PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes.
PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes.
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DOI：
10.1126/scitranslmed.aam7543
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发表时间：
2017-11-15
影响因子：
17.1
通讯作者：
Fiorina P
中科院分区：
文献类型：
--
作者：
Ben Nasr M;Tezza S;D'Addio F;Mameli C;Usuelli V;Maestroni A;Corradi D;Belletti S;Albarello L;Becchi G;Fadini GP;Schuetz C;Markmann J;Wasserfall C;Zon L;Zuccotti GV;Fiorina P
迄今为止，基于免疫学的临床试验未能治愈1型糖尿病（T1 D），部分原因是这些方法是非特异性的。由于该疾病是由自身反应性CD 4 T细胞驱动的，其破坏β细胞，因此造血干细胞和祖细胞（HSPC）的移植最近已被提供作为T1 D的疗法。我们对HSPC的转录组学分析显示，在T1 D非肥胖糖尿病（NOD）小鼠模型中，这些细胞缺乏程序性死亡配体1（PD-L1），这是一种重要的免疫检查点。值得注意的是，免疫调节分子PD-L1在控制/抑制活化的T细胞中起决定性作用，从而维持免疫耐受。此外，我们的全基因组和生物信息学分析揭示了控制PD-L1表达的microRNA（miRNAs）网络的存在，并且沉默一种关键的改变的miRNAs恢复了HSPC中的PD-L1表达。因此，我们试图确定是否恢复这一缺陷将治愈T1 D作为替代免疫抑制。过表达PD-L1的基因工程改造的或基因调控的HSPC在体外抑制自身免疫反应，在体内逆转新的高血糖NOD小鼠的糖尿病，并归巢到高血糖NOD小鼠的胰腺。在T1 D患者的人HSPC中也证实了PD-L1表达缺陷，并且PD-L1调节的人HSPC也在体外抑制自身免疫应答。因此，靶向HSPC中的特定免疫检查点缺陷可能有助于建立T1 D的治愈方法。
Immunologically based clinical trials performed thus far have failed to cure type 1 diabetes (T1D), in part because these approaches were nonspecific. Because the disease is driven by autoreactive CD4 T cells, which destroy β cells, transplantation of hematopoietic stem and progenitor cells (HSPCs) has been recently offered as a therapy for T1D. Our transcriptomic profiling of HSPCs revealed that these cells are deficient in programmed death ligand 1 (PD-L1), an important immune checkpoint, in the T1D nonobese diabetic (NOD) mouse model. Notably, the immunoregulatory molecule PD-L1 plays a determinant role in controlling/inhibiting activated T cells and thus maintains immune tolerance. Furthermore, our genome-wide and bioinformatic analysis revealed the existence of a network of microRNAs (miRNAs) controlling PD-L1 expression, and silencing one of key altered miRNAs restored PD-L1 expression in HSPCs. We therefore sought to determine whether restoration of this defect would cure T1D as an alternative to immunosuppression. Genetically engineered or pharmacologically modulated HSPCs overexpressing PD-L1 inhibited the autoimmune response in vitro, reverted diabetes in newly hyperglycemic NOD mice in vivo, and homed to the pancreas of hyperglycemic NOD mice. The PD-L1 expression defect was confirmed in human HSPCs in T1D patients as well, and pharmacologically modulated human HSPCs also inhibited the autoimmune response in vitro. Targeting a specific immune checkpoint defect in HSPCs thus may contribute to establishing a cure for T1D.
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影响因子：
4.6
作者：
von Herrath, M. G.;Korsgren, O.;Atkinson, M. A.
通讯作者：
Atkinson, M. A.
影响因子：
16.2
作者：
Haller MJ;Wasserfall CH;McGrail KM;Cintron M;Brusko TM;Wingard JR;Kelly SS;Shuster JJ;Atkinson MA;Schatz DA
通讯作者：
Schatz DA
DOI：
10.4049/jimmunol.0900803
发表时间：
2009-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Fiorina P;Jurewicz M;Augello A;Vergani A;Dada S;La Rosa S;Selig M;Godwin J;Law K;Placidi C;Smith RN;Capella C;Rodig S;Adra CN;Atkinson M;Sayegh MH;Abdi R
通讯作者：
Abdi R
DOI：
10.4049/jimmunol.1000799
发表时间：
2011-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Fiorina P;Jurewicz M;Vergani A;Petrelli A;Carvello M;D'Addio F;Godwin JG;Law K;Wu E;Tian Z;Thoma G;Kovarik J;La Rosa S;Capella C;Rodig S;Zerwes HG;Sayegh MH;Abdi R
通讯作者：
Abdi R
影响因子：
8.6
作者：
Guleria, Indira;Bupp, Melanie Gubbels;Sayegh, Mohamed H.
通讯作者：
Sayegh, Mohamed H.