Blockade of the programmed death-1 (PD1) pathway undermines potent genetic protection from type 1 diabetes.
Blockade of the programmed death-1 (PD1) pathway undermines potent genetic protection from type 1 diabetes.
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DOI：
10.1371/journal.pone.0089561
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Guleria I
中科院分区：
文献类型：
--
作者：
Kochupurakkal NM;Kruger AJ;Tripathi S;Zhu B;Adams LT;Rainbow DB;Rossini A;Greiner DL;Sayegh MH;Wicker LS;Guleria I
NOD小鼠中PD 1-PDL 1信号传导的抑制加速了1型糖尿病的发作，暗示该途径抑制胰腺β细胞反应性T细胞的出现。然而，PD 1信号传导保护1型糖尿病的分子机制尚不清楚。我们假设，当用抗PDL 1抗体攻击时，Idd小鼠品系对1型糖尿病的不同易感性将鉴定与PD 1信号转导合作抑制1型糖尿病的基因组位点。在10周龄时向NOD和各种Idd小鼠品系施用抗PDL 1，并通过测量血糖水平来监测疾病的发作。此外，对胰腺进行组织学评价，以确定胰岛炎的程度。使用对数秩和学生t检验进行数据的统计分析。在几乎所有测试的NOD Idd同源菌株中，PDL 1的阻断都迅速促成了1型糖尿病，尽管所有菌株都因其保护性Idd基因而受到中度（Idd 5，Idd 3和Idd 10/18）或高度（Idd 3/10/18和Idd 9）保护，免于自发性1型糖尿病。只有Idd 3/5菌株，几乎100%免于自发性疾病，在PDL 1阻断后保持血糖正常。这些结果表明，多个Idd基因座与PD 1信号传导协作。抗PDL 1治疗破坏了1型糖尿病NOD模型中Idd基因介导的大部分遗传保护。基底胰岛炎与1型糖尿病易感性增高相关。这些发现具有重要意义，因为PD 1通路是免疫治疗的靶点。
Inhibition of PD1-PDL1 signaling in NOD mice accelerates onset of type 1 diabetes implicating this pathway in suppressing the emergence of pancreatic beta cell reactive T-cells. However, the molecular mechanism by which PD1 signaling protects from type 1 diabetes is not clear. We hypothesized that differential susceptibility of Idd mouse strains to type 1 diabetes when challenged with anti PDL1 will identify genomic loci that collaborate with PD1 signaling in suppressing type 1 diabetes. Anti PDL1 was administered to NOD and various Idd mouse strains at 10 weeks of age and onset of disease was monitored by measuring blood glucose levels. Additionally, histological evaluation of the pancreas was performed to determine degree of insulitis. Statistical analysis of the data was performed using Log-Rank and Student's t-test. Blockade of PDL1 rapidly precipitated type 1 diabetes in nearly all NOD Idd congenic strains tested, despite the fact that all are moderately (Idd5, Idd3 and Idd10/18) or highly (Idd3/10/18 and Idd9) protected from spontaneous type 1 diabetes by virtue of their protective Idd genes. Only the Idd3/5 strain, which is nearly 100% protected from spontaneous disease, remained normoglycemic following PDL1 blockade. These results indicate that multiple Idd loci collaborate with PD1 signaling. Anti PDL1 treatment undermines a large portion of the genetic protection mediated by Idd genes in the NOD model of type 1 diabetes. Basal insulitis correlated with higher susceptibility to type 1 diabetes. These findings have important implications since the PD1 pathway is a target for immunotherapy.
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通过PD-1-PD-1配体阻滞来振兴耗尽的HIV特异性T细胞。
影响因子：
15.3
作者：
Freeman, Gordon J.;Wherry, E. John;Ahmed, Rafi;Sharpe, Arlene H.
通讯作者：
Sharpe, Arlene H.
影响因子：
7.7
作者：
Hamilton-Williams, Emma E.;Cheung, Jocelyn;Sherman, Linda A.
通讯作者：
Sherman, Linda A.
影响因子：
4.4
作者：
Hunter, Kara;Rainbow, Dan;Wicker, Linda S.
通讯作者：
Wicker, Linda S.
影响因子：
4.4
作者：
Matsuki, N;Stanic, AK;Joyce, S
通讯作者：
Joyce, S
DOI：
10.4049/jimmunol.1203422
发表时间：
2013-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lin X;Hamilton-Williams EE;Rainbow DB;Hunter KM;Dai YD;Cheung J;Peterson LB;Wicker LS;Sherman LA
通讯作者：
Sherman LA