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Barber DL Wherry EJ Masopust D Zhu B Allison JP Sharpe AH Freeman GJ Ahmed R 《Nature》2006,439(7077):682-687
Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the 'helpless' CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections. 相似文献
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Résumé Le zymogramme des LDH du muscle de souriceau nouveau-né souffrant de myosite diffuse causée par le virus de Coxsackie Groupe A est semblable à celui du souriceau sain de même âge, suggérant qu'un zymogramme anormal des LDH dans les affections musculaires n'est pathognomonique que chez certaines espèces. 相似文献
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Goudie DR D'Alessandro M Merriman B Lee H Szeverényi I Avery S O'Connor BD Nelson SF Coats SE Stewart A Christie L Pichert G Friedel J Hayes I Burrows N Whittaker S Gerdes AM Broesby-Olsen S Ferguson-Smith MA Verma C Lunny DP Reversade B Lane EB 《Nature genetics》2011,43(4):365-369
Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinoma-like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars. High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndrome-related disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cancer. 相似文献
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Turnbull C Perdeaux ER Pernet D Naranjo A Renwick A Seal S Munoz-Xicola RM Hanks S Slade I Zachariou A Warren-Perry M Ruark E Gerrard M Hale J Hewitt M Kohler J Lane S Levitt G Madi M Morland B Neefjes V Nicholdson J Picton S Pizer B Ronghe M Stevens M Traunecker H Stiller CA Pritchard-Jones K Dome J Grundy P Rahman N 《Nature genetics》2012,44(6):681-684
Wilms tumor is the most common renal malignancy of childhood. To identify common variants that confer susceptibility to Wilms tumor, we conducted a genome-wide association study in 757 individuals with Wilms tumor (cases) and 1,879 controls. We evaluated ten SNPs in regions significantly associated at P < 5 × 10(-5) in two independent replication series from the UK (769 cases and 2,814 controls) and the United States (719 cases and 1,037 controls). We identified clear significant associations at 2p24 (rs3755132, P = 1.03 × 10(-14); rs807624, P = 1.32 × 10(-14)) and 11q14 (rs790356, P = 4.25 × 10(-15)). Both regions contain genes that are plausibly related to Wilms tumorigenesis. We also identified candidate association signals at 5q14, 22q12 and Xp22. 相似文献
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