型狼疮肾炎（LN）患者肾组织中吲哚胺2，3-双加氧酶（IDO）的表达情况及其与肾间质浸润炎细胞的增殖和肾小管-间质病理损害程度之间的关系。方法采用免疫组织化学染色法观察正常肾组织和Ⅳ型LN患者肾组织IDO的表达情况，并进一步分析其表达与肾间质浸润核增殖抗原（PCNA）阳性淋巴细胞数及肾小管-间质（TIL）病理损害程度之间的相关关系。结果正常肾组织未检测到IDO表达，而在Ⅳ型LN肾小管上皮细胞IDO的表达阳性，并且LN肾小管上皮细胞表达IDO的阳性强度与TIL PCNA＋浸润细胞数及TIL病理损害程度呈显著负相关。结论IDO在Ⅳ型LN肾小管上皮细胞中呈高表达，并与TIL浸润细胞增殖情况及TIL病理变化呈负相关，提示IDO可能参与LNTIL病理损害过程。     

吲哚胺2,3二氧化酶与慢性乙型肝炎的免疫重建

细胞免疫不足是HBV感染持续状态和慢性乙型肝炎(CHB)重要发病机制[1].探索CHB患者对HBV免疫耐受机制,重建其主动免疫,将为HBV的治疗提供新的思路.目前研究发现,吲哚胺2,3二氧化酶(indoleamine-2,3 dioxygenase,IDO)广泛表达于免疫系统,参与机体肿瘤免疫、感染免疫及妊娠免疫,是CHB免疫重建的重要靶点[2].     

Indoleamine 2,3-dioxygenase is a critical regulator of acute graft-versus-host disease lethality

Graft-versus-host disease (GVHD) is initiated after activation of donor T cells by host antigen-presenting cells (APCs). The immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) is expressed by APCs and parenchymal cells and is further inducible by inflammation. We investigated whether lethal conditioning and GVHD induce IDO and if IDO prevents tissue injury by suppressing immune responses at the induction site. We determined that IDO is a critical regulator of GVHD, most strikingly in the colon, where epithelial cells dramatically up-regulated IDO expression during GVHD. IDO(-/-) mice died more quickly from GVHD, displaying increased colonic inflammation and T-cell infiltration. GVHD protection was not mediated by control of T-cell proliferation, apoptosis, or effector mechanisms in lymphoid organs, nor did it require donor T regulatory cells. Instead, T cells in IDO(-/-) colons underwent increased proliferation and decreased apoptosis compared with their wild-type counterparts. This evidence suggests that IDO can act at the site of expression to decrease T-cell proliferation and survival, diminishing colonic inflammation and reducing disease severity. These studies are the first to identify a function for IDO in GVHD lethality and indicate that modulation of the IDO pathway may be an effective strategy for treatment of this disease.     

Indoleamine 2,3-dioxygenase: As a potential prognostic marker and immunotherapeutic target for hepatocellular carcinoma

Tumor cells induce an immunosuppressive microen-vironment which leads towards tumor immune escape. Understanding the intricacy of immunomodulation by tumor cells is essential for immunotherapy. Indoleamine 2,3-dioxygenase(IDO) is an immunosuppressive enzyme which mediates tumor immune escape in various cancers including hepatocellular carcinoma(HCC). IDO up-regulation in HCC may lead to recruitment of regulatory T-cells into tumor microenvironment and therefore inhibit local immune responses and promote metastasis. HCC associated fibroblasts stimulate natural killer cells dysfunction through prostaglandin E2 and subsequently IDO promotes favorable condition for tumor metastasis. IDO up-regulation induces immuno-suppression and may enhance the risk of hepatitis C virus and hepatitis B virus induced HCC. Therefore, IDO inhibitors as adjuvant therapeutic agents may have clinical implications in HCC. This review proposes future prospects of IDO not only as a therapeutic target but also as a prognostic marker for HCC.     

Perceiving control: a double-edged sword in old age

Although control beliefs are thought to be pivotal contributors to emotional well-being in old age, questions remain about the specific and long-term emotional implications of different types of control beliefs. We examined three generalized beliefs about control (personal control over desirable outcomes, personal responsibility for undesirable outcomes, perceived others' control) and their associations with emotional well-being (positive and negative affect) using cross-sectional (N = 516) and longitudinal (N = 206) samples from the Berlin Aging Study (age range = 70-103 years). Relationships between control beliefs and emotional well-being were dependent on the type of control belief and the dimension of emotional well-being considered, the sample investigated, and on whether individual differences at a given point in time or individual differences in intraindividual changes over time were examined. Despite these complexities, findings suggest that perceived control over desirable outcomes is associated with high emotional well-being, whereas perceived others' control is an emotional risk factor in old age.     

MicroRNA-223: a double-edged sword in rheumatoid arthritis

Increased expression of microRNA-223 (miR-223) has been demonstrated in rheumatoid arthritis (RA) patients. Two research teams focus recently on the underlying mechanisms mediated by miR-223 but two stories are developed in opposite ways.     

Immunological role of indoleamine 2,3-dioxygenase in rat liver allograft rejection and tolerance

Background and Aim:  Indoleamine 2,3-dioxygenase (IDO) is expressed in the placenta and plays an essential role in maternal tolerance. Recent data showed that giving IDO inhibitor blocked liver allograft tolerance. However, the immunological role of IDO in rat liver allograft models has not been characterized. In the present study, the time-course of IDO expression and the localization of IDO were analyzed to address the role of IDO in the induction of tolerance.
Methods:  Rat orthotopic liver transplantations (OLT) were performed and IDO gene expression of OLT livers was analyzed. Immunohistochemistry was used to evaluate the localization of IDO-expressed cells in the liver.
Results:  The IDO gene was detected in the allogeneic liver graft at the acute phase but the signal could not be detected when these OLT rats were treated with cyclosporinee A. The time-course of IDO gene expression in liver grafts of the spontaneous tolerant OLT model revealed that the IDO mRNA was expressed in both the rejection phase and the induction phase of tolerance, but the signal was gradually lowered during the maintenance phase of tolerance. Immunohistochemistry confirmed that the IDO protein was detected in antigen-presenting cells but not in hepatocytes.
Conclusion:  Our results demonstrated that IDO is induced in antigen-presenting cells of rat liver allografts under drug-free status, suggesting that indirect or direct recognition of donor antigen and further T-cell activation may be inhibited. IDO may act as a local immunosuppressive molecule to protect transplanted cells, tissues and organs from immune attack.     

Type 2 transglutaminase in Huntington's disease: a double-edged sword with clinical potential

Huntington's disease (HD) is a dominant genetic neurodegenerative disorder. The pathology affects principally neurons in the basal ganglia circuits and terminates invariably in death. There is compelling necessity for safe and effective therapeutic strategies to arrest, or even retard the progression of the pathogenesis. Recent findings indicate the autophagy-lysosome systems as appealing targets for pharmacological intervention. Autophagy exerts a critical role in controlling neuronal protein homeostasis, which is perturbed in HD, and is compromised in the pathogenesis of several neurodegenerative diseases. Type 2 transglutaminase (TG2) plays an important role both in apoptosis and autophagy regulation, and accumulates at high levels in cells under stressful conditions. TG2 inhibition, achieved either via drug treatments or genetic approaches, has been shown to be beneficial for the treatment of HD in animal models. In this review we will discuss the relevance of TG2 to the pathogenesis of HD, in an effort to define novel therapeutic avenues.