a-mouse-tumor-model-surgical-stress-to-explore-mechanisms

A Mouse Tumor Model of Surgical Stress to Explore the Mechanisms of Postoperative Immunosuppression and Evaluate Novel Perioperative Immunotherapies

Surgical resection is an essential treatment for most cancer patients, but surgery induces dysfunction in the immune system and this has been linked to ...

Ottawa Hospital Research Institute

NK1.1 alloantigen expression can be used to define NK cells in certain mouse strains, such as B6 (NKR-P1C) and SJL (NKR-P1B). However, BALB/c NK cells do not react with the anti-NK1.1 mAb, PK136. To investigate the NK1.1(-) phenotype of BALB/c NK cells, we have undertaken NK1.1 epitope mapping and genomic analysis of the BALB/c Nkrp1 region. Bacterial artificial chromosome library analysis reveals that, unlike the Ly49 region, the Nkrp1-Ocil/Clr region displays limited genetic divergence between B6 and BALB/c mice. In fact, significant divergence is confined to the Nkrp1b and Nkrp1c genes. Strikingly, the B6 Nkrp1d gene appears to represent a divergent allele of the Nkrp1b gene in BALB/c mice and other strains. Importantly, BALB/c NK cells express abundant and functional Nkrp1 transcripts, and the BALB/c NKR-P1B receptor functionally binds Ocil/Clr-b ligand. However, the BALB/c NKR-P1B/C sequences differ from those of the known NK1.1 alloantigens, and epitope mapping demonstrates that directed mutation of a single amino acid in the NKR-P1B(BALB) protein confers NK1.1 reactivity. Thus, PK136 mAb recognizes, in part, a distal C-terminal epitope present in NKR-P1B(Sw/SJL) and NKR-P1C(B6), but absent in NKR-P1A/D/F(B6) and NKR-P1B/C(BALB). Allelic divergence of the Nkrp1b/c gene products and limited divergence of the BALB/c Nkrp1-Ocil/Clr region explain a longstanding confusion regarding the strain-specific NK1.1 alloantigen reactivity of mouse NK cells.

Molecular and genetic basis for strain-dependent NK1.1 alloreactivity of mouse NK cells.

Ly49Q is a member of the polymorphic Ly49 family of NK cell receptors that displays both a high degree of conservation and a unique expression pattern restricted to myeloid lineage cells, including plasmacytoid dendritic cells (pDC). The function and ligand specificity of Ly49Q are unknown. Here, we use reporter cell analysis to demonstrate that a high-affinity ligand for Ly49Q is present on H-2(b), but not H-2(d), H-2(k), H-2(q), or H-2(a)-derived tumor cells and normal cells ex vivo. The ligand is peptide-dependent and MHC Ia-like, as revealed by its functional absence on cells deficient in TAP-1, beta(2)m, or H-2K(b)D(b) expression. Furthermore, Ly49Q is specific for H-2K(b), as the receptor binds peptide-loaded H-2K(b) but not H-2D(b) complexes, and Ly49Q recognition can be blocked using anti-K(b) but not anti-D(b) mAb. Greater soluble H-2K(b) binding to ligand-deficient pDC also suggests cis interactions of Ly49Q and H-2K(b). These results demonstrate that Ly49Q efficiently binds H-2K(b) ligand, and suggest that pDC function, like that of NK cells, is regulated by classical MHC Ia molecules. MHC recognition capability by pDC has important implications for the role of this cell type during innate immune responses.

Recognition of H-2K(b) by Ly49Q suggests a role for class Ia MHC regulation of plasmacytoid dendritic cell function.

&#x8F6C;&#x5F55;&#x6D3B;&#x5316;&#x7684;&#x7EC6;&#x80DE;&#x56E0;&#x5B50;&#xFF0C;&#x5982;&#x7C7B;&#x578B;-&#x6211;&#x5E72;&#x6270;&#x7D20; (&#x5E72;&#x6270;&#x7D20; &#xFF08;&#x5E72;&#x6270;&#x7D20;&#xFF09;-&#x963F;&#x5C14;&#x6CD5;&#x548C;&#x8D1D;&#x5854;&#x5E72;&#x6270;&#x7D20;&#xFF09;&#xFF0C;&#x6784;&#x6210;&#x4E86;&#x6297;&#x75C5;&#x6BD2;&#x7684;&#x7B2C;&#x4E00;&#x9632;&#x7EBF;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x663E;&#x793A;&#x5E73;&#x79FB;&#x63A7;&#x5236;&#x662F;&#x5173;&#x952E;&#x7C7B;&#x578B;&#x7684;&#x611F;&#x5E94;-&#x6211;&#x5E72;&#x6270;&#x7D20;&#x751F;&#x4EA7;&#x3002;&#x5728;&#x5C0F;&#x9F20;&#x80DA;&#x80CE;&#x6210;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x7F3A;&#x4E4F;&#x7684;&#x5E73;&#x79FB; repressors 4E BP1 &#x548C; 4E-BP2&#xFF0C;&#x6355;&#x83B7;&#x7C7B;&#x578B;&#x9608;&#x503C;-&#x6211;&#x5E72;&#x6270;&#x7D20;&#x751F;&#x4EA7;&#x964D;&#x4F4E;&#x4E86;&#x3002;&#x56E0;&#x6B64;&#xFF0C;&#x88AB;&#x660E;&#x663E;&#x6291;&#x5236;&#x8111;&#x5FC3;&#x808C;&#x708E;&#x75C5;&#x6BD2;&#x3001; &#x6C34;&#x75B1;&#x6027;&#x53E3;&#x708E;&#x75C5;&#x6BD2;&#x3001; &#x6D41;&#x611F;&#x75C5;&#x6BD2;&#x548C;&#x8F9B;&#x5FB7;&#x6BD5;&#x65AF;&#x75C5;&#x6BD2;&#x7684;&#x590D;&#x5236;&#x3002;&#xFF08;&#x4E5F;&#x79F0;&#x4E3A; Eif4ebp1 &#x548C; Eif4ebp2&#xFF0C;&#x5206;&#x522B;&#xFF09; &#x8FD9;&#x4E24;&#x4E2A; 4E &#x548C; 4E BP2 &#x57FA;&#x56E0;&#x5C0F;&#x9F20;&#x649E;&#x6709;&#x6297;&#x836F;&#x6027;&#x6C34;&#x75B1;&#x6027;&#x53E3;&#x708E;&#x75C5;&#x6BD2;&#x611F;&#x67D3;&#xFF0C;&#x800C;&#x4E14;&#xFF0C;&#x8FD9;&#x6709;&#x5173;&#x8054;&#x7684;&#x589E;&#x5F3A;&#x578B;-&#x6211;&#x5E72;&#x6270;&#x7D20;&#x751F;&#x4EA7;&#x4E2D;&#x6D46;&#x7EC6;&#x80DE;&#x6837;&#x6811;&#x7A81;&#x72B6;&#x7EC6;&#x80DE;&#x548C;&#x80BA;&#x5E72;&#x6270;&#x7D20;&#x8C03;&#x8282;&#x57FA;&#x56E0;&#x7684;&#x8868;&#x8FBE;&#x3002;&#x589E;&#x5F3A;&#x7684;&#x578B;-&#x6211;&#x5E72;&#x6270;&#x7D20; 4E-BP1-/-4E-BP2-/-&#x53CC;&#x6572;&#x9664;&#x5C0F;&#x9F20;&#x80DA;&#x80CE;&#x6210;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x7684;&#x53CD;&#x5E94;&#x5F15;&#x8D77;&#x5E72;&#x6270;&#x7D20;&#x8C03;&#x8282;&#x56E0;&#x5B50;&#x8868;&#x8FBE;&#x4E0A;&#x8C03; 7 (Irf7&#xFF09; &#x4FE1;&#x4F7F; RNA &#x7FFB;&#x8BD1;&#x3002;&#x8FD9;&#x4E9B;&#x7814;&#x7A76;&#x7ED3;&#x679C;&#x7A81;&#x51FA;&#x663E;&#x793A;&#x8D1F;&#x76D1;&#x7BA1;&#x673A;&#x6784;&#x7684;&#x7C7B;&#x578B;&#x4F5C;&#x4E3A; 4E BPs &#x7684;&#x4F5C;&#x7528;-&#x6211;&#x5E72;&#x6270;&#x7D20;&#x751F;&#x4EA7;&#xFF0C;&#x901A;&#x8FC7;&#x5E73;&#x79FB; Irf7 mRNA &#x7684;&#x9547;&#x538B;&#x3002;

&#x5E73;&#x79FB;&#x63A7;&#x5236;&#x901A;&#x8FC7; IRF 7 &#x7684;&#x975E;&#x7279;&#x5F02;&#x6027;&#x514D;&#x75AB;&#x53CD;&#x5E94;&#x3002;

Transcriptional activation of cytokines, such as type-I interferons (interferon (IFN)-alpha and IFN-beta), constitutes the first line of antiviral defence. Here we show that translational control is critical for induction of type-I IFN production. In mouse embryonic fibroblasts lacking the translational repressors 4E-BP1 and 4E-BP2, the threshold for eliciting type-I IFN production is lowered. Consequently, replication of encephalomyocarditis virus, vesicular stomatitis virus, influenza virus and Sindbis virus is markedly suppressed. Furthermore, mice with both 4E- and 4E-BP2 genes (also known as Eif4ebp1 and Eif4ebp2, respectively) knocked out are resistant to vesicular stomatitis virus infection, and this correlates with an enhanced type-I IFN production in plasmacytoid dendritic cells and the expression of IFN-regulated genes in the lungs. The enhanced type-I IFN response in 4E-BP1-/- 4E-BP2-/- double knockout mouse embryonic fibroblasts is caused by upregulation of interferon regulatory factor 7 (Irf7) messenger RNA translation. These findings highlight the role of 4E-BPs as negative regulators of type-I IFN production, via translational repression of Irf7 mRNA.

Translational control of the innate immune response through IRF-7.

Activation de la transcription des cytokines, telles que le type-I (interf&#xE9;rons (IFN)-alpha et IFN-b&#xEA;ta), constitue la premi&#xE8;re ligne de d&#xE9;fense antivirale. Nous montrons ici que le contr&#xF4;le traductionnel est essentiel pour l&#x26;#39;induction de type I la production d&#x26;#39;IFN. Dans les fibroblastes de souris embryonnaires n&#x26;#39;ont pas les r&#xE9;presseurs traductionnels 4E-BP1 et 4E-BP2, le seuil pour d&#xE9;clencher de type I la production d&#x26;#39;IFN est abaiss&#xE9;. Par cons&#xE9;quent, la r&#xE9;plication du virus de l&#x26;#39;enc&#xE9;phalomyocardite, virus de la stomatite v&#xE9;siculeuse, virus de la grippe et le virus Sindbis est nettement supprim&#xE9;e. En outre, les souris avec deux g&#xE8;nes 4E-et 4E-BP2 (&#xE9;galement connu sous le nom Eif4ebp1 et Eif4ebp2, respectivement) sont &#xE9;limin&#xE9;s r&#xE9;sistantes &#xE0; l&#x26;#39;infection du virus de la stomatite v&#xE9;siculaire, et cela en corr&#xE9;lation avec une am&#xE9;lioration de type I la production d&#x26;#39;IFN dans les cellules dendritiques plasmacyto&#xEF;des et l&#x26;#39;expression de l&#x26;#39;IFN-g&#xE8;nes r&#xE9;gul&#xE9;s dans les poumons. Le type I am&#xE9;lior&#xE9; la r&#xE9;ponse IFN dans 4E-BP1-/ - 4E-BP2-/ - doubles fibroblastes embryonnaires de souris knockout est caus&#xE9;e par une r&#xE9;gulation positive de l&#x26;#39;interf&#xE9;ron r&#xE9;glementaire facteur 7 (IRF-7) ARN messager de la traduction. Ces r&#xE9;sultats mettent en &#xE9;vidence le r&#xF4;le de 4E-BP en tant que r&#xE9;gulateurs n&#xE9;gatifs de type I la production d&#x26;#39;IFN, par l&#x26;#39;interm&#xE9;diaire de la r&#xE9;pression traductionnelle IRF-7 ARNm.

Le contr&#xF4;le traductionnel de la r&#xE9;ponse immunitaire inn&#xE9;e Gr&#xE2;ce &#xE0; l&#x26;#39;IRF-7

Transkriptionelle Aktivierung von Zytokinen, wie Typ-ich Interferone (Interferon (IFN)-Alpha und Interferon-Beta), bildet die erste Verteidigungslinie antiviral. Hier zeigen wir, dass translational Steuerung f&uuml;r Induktion von Typ wichtig ist-ich IFN Produktion. In M&auml;useembryonalen fehlt die translatorischen Repressoren 4E-BP1 und 4E-BP2, die Schwelle f&uuml;r technologieorientierter Typ-ich IFN Produktion gesenkt ist. Folglich wird die Replikation von Enzephalomyocarditis Virus, vesikul&auml;re Stomatitis-Virus, Influenza-Virus und Sindbis-Virus deutlich unterdr&uuml;ckt. Au&szlig;erdem M&auml;use mit beiden 4E und 4E-BP2-Genen (auch bekannt als Eif4ebp1 und Eif4ebp2, beziehungsweise) ausgeschieden sind resistent gegen vesikul&auml;re Stomatitis-Virus-Infektion, und dies korreliert mit einem verbesserten Typ-ich IFN Produktion in Plasmacytoid dendritische Zellen und den Ausdruck der IFN-regulierten Gene in der Lunge. Der verbesserte Typ-ich IFN Antwort in 4E-BP1-/-4E-BP2-/-Double-ko M&auml;useembryonalen durch Hochregulation von Interferon regulatory Factor 7 (Irf7) Boten-RNA &Uuml;bersetzung verursacht wird. Diese Erkenntnisse unterstreichen die Rolle der 4E-BPs als negative Regler des Typs-ich IFN-Produktion, &uuml;ber translatorische Unterdr&uuml;ckung der Irf7 mRNA.

Translational Steuerung der angeborenen Immunantwort durch IRF-7.

Attivazione trascrizionale di citochine, come il tipo-io interferoni (interferone (IFN)-Alfa e IFN-beta), costituisce la prima linea di difesa antivirale. Qui vi mostriamo che traslazionale controllo &egrave; critico per l&#39;induzione del tipo-I IFN produzione. In fibroblasti embrionali del mouse mancano i repressori traslazionale 4E-BP1 e 4E-BP2, la soglia per suscitare tipo-I IFN produzione &egrave; abbassato. Di conseguenza, replicazione del virus dell&#39;encefalomiocardite, stomatite vescicolare virus, virus dell&#39;influenza e virus Sindbis marcatamente &egrave; soppressa. Inoltre, topi con entrambi i geni 4E e 4E BP2 (noti anche come Eif4ebp1 ed Eif4ebp2, rispettivamente) knock-out sono resistenti all&#39;infezione del virus di stomatite vescicolare, e ci&ograve; correla con un tipo avanzato-I IFN produzione in cellule dendritiche plasmacytoid e l&#39;espressione dei geni regolati IFN nei polmoni. Il tipo migliorato-che IFN risposta in fibroblasti embrionali di topo 4E-BP1-/-4E-BP2-/-doppio knockout &egrave; causata da upregulation di fattore regolatore interferone traduzione di RNA messaggero (Irf7) 7. Questi risultati sottolineano il ruolo di 4E-BPs come regolatori negativi del tipo-I IFN produzione, via repressione traslazionale di mRNA Irf7.

Controllo translazionale della risposta immunitaria innata attraverso IRF-7.

&#x3053;&#x306E;&#x3088;&#x3046;&#x306A;I&#x578B;&#x30A4;&#x30F3;&#x30BF;&#x30FC;&#x30D5;&#x30A7;&#x30ED;&#x30F3;&#xFF08;&#x30A4;&#x30F3;&#x30BF;&#x30FC;&#x30D5;&#x30A7;&#x30ED;&#x30F3;&#xFF08;IFN&#xFF09;-&#x3B1;&#x3068;IFN-&#x3B2;&#xFF09;&#x306A;&#x3069;&#x306E;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x306E;&#x8EE2;&#x5199;&#x6D3B;&#x6027;&#x5316;&#x306F;&#x3001;&#x6297;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x9632;&#x5FA1;&#x306E;&#x6700;&#x521D;&#x306E;&#x884C;&#x3092;&#x69CB;&#x6210;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x7FFB;&#x8A33;&#x5236;&#x5FA1;&#x306F;I&#x578B;IFN&#x7523;&#x751F;&#x306E;&#x8A98;&#x5C0E;&#x306B;&#x91CD;&#x8981;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002; 4E-BP1&#x3084;4E-BP2&#x7FFB;&#x8A33;&#x30EA;&#x30D7;&#x30EC;&#x30C3;&#x30B5;&#x30FC;&#x3092;&#x6B20;&#x640D;&#x3059;&#x308B;&#x30DE;&#x30A6;&#x30B9;&#x80DA;&#x6027;&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x3067;&#x306F;&#x3001;I&#x578B;IFN&#x306E;&#x7523;&#x751F;&#x3092;&#x8A98;&#x5C0E;&#x3059;&#x308B;&#x305F;&#x3081;&#x306E;&#x95BE;&#x5024;&#x304C;&#x4F4E;&#x4E0B;&#x3059;&#x308B;&#x3002;&#x305D;&#x306E;&#x7D50;&#x679C;&#x3001;&#x8133;&#x5FC3;&#x7B4B;&#x708E;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x3001;&#x6C34;&#x75B1;&#x6027;&#x53E3;&#x5185;&#x708E;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x3001;&#x30A4;&#x30F3;&#x30D5;&#x30EB;&#x30A8;&#x30F3;&#x30B6;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x3084;&#x30B7;&#x30F3;&#x30C9;&#x30D3;&#x30B9;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x306E;&#x8907;&#x88FD;&#x304C;&#x8457;&#x3057;&#x304F;&#x6291;&#x5236;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;4E&#x3068;4E-BP2&#x306E;&#x4E21;&#x65B9;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x304C;&#xFF08;&#x307E;&#x305F;&#x3001;&#x305D;&#x308C;&#x305E;&#x308C;Eif4ebp1&#x3068;Eif4ebp2&#x3001;&#x3068;&#x3057;&#x3066;&#x77E5;&#x3089;&#x308C;&#x3066;&#x3044;&#x308B;&#xFF09;&#x3092;&#x30CE;&#x30C3;&#x30AF;&#x30A2;&#x30A6;&#x30C8;&#x3057;&#x305F;&#x30DE;&#x30A6;&#x30B9;&#x306F;&#x3001;&#x6C34;&#x75B1;&#x6027;&#x53E3;&#x5185;&#x708E;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x306E;&#x611F;&#x67D3;&#x306B;&#x8010;&#x6027;&#x3067;&#x3042;&#x308A;&#x3001;&#x5F62;&#x8CEA;&#x7D30;&#x80DE;&#x69D8;&#x6A39;&#x72B6;&#x7D30;&#x80DE;&#x3067;&#x5F37;&#x5316;&#x3055;&#x308C;&#x305F;I&#x578B;IFN&#x306E;&#x7523;&#x751F;&#x3068;&#x767A;&#x73FE;&#x3001;&#x3053;&#x306E;&#x76F8;&#x95A2;&#x80BA;&#x306E;IFN-&#x8ABF;&#x7BC0;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x3002; 4E-BP1-/&#x3067;&#x5F37;&#x5316;&#x3055;&#x308C;&#x305F;I&#x578B;IFN&#x5FDC;&#x7B54; -  4E-BP2-/  - &#x30C0;&#x30D6;&#x30EB;&#x30CE;&#x30C3;&#x30AF;&#x30A2;&#x30A6;&#x30C8;&#x30DE;&#x30A6;&#x30B9;&#x80DA;&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x306F;&#x3001;&#x30A4;&#x30F3;&#x30BF;&#x30FC;&#x30D5;&#x30A7;&#x30ED;&#x30F3;&#x5236;&#x5FA1;&#x56E0;&#x5B50;7&#xFF08;IRF7&#xFF09;&#x30E1;&#x30C3;&#x30BB;&#x30F3;&#x30B8;&#x30E3;&#x30FC;RNA&#x7FFB;&#x8A33;&#x306E;&#x4E0A;&#x65B9;&#x5236;&#x5FA1;&#x306B;&#x3088;&#x3063;&#x3066;&#x5F15;&#x304D;&#x8D77;&#x3053;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x77E5;&#x898B;&#x306F;&#x3001;IRF7 mRNA&#x306E;&#x7FFB;&#x8A33;&#x6291;&#x5236;&#x3092;&#x4ECB;&#x3057;&#x3066;I&#x578B;IFN&#x7523;&#x751F;&#x306E;&#x8CA0;&#x306E;&#x8ABF;&#x7BC0;&#x56E0;&#x5B50;&#x3068;&#x3057;&#x3066;&#x3001;4E-BPS&#x306E;&#x5F79;&#x5272;&#x3092;&#x5F37;&#x8ABF;&#x8868;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;

IRF-7&#x3092;&#x4ECB;&#x3057;&#x3066;&#x81EA;&#x7136;&#x514D;&#x75AB;&#x5FDC;&#x7B54;&#x306E;&#x7FFB;&#x8A33;&#x5236;&#x5FA1;

Cytokines, &#xD615;&#xC2DD; &#xB4F1;&#xC758; transcriptional &#xD65C;&#xC131;&#xD654;-&#xB09C; interferons (&#xC778;&#xD130;&#xD398;&#xB860; (IFN)-&#xC54C;&#xD30C;&#xC640; IFN-&#xBCA0;&#xD0C0;), &#xD56D; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xBC29;&#xC5B4;&#xC758; &#xCCAB; &#xBC88;&#xC9F8; &#xB77C;&#xC778;&#xC744; &#xAD6C;&#xC131; &#xD55C;&#xB2E4;. &#xC5EC;&#xAE30; &#xC6B0;&#xB9AC;&#xAC00; &#xBCC0;&#xD658; &#xC81C;&#xC5B4; &#xD615;&#xC2DD;&#xC758; &#xC720;&#xB3C4; &#xC704;&#xD574; &#xD544;&#xC218;&#xC801;&#xC785;&#xB2C8;&#xB2E4; &#xBCF4;&#xC5EC;&#xC90D;&#xB2C8;&#xB2E4;-&#xB09C; IFN &#xC0DD;&#xC0B0;. &#xB9C8;&#xC6B0;&#xC2A4; &#xBBF8; &#xBC1C;&#xB2EC; &#xC12C;&#xC720; &#xC544; &#xC138;&#xD3EC; &#xBCC0;&#xD658; repressors 4E BP1 &#xBC0F; &#xC720;&#xD615; &#xB3C4;&#xCD9C;&#xC5D0; &#xB300; &#xD55C; &#xC784;&#xACC4;&#xAC12; 4E BP2 &#xBD80;&#xC871;&#xC5D0;-&#xB0B4;&#xAC00; IFN &#xC0DD;&#xC0B0;&#xC744; &#xB0AE; &#xCDC4; &#xB2E4;. &#xB530;&#xB77C;&#xC11C;, encephalomyocarditis &#xBC14;&#xC774;&#xB7EC;&#xC2A4;, vesicular &#xAD6C; &#xC5FC; &#xBC14;&#xC774;&#xB7EC;&#xC2A4;, &#xC778;&#xD50C;&#xB8E8;&#xC5D4;&#xC790; &#xBC14;&#xC774;&#xB7EC;&#xC2A4;&#xC640; Sindbis&#xC758; &#xBCF5;&#xC81C; &#xD604;&#xC800; &#xD558; &#xAC8C; &#xD45C;&#xC2DC; &#xB418;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4;. &#xB610;&#xD55C;, &#xAE30; &#xC808; (&#xC77C;&#xCEEC;&#xC5B4; Eif4ebp1 &#xBC0F; Eif4ebp2, &#xAC01;&#xAC01;) &#xB450; 4E &#xBC0F; 4E BP2 &#xC720;&#xC804;&#xC790;&#xC640; &#xC950; vesicular &#xAD6C; &#xC5FC; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xAC10;&#xC5FC;&#xC744; &#xBC29;&#xC9C0; &#xD558; &#xACE0;&#xC774; &#xD5A5;&#xC0C1; &#xB41C; &#xD615;&#xC2DD;&#xC744; &#xAD00;&#xB828;-&#xB098; IFN plasmacytoid &#xC218;&#xC9C0;&#xC0C1; &#xC138;&#xD3EC;&#xC640; &#xD3D0;&#xC5D0; IFN &#xADDC;&#xC81C; &#xC720;&#xC804;&#xC790;&#xC758; &#xD45C;&#xD604;&#xC5D0; &#xC0DD;&#xC0B0;. &#xD5A5;&#xC0C1; &#xB41C; &#xD615;&#xC2DD;-&#xB098; IFN 4E BP1-/-4E-BP2-/-&#xB354;&#xBE14; &#xB179;&#xC544;&#xC6C3; &#xB9C8;&#xC6B0;&#xC2A4; &#xBBF8; &#xBC1C;&#xB2EC; &#xC12C;&#xC720; &#xC544; &#xC138;&#xD3EC;&#xC5D0;&#xC11C; &#xC751;&#xB2F5; 7 (Irf7) &#xBA54;&#xC2E0;&#xC800; RNA &#xBC88;&#xC5ED; &#xC778;&#xD130;&#xD398;&#xB860; &#xADDC;&#xC81C; &#xC694;&#xC778;&#xC758; upregulation&#xC5D0; &#xC758;&#xD574; &#xBC1C;&#xC0DD; &#xD569;&#xB2C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xACB0;&#xACFC; &#xD615;&#xC2DD;&#xC774; &#xBD80;&#xC815;&#xC801;&#xC778; &#xB808; &#xADE4; &#xB808;&#xC774; &#xD130;&#xB85C; 4E Bps&#xC758; &#xC5ED;&#xD560;&#xC744; &#xAC15;&#xC870;-&#xB098; IFN Irf7 Mrna&#xC758; &#xBCC0;&#xD658; &#xC5B5;&#xC555;&#xC744; &#xD1B5;&#xD574; &#xC0DD;&#xC0B0;.

-IRF 7 &#xD0C0;&#xACE0; &#xB09C; &#xBA74;&#xC5ED; &#xBC18;&#xC751;&#xC758; &#xBCC0;&#xD658; &#xC81C;&#xC5B4;.

Activaci&#xF3;n de la transcripci&#xF3;n de citocinas, como interferones de tipo I (interfer&#xF3;n (IFN)-alfa y IFN-beta), que constituye la primera l&#xED;nea de defensa antiviral. Aqu&#xED; nos muestran que la traducci&#xF3;n de control es cr&#xED;tico para la inducci&#xF3;n de tipo I, la producci&#xF3;n de IFN. En fibroblastos embrionarios de rat&#xF3;n que carecen de los represores traduccionales 4E-BP1 y 4E-BP2, el umbral para provocar el tipo I se reduce la producci&#xF3;n de IFN. En consecuencia, la replicaci&#xF3;n del virus de la encefalomiocarditis, virus de la estomatitis vesicular, virus de la gripe y el virus de Sindbis est&#xE1; marcadamente suprimida. Adem&#xE1;s, los ratones con ambos genes 4E-4E y BP2-(tambi&#xE9;n conocido como Eif4ebp1 y Eif4ebp2, respectivamente) se elimin&#xF3; resistentes a la infecci&#xF3;n por virus de la estomatitis vesicular, y esto se correlaciona con una mayor producci&#xF3;n de tipo I IFN en c&#xE9;lulas dendr&#xED;ticas plasmocitoides y la expresi&#xF3;n de IFN-genes regulados en los pulmones. El tipo I en la mayor respuesta de IFN-4E-BP1 / - 4E-BP2-/ - de doble fibroblastos de rat&#xF3;n knock-out embrionarias se debe a la regulaci&#xF3;n positiva de interfer&#xF3;n factor regulador 7 (IRF7) traducci&#xF3;n del ARN mensajero. Estos resultados ponen de relieve el papel de 4E-BPs como reguladores negativos de tipo I, la producci&#xF3;n de IFN, a trav&#xE9;s de la represi&#xF3;n de traducci&#xF3;n de ARNm IRF7.

Control de la traducci&#xF3;n de la respuesta inmune innata a trav&#xE9;s de IRF-7

The Ly49 and Nkrp1 loci encode structurally and functionally related cell surface proteins that positively or negatively regulate natural killer (NK) cell-mediated cytotoxicity and cytokine production. Yet despite their clear relatedness and genetic linkage within the NK gene complex (NKC), these two multi-gene families have adopted dissimilar evolutionary strategies. The Ly49 genes are extremely polymorphic and evolutionarily dynamic, with distinct gene numbers, remarkable allelic diversity, and varying MHC-I-ligand specificities and affinities among different murine haplotypes. In contrast, the Nkrp1 genes have opted for overall conservation of genomic organization, sequences, and ligand specificities, with only limited and focused allelic polymorphism. Possible selection pressures driving such varied evolution of the two gene families may include disequilibrium from ligand co-inheritance, pathogen immunoevasin strategies, flexibility in host counter-evolution mechanisms, and the prevalence and dynamics of inherent repetitive elements.

Evolution of the Ly49 and Nkrp1 recognition systems.

Plasmacytoid dendritic cells (pDCs) are an important source of type I interferon (IFN) during initial immune responses to viral infections. In mice, pDCs are uniquely characterized by high-level expression of Ly49Q, a C-type lectin-like receptor specific for class I major histocompatibility complex (MHC) molecules. Despite having a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, Ly49Q was found to enhance pDC function in vitro, as pDC cytokine production in response to the Toll-like receptor (TLR) 9 agonist CpG-oligonucleotide (ODN) could be blocked using soluble monoclonal antibody (mAb) to Ly49Q or H-2K(b). Conversely, CpG-ODN-dependent IFN-alpha production by pDCs was greatly augmented upon receptor cross-linking using immobilized anti-Ly49Q mAb or recombinant H-2K(b) ligand. Accordingly, Ly49Q-deficient pDCs displayed a severely reduced capacity to produce cytokines in response to TLR7 and TLR9 stimulation both in vitro and in vivo. Finally, TLR9-dependent antiviral responses were compromised in Ly49Q-null mice infected with mouse cytomegalovirus. Thus, class I MHC recognition by Ly49Q on pDCs is necessary for optimal activation of innate immune responses in vivo.

Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC.

The class I MHC-specific receptors expressed by murine NK cells exhibit remarkable variation. Specific activating killer Ig-related receptor/Ly49 have major effects on autoimmune and infectious disease induction and outcome in humans and mice. However, these studies are greatly affected by individual background genetics. Furthermore, the educational impact of variable inhibitory KIR/Ly49 gene numbers on NK cell development and the subsequent ability to survey for MHC class I (MHC-I) expression remain unknown. To address these questions, Ly49 congenic mice were generated that maintain a 129-derived Ly49 gene cluster on a C57BL/6 genetic background (B6.Ly49(129) mice), and the in vitro and in vivo NK cell function of these mice was compared with their inbred parental 129S1 and C57BL/6 counterparts. Notably, target cell recognition directed by activating Ly49 receptors was profoundly affected by allelic variation in B6.Ly49(129) congenic cells versus C57BL/6 NK cells. Furthermore, when assessing NK cell function based on education and subsequent recognition of the C57BL/6 MHC-I haplotype by inhibitory Ly49 receptors, B6.Ly49(129) congenic mice exhibited robust NK cell activity, demonstrating efficient NK cell education by the 129S1 Ly49 cluster during development. The responsiveness of NK cells expressing 129S1 Ly49 was shown to be mediated by subsets expressing one or more self-MHC receptors, including Ly49I, Ly49O, Ly49V, and NKG2A. These findings demonstrate that the genetically segregating and diverse MHC-I and Ly49 loci in mice exhibit independent and epistatic effects on NK cell education that can be uncoupled during the intercrossing of inbred strains.

Effect of Ly49 haplotype variance on NK cell function and education.

&#x590D;&#x5236;&#x75C5;&#x6BD2;&#x6CBB;&#x7597;&#x764C;&#x75C7;&#x6709;&#x5F88;&#x591A;&#x7684;&#x4F20;&#x7EDF;&#x6CBB;&#x7597;&#x65B9;&#x6CD5;&#x7684;&#x4F18;&#x52BF;&#x3002;&#x4ED6;&#x4EEC;&#x975E;&#x5E38;&#x6709;&#x9488;&#x5BF9;&#x6027;&#xFF0C;self-amplifying&#xFF0C;&#x5E76;&#x4E14;&#x4F5C;&#x4E3A;&#x57FA;&#x56E0;&#x6CBB;&#x7597;&#x8FD0;&#x8F7D;&#x5DE5;&#x5177;&#x548C;&#x6EB6;&#x7624;&#x4EE3;&#x7406;&#x6DFB;&#x52A0;&#x7684;&#x6F5C;&#x529B;&#x3002;Parapoxvirus &#x5C5E;&#xFF0C;&#x9020;&#x6210;&#x4E00;&#x79CD;&#x826F;&#x6027;&#x7684;&#x75BE;&#x75C5;&#x5728;&#x5176;&#x81EA;&#x7136;&#x6709;&#x8E44;&#x5BBF;&#x4E3B;&#x7684;&#x539F;&#x578B;&#x79CD; Parapoxvirus &#x7EF5;&#x7F8A;&#x6216;&#x7F8A;&#x53E3;&#x75AE;&#x75C5;&#x6BD2; (ORFV)&#x3002;ORFV &#x62E5;&#x6709;&#x8BB8;&#x591A;&#x72EC;&#x7279;&#x5C5E;&#x6027;&#xFF0C;&#x4F7F;&#x5B83;&#x7406;&#x60F3;&#x7684;&#x75C5;&#x6BD2;&#x6027;&#x9AA8;&#x5E72;&#x53D1;&#x5C55;&#x7684;&#x4E00;&#x79CD;&#x764C;&#x75C7;&#x6CBB;&#x7597;&#xFF1A; &#x5B83;&#x662F;&#x5B89;&#x5168;&#x7684;&#x5728;&#x4EBA;&#x7C7B;&#x4E2D;&#xFF0C;&#x6709;&#x80FD;&#x529B;&#x9020;&#x6210;&#x91CD;&#x590D;&#x611F;&#x67D3;&#x5373;&#x4F7F;&#x5B58;&#x5728;&#x6297;&#x4F53;&#xFF0C;&#x548C;&#x5B83;&#x8BF1;&#x4F7F;&#x70C8;&#x6027; T (h)-1-&#x5360;&#x4E3B;&#x5BFC;&#x5730;&#x4F4D;&#x7684;&#x514D;&#x75AB;&#x53CD;&#x5E94;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x663E;&#x793A;&#x5B9E;&#x65F6;&#x590D;&#x5236; ORFV &#x8BF1;&#x5BFC;&#x591A;&#x4E2A;&#x81EA;&#x4F53;&#x5C0F;&#x9F20;&#x6A21;&#x578B;&#x7684;&#x764C;&#x75C7;&#xFF0C;&#x5F88;&#x5927;&#x7A0B;&#x5EA6;&#x4E0A;&#x4ECB;&#x5BFC;&#x70C8;&#x6027;&#x6FC0;&#x6D3B;&#x7EC6;&#x80DE;&#x56E0;&#x5B50;&#x5206;&#x6CCC;&#x548C;&#x6297;&#x7624;&#x81EA;&#x7136;&#x6740;&#x624B; (NK) &#x7EC6;&#x80DE;&#x7684;&#x6297;&#x80BF;&#x7624;&#x514D;&#x75AB;&#x53CD;&#x5E94;&#x3002;&#x6211;&#x4EEC;&#x4E5F;&#x5DF2;&#x5F3A;&#x8C03;&#x4E86;&#x793A;&#x8303;&#x6548;&#x679C;&#x5305;&#x62EC;&#x764C;&#x75C7; A549 &#x5F02;&#x79CD;&#x79FB;&#x690D;&#x6A21;&#x578B;&#x4E2D;&#x7684;&#x4EBA;&#x7C7B;&#x764C;&#x75C7;&#x7EC6;&#x80DE;&#x88C2;&#x7684;&#x75C5;&#x6BD2;&#x7684;&#x4E34;&#x5E8A;&#x6F5C;&#x529B;&#x3002;

ORFV&#xFF1A; &#x4E00;&#x79CD;&#x65B0;&#x578B;&#x6EB6;&#x7624;&#x548C;&#x514D;&#x75AB;&#x523A;&#x6FC0; Parapoxvirus &#x6CBB;&#x7597;&#x3002;

Replicating viruses for the treatment of cancer have a number of advantages over traditional therapeutic modalities. They are highly targeted, self-amplifying, and have the added potential to act as both gene-therapy delivery vehicles and oncolytic agents. Parapoxvirus ovis or Orf virus (ORFV) is the prototypic species of the Parapoxvirus genus, causing a benign disease in its natural ungulate host. ORFV possesses a number of unique properties that make it an ideal viral backbone for the development of a cancer therapeutic: it is safe in humans, has the ability to cause repeat infections even in the presence of antibody, and it induces a potent T(h)-1-dominated immune response. Here, we show that live replicating ORFV induces an antitumor immune response in multiple syngeneic mouse models of cancer that is mediated largely by the potent activation of both cytokine-secreting, and tumoricidal natural killer (NK) cells. We have also highlighted the clinical potential of the virus by demonstration of human cancer cell oncolysis including efficacy in an A549 xenograft model of cancer.

ORFV: A Novel Oncolytic and Immune Stimulating Parapoxvirus Therapeutic.

R&#xE9;plication des virus pour le traitement du cancer ont un certain nombre d&#x26;#39;avantages par rapport modalit&#xE9;s th&#xE9;rapeutiques traditionnelles. Ils sont tr&#xE8;s cibl&#xE9;es, l&#x26;#39;auto-amplification, et ont le potentiel ajout&#xE9; &#xE0; agir en tant que deux v&#xE9;hicules de livraison de th&#xE9;rapie g&#xE9;nique et les agents oncolytiques. Parapoxvirus ovis ou Orf virus (ORFV) est l&#x26;#39;esp&#xE8;ce la prototypes du genre Parapoxvirus, causant une maladie b&#xE9;nigne chez son h&#xF4;te naturel des ongul&#xE9;s. ORFV poss&#xE8;de un certain nombre de propri&#xE9;t&#xE9;s uniques qui en font un squelette id&#xE9;al virale pour le d&#xE9;veloppement d&#x26;#39;un cancer th&#xE9;rapeutique: il est s&#xFB;r chez l&#x26;#39;homme, a la capacit&#xE9; de causer des infections &#xE0; r&#xE9;p&#xE9;tition, m&#xEA;me en pr&#xE9;sence d&#x26;#39;anticorps, et il induit une puissante T (h )-1-domin&#xE9; r&#xE9;ponse immunitaire. Ici, nous montrons que ORFV direct r&#xE9;plication induit une r&#xE9;ponse immunitaire antitumorale dans plusieurs mod&#xE8;les de souris syng&#xE9;niques de cancer qui est la m&#xE9;diation en grande partie par l&#x26;#39;activation puissante &#xE0; la fois de cytokine-s&#xE9;cr&#xE9;tant, et tumoricide natural killer (NK). Nous avons &#xE9;galement mis en &#xE9;vidence le potentiel clinique du virus par la d&#xE9;monstration de oncolyse cancer des cellules humaines, y compris l&#x26;#39;efficacit&#xE9; dans un mod&#xE8;le de x&#xE9;nogreffe de cancer A549.

ORFV: A Novel Parapoxvirus oncolytiques et stimulant immunitaire th&#xE9;rapeutique

Replizierende Viren zur Behandlung von Krebs haben eine Reihe von Vorteilen gegen&uuml;ber traditionellen therapeutischen Modalit&auml;ten. Sie sind sehr gezielte, self-amplifying, und haben das zus&auml;tzliche Potenzial zu Gentherapie Lieferfahrzeuge und Onkolytische Agenten. Parapoxvirus Ovis oder Orf-Virus (ORFV) ist die prototypische Pflanzenart der Gattung Parapoxvirus, verursacht eine gutartige Krankheit in seinem nat&uuml;rlichen Huftier Host. ORFV besitzt eine Reihe von einzigartigen Eigenschaften, die eine ideale virale R&uuml;ckgrat f&uuml;r die Entwicklung von Krebs therapeutische machen: Es ist sicher beim Menschen hat die F&auml;higkeit zu wiederholte Infektionen auch in Gegenwart von Antik&ouml;rpern verursachen, und er macht eine potente T (h)-1-dominierten Immunantwort. Hier zeigen wir, dass Leben Repro ORFV induziert eine antitumor Immunantwort in mehreren syngenen Mausmodelle von Krebs, die weitgehend durch die starke Aktivierung der Zytokin-sezernierende sowohl Tumoricidal nat&uuml;rlichen killer (NK) Zellen vermittelt wird. Wir haben auch das klinische Potenzial des Virus durch Demonstration von menschlichen Krebs Zelle Oncolysis Wirksamkeit in einem A549-Xenograft--Modell des Krebses einschlie&szlig;lich hervorgehoben.

ORFV: Eine neuartige Onkolytische und das Immunsystem stimulieren Parapoxvirus therapeutische.

Replicazione virus per il trattamento del cancro hanno un certo numero di vantaggi rispetto ai tradizionali modalit&agrave; terapeutiche. Essi sono altamente mirati, self-amplifying e hanno il potenziale di agire sia come veicoli di consegna di terapia genica e agenti oncolytic aggiunto. Parapoxvirus ovis o Orf virus (ORFV) &egrave; la specie prototipiche del genere Parapoxvirus, causando una malattia benigna in suo ospite naturale di ungulati. ORFV possiede un certo numero di caratteristiche uniche che lo rendono una dorsale virale ideale per lo sviluppo di un cancro terapeutico: &egrave; sicuro in esseri umani, ha la capacit&agrave; di provocare infezioni ripetute anche in presenza di anticorpi, e induce una potente T (h) -1-dominato la risposta immunitaria. Qui, ci mostra che ORFV replicare dal vivo induce una risposta immunitaria antitumorale in pi&ugrave; modelli di mouse Carlo di cancro che &egrave; mediato in gran parte dall&#39;attivazione potente di sia che secernono citochine e tumoricidal naturali killer (NK) celle. Abbiamo anche evidenziato il potenziale clinico del virus da dimostrazione di cancro umano cellule oncolysis tra cui efficacia in un modello di xenoinnesto A549 di cancro.

ORFV: Un romanzo Oncolytic e immunitario stimolando Parapoxvirus terapeutico.

&#x764C;&#x306E;&#x6CBB;&#x7642;&#x306E;&#x305F;&#x3081;&#x306E;&#x8907;&#x88FD;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x306F;&#x3001;&#x5F93;&#x6765;&#x306E;&#x6CBB;&#x7642;&#x6CD5;&#x306B;&#x6BD4;&#x3079;&#x3066;&#x591A;&#x304F;&#x306E;&#x5229;&#x70B9;&#x3092;&#x6301;&#x3063;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x5F7C;&#x3089;&#x306F;&#x975E;&#x5E38;&#x306B;&#x3001;&#x5BFE;&#x8C61;&#x3068;&#x81EA;&#x5DF1;&#x5897;&#x5E45;&#x3057;&#x3001;&#x907A;&#x4F1D;&#x5B50;&#x6CBB;&#x7642;&#x9001;&#x9054;&#x5A92;&#x4F53;&#x3068;&#x816B;&#x760D;&#x6EB6;&#x89E3;&#x5264;&#x306E;&#x4E21;&#x65B9;&#x3068;&#x3057;&#x3066;&#x6A5F;&#x80FD;&#x3059;&#x308B;&#x3088;&#x3046;&#x306B;&#x8FFD;&#x52A0;&#x3055;&#x308C;&#x305F;&#x53EF;&#x80FD;&#x6027;&#x3092;&#x6301;&#x3063;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x30D1;&#x30E9;&#x30DD;&#x30C3;&#x30AF;&#x30B9;&#x30A6;&#x30A4;&#x30EB;&#x30B9;OVIS&#x307E;&#x305F;&#x306F;ORF&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#xFF08;ORFV&#xFF09;&#x306F;&#x3001;&#x5929;&#x7136;&#x306E;&#x6709;&#x8E44;&#x985E;&#x30DB;&#x30B9;&#x30C8;&#x3067;&#x826F;&#x6027;&#x75BE;&#x60A3;&#x3092;&#x5F15;&#x304D;&#x8D77;&#x3053;&#x3057;&#x3001;&#x30D1;&#x30E9;&#x30DD;&#x30C3;&#x30AF;&#x30B9;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x5C5E;&#x306E;&#x539F;&#x578B;&#x7A2E;&#x3067;&#x3042;&#x308B;&#x3002; ORFV&#x306F;&#x3001;&#x6CBB;&#x7642;&#x764C;&#x306E;&#x958B;&#x767A;&#x306E;&#x305F;&#x3081;&#x306E;&#x7406;&#x60F3;&#x7684;&#x306A;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x306E;&#x30D0;&#x30C3;&#x30AF;&#x30DC;&#x30FC;&#x30F3;&#x306B;&#x3059;&#x308B;&#x30E6;&#x30CB;&#x30FC;&#x30AF;&#x306A;&#x30D7;&#x30ED;&#x30D1;&#x30C6;&#x30A3;&#x306E;&#x6570;&#x3092;&#x6301;&#x3063;&#x3066;&#x3044;&#x308B;&#xFF1A;&#x305D;&#x308C;&#x306F;&#x4EBA;&#x9593;&#x306B;&#x5B89;&#x5168;&#x3067;&#x3082;&#x3001;&#x6297;&#x4F53;&#x306E;&#x5B58;&#x5728;&#x4E0B;&#x3067;&#x7E70;&#x308A;&#x8FD4;&#x3057;&#x611F;&#x67D3;&#x3092;&#x5F15;&#x304D;&#x8D77;&#x3053;&#x3059;&#x80FD;&#x529B;&#x3092;&#x6301;&#x3063;&#x3066;&#x304A;&#x308A;&#x3001;&#x305D;&#x308C;&#x304C;&#x5F37;&#x529B;&#x306A;T&#xFF08;h&#x3092;&#x8A98;&#x5C0E;&#x3059;&#x308B;&#xFF09;-1-&#x512A;&#x4F4D;&#x514D;&#x75AB;&#x5FDC;&#x7B54;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x305D;&#x306E;&#x30E9;&#x30A4;&#x30D6;&#x306E;&#x8907;&#x88FD;ORFV&#x3092;&#x8868;&#x793A;&#x3057;&#x3001;&#x4E21;&#x65B9;&#x306E;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x5206;&#x6CCC;&#x306E;&#x5F37;&#x529B;&#x306A;&#x6D3B;&#x6027;&#x5316;&#x3001;&#x6297;&#x816B;&#x760D;&#x30CA;&#x30C1;&#x30E5;&#x30E9;&#x30EB;&#x30AD;&#x30E9;&#x30FC;&#xFF08;NK&#xFF09;&#x7D30;&#x80DE;&#x306B;&#x3088;&#x3063;&#x3066;&#x4E3B;&#x306B;&#x5A92;&#x4ECB;&#x3055;&#x308C;&#x308B;&#x764C;&#x306E;&#x8907;&#x6570;&#x306E;&#x540C;&#x7CFB;&#x30DE;&#x30A6;&#x30B9;&#x30E2;&#x30C7;&#x30EB;&#x306B;&#x304A;&#x3044;&#x3066;&#x6297;&#x816B;&#x760D;&#x514D;&#x75AB;&#x5FDC;&#x7B54;&#x3092;&#x8A98;&#x5C0E;&#x3059;&#x308B;&#x3002;&#x6211;&#x3005;&#x306F;&#x307E;&#x305F;&#x3001;&#x764C;&#x306E;A549&#x7570;&#x7A2E;&#x79FB;&#x690D;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x6709;&#x52B9;&#x6027;&#x3092;&#x542B;&#x3080;&#x30D2;&#x30C8;&#x764C;&#x7D30;&#x80DE;&#x306E;&#x816B;&#x760D;&#x5D29;&#x58CA;&#x306E;&#x5B9F;&#x8A3C;&#x306B;&#x3088;&#x3063;&#x3066;&#x3001;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x306E;&#x81E8;&#x5E8A;&#x7684;&#x53EF;&#x80FD;&#x6027;&#x3092;&#x5F37;&#x8ABF;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

ORFV&#xFF1A;&#x65B0;&#x898F;&#x816B;&#x760D;&#x6EB6;&#x89E3;&#x6027;&#x3068;&#x514D;&#x75AB;&#x523A;&#x6FC0;&#x30D1;&#x30E9;&#x30DD;&#x30C3;&#x30AF;&#x30B9;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x6CBB;&#x7642;

&#xC554; &#xCE58;&#xB8CC;&#xC5D0; &#xB300; &#xD55C; &#xBCF5;&#xC81C; &#xBC14;&#xC774;&#xB7EC;&#xC2A4;&#xC5D0;&#xB294; &#xC804;&#xD1B5;&#xC801;&#xC778; &#xCE58;&#xB8CC; modalities &#xC774;&#xC810;&#xC774; &#xC218;&#xAC00; &#xD45C;&#xC2DC; &#xB429;&#xB2C8;&#xB2E4;. &#xADF8;&#xB4E4;&#xC740; &#xB192;&#xC740; &#xD0C0;&#xAC9F;&#xC73C;&#xB85C;&#xD558;&#xB294; self-amplifying, &#xADF8;&#xB9AC;&#xACE0; &#xC720;&#xC804;&#xC790; &#xCE58;&#xB8CC; &#xBC30;&#xB2EC; &#xCC28;&#xB7C9; &#xBC0F; oncolytic &#xC5D0;&#xC774;&#xC804;&#xD2B8; &#xC5ED;&#xD560; &#xCD94;&#xAC00; &#xAC00;&#xB2A5;&#xC131;&#xC774; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. Parapoxvirus ovis &#xB610;&#xB294; Orf &#xBC14;&#xC774;&#xB7EC;&#xC2A4; (ORFV) &#xC790;&#xC5F0; &#xC720;&#xC81C;&#xB958; &#xD638;&#xC2A4;&#xD2B8; &#xC591;&#xC131; &#xC9C8;&#xD658;&#xC744; &#xC77C;&#xC73C;&#xD0A4;&#xB294; Parapoxvirus &#xC18D;&#xC758; prototypic &#xC885;&#xC785;&#xB2C8;&#xB2E4;. ORFV &#xCE58;&#xB8CC;&#xB294; &#xC554; &#xAC1C;&#xBC1C;&#xC5D0; &#xB300; &#xD55C; &#xC774;&#xC0C1;&#xC801;&#xC778; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xBC31;&#xBCF8; &#xB9CC;&#xB4DC;&#xB294; &#xB3C5;&#xD2B9;&#xD55C; &#xC18D;&#xC131;&#xC758; &#xC218;&#xB97C;&#xAC00;&#xC9C0;&#xACE0;: &#xADF8;&#xAC83;&#xC740; &#xC778; &#xAC04;&#xC5D0; &#xC548;&#xC804; &#xD558; &#xAC8C; &#xD56D; &#xCCB4;&#xC758; &#xC874;&#xC7AC;&#xB3C4; &#xBC18;&#xBCF5; &#xAC10;&#xC5FC;&#xC744; &#xC77C;&#xC73C;&#xD0AC; &#xC218; &#xC788;&#xC73C;&#xBA70; &#xAC15;&#xB825;&#xD55C; T (h)-1 &#xC720;&#xB3C4;-&#xBA74;&#xC5ED; &#xBC18;&#xC751;&#xC744; &#xC9C0;&#xBC30;. &#xC790;, &#xC6B0;&#xB9AC; &#xB77C;&#xC774;&#xBE0C; &#xBCF5;&#xC81C; ORFV cytokine &#xBD84; &#xBE44; &#xBC0F; &#xCCAD;&#xC18C;&#xB144; &#xC790;&#xC5F0; &#xD0AC;&#xB7EC; (NK) &#xC138;&#xD3EC;&#xC758; &#xAC15;&#xB825;&#xD55C; &#xD65C;&#xC131;&#xD654; &#xC8FC;&#xB85C; &#xC911;&#xC7AC; &#xC554;&#xC758; &#xC5EC;&#xB7EC; syngeneic &#xB9C8;&#xC6B0;&#xC2A4; &#xBAA8;&#xB378;&#xC5D0;&#xC11C; antitumor &#xBA74;&#xC5ED; &#xBC18;&#xC751; &#xC720;&#xB3C4; &#xBCF4;&#xC5EC;. &#xC6B0;&#xB9AC; &#xB610;&#xD55C; &#xC554; A549 &#xB1CC;&#xC885;&#xC591; &#xBAA8;&#xB378;&#xC5D0; &#xD6A8;&#xB2A5; &#xB4F1; &#xC778;&#xAC04; &#xC554; &#xC138;&#xD3EC; oncolysis&#xC758; &#xB370;&#xBAA8;&#xC5D0; &#xC758;&#xD574; &#xBC14;&#xC774;&#xB7EC;&#xC2A4;&#xC758; &#xC784;&#xC0C1; &#xC7A0;&#xC7AC;&#xB825;&#xC744; &#xAC15;&#xC870; &#xD588;&#xB2E4;.

ORFV: &#xD55C; &#xC18C;&#xC124; Oncolytic &#xBC0F; &#xBA74;&#xC5ED; &#xC790;&#xADF9; &#xCE58;&#xB8CC; Parapoxvirus.

Virus que se replican para el tratamiento de c&#xE1;ncer tienen una serie de ventajas sobre los tradicionales modalidades terap&#xE9;uticas. Ellos son muy espec&#xED;ficas, la auto-amplificaci&#xF3;n, y tienen el potencial a&#xF1;adido de actuar como dos veh&#xED;culos de reparto terapia g&#xE9;nica y los agentes oncol&#xED;ticos. Parapoxvirus ovis o virus Orf (ORFV) es la especie protot&#xED;picos del g&#xE9;nero parapoxvirus, causando una enfermedad benigna en su hu&#xE9;sped natural de ungulados. ORFV posee un n&#xFA;mero de propiedades &#xFA;nicas que lo hacen ideal para una columna vertebral viral para el desarrollo de un c&#xE1;ncer terap&#xE9;utico: es seguro en humanos, tiene la capacidad de causar infecciones de repetici&#xF3;n, incluso en presencia de anticuerpo, y se induce una potente T (h )-1-dominado por la respuesta inmune. Aqu&#xED;, mostramos que ORFV replicar en vivo induce una respuesta inmune antitumoral en varios modelos de rat&#xF3;n sing&#xE9;nicas de c&#xE1;ncer que se est&#xE1; mediada en gran parte por la activaci&#xF3;n potente de la secreci&#xF3;n de citoquinas tanto, y el asesino tumoricida naturales (c&#xE9;lulas NK). Tambi&#xE9;n hemos destacado el potencial cl&#xED;nico del virus mediante la demostraci&#xF3;n de oncolysis de c&#xE9;lulas humanas del c&#xE1;ncer, incluido la eficacia en un modelo de xenoinjerto de c&#xE1;ncer de A549.

ORFV: Una Novela parapoxvirus oncol&#xED;tica estimulante y terap&#xE9;utico inmunol&#xF3;gico

Ly49 &#x4ECB;&#x5BFC;&#x8BC6;&#x522B;&#x7684; MHC-&#x6211;&#x5BF9;&#x5BBF;&#x4E3B;&#x7EC6;&#x80DE;&#x7684;&#x5206;&#x5B50;&#x88AB;&#x8BA4;&#x4E3A;&#x662F;&#x91CD;&#x8981;&#x7684;&#x81EA;&#x7136;&#x6740;&#x624B; (NK)-&#x7EC6;&#x80DE;&#x8C03;&#x63A7;&#x548C;&#x6559;&#x80B2; &#xFF1B;&#x4F46;&#x662F;&#xFF0C;&#x56E0;&#x4E3A;&#x5220;&#x53BB;&#x6B64;&#x5927;&#x9176;&#x5BB6;&#x65CF;&#x56F0;&#x96BE;&#x7F3A;&#x4E4F;&#x57FA;&#x56E0;&#x7F3A;&#x9677;&#x52A8;&#x7269;&#x6A21;&#x578B;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x4ECB;&#x7ECD; NK &#x57FA;&#x56E0;&#x590D;&#x6742;&#x7EC4;&#x5408;&#x5F0F; (NKC(KD)) &#x5C0F;&#x9F20;&#xFF0C;&#x7F3A;&#x4E4F;&#x8868;&#x8FBE;&#x7684; Ly49 &#x548C;&#x76F8;&#x5173;&#x7684; MHC-&#x6211;&#x5927;&#x591A;&#x6570; NK &#x7EC6;&#x80DE;&#x53D7;&#x4F53;&#x3002;NKC(KD) NK &#x7EC6;&#x80DE;&#x5C55;&#x54C1;&#x6709;&#x7F3A;&#x9677;&#x6740;&#x5BB3; MHC-&#x7F3A;&#xFF0C;&#x4F46;&#x53E6;&#x6709;&#x6B63;&#x5E38;&#xFF0C;&#x76EE;&#x6807;&#x5355;&#x5143;&#x683C;&#xFF0C;&#x4ECE;&#x5404;&#x79CD;&#x7C7B;&#x578B;&#x7684; MHC &#x57FA;&#x56E0;&#x7F3A;&#x9677;&#x5C0F;&#x9F20;&#x79FB;&#x690D; NKC(KD) &#x5C0F;&#x9F20;&#x4E2D;&#x6709;&#x7F3A;&#x9677;&#x7684;&#x62D2;&#x7EDD;&#x6240;&#x9020;&#x6210;&#x3002;&#x81EA;&#x6211;-MHC-&#x6211;&#x6CB9;&#x70DF;&#x7531; NKC(KD) &#x5C0F;&#x9F20; NK &#x7EC6;&#x80DE;&#x53EF;&#x4EE5;&#x7531;&#x81EA;&#x6211; MHC-&#x6211;-&#x7279;&#x5B9A; Ly49 &#x8F6C;&#x57FA;&#x56E0;&#x6551;&#x51FA;&#x3002;&#x867D;&#x7136; NKC(KD) &#x5C0F;&#x9F20;&#x663E;&#x793A;&#x6709;&#x7F3A;&#x9677;&#x8BC6;&#x522B; MHC &#x7F3A;&#x80BF;&#x7624;&#x7EC6;&#x80DE;&#xFF0C;&#x4ECE;&#x800C;&#x51CF;&#x5C11;&#x4F53;&#x5185;&#x80BF;&#x7624;&#x7EC6;&#x80DE;&#x95F4;&#x9699;&#xFF0C;NKG2D-&#x6216;&#x6297;&#x4F53;&#x4F9D;&#x8D56;&#x7684;&#x7EC6;&#x80DE;&#x4ECB;&#x5BFC;&#x7684;&#x7EC6;&#x80DE;&#x6BD2;&#x4F5C;&#x7528;&#x8BF1;&#x5BFC;&#x80BF;&#x7624;&#x7EC6;&#x80DE;&#x7684;&#x7EC6;&#x80DE;&#x6BD2;&#x6027;&#x548C;&#x7EC6;&#x80DE;&#x56E0;&#x5B50;&#x751F;&#x4EA7;&#x8BF1;&#x5BFC;&#x6FC0;&#x6D3B;&#x53D7;&#x4F53;&#x662F;&#x9AD8;&#x6548; Ly49 &#x7F3A; NK &#x7EC6;&#x80DE;&#xFF0C;&#x8FD9;&#x8868;&#x660E; MHC-&#x6211;&#x6559;&#x80B2;&#x7684; NK &#x7EC6;&#x80DE;&#x662F;&#x5355;&#x4E00;&#x65B9;&#x9762;&#x8C03;&#x8282;&#x4ED6;&#x4EEC;&#x6240;&#x6709;&#x7684;&#x6F5C;&#x529B;&#x3002;&#x8FD9;&#x4E9B;&#x7ED3;&#x679C;&#x63D0;&#x4F9B;&#x4E86;&#x76F4;&#x63A5;&#x7684;&#x9057;&#x4F20;&#x8BC1;&#x636E; Ly49 &#x8868;&#x8FBE;&#x5F0F;&#x662F; NK &#x7EC6;&#x80DE;&#x6559;&#x80B2;&#x81EA;&#x6211;-MHC-&#x6211;&#x7684;&#x5206;&#x5B50;&#x7684;&#x5FC5;&#x8981;&#x6761;&#x4EF6;&#xFF0C;&#x6CA1;&#x6709;&#x8FD9;&#x4E9B;&#x53D7;&#x4F53;&#x7684;&#x60C5;&#x51B5;&#x4E0B;&#x7531; NK &#x7EC6;&#x80DE;&#x5BFC;&#x81F4;&#x635F;&#x5931;&#x7684; MHC &#x4F9D;&#x8D56;&quot;&#x7F3A;&#x5C11;&#x81EA;&#x6211;&quot;&#x6CB9;&#x70DF;&#x3002;

&#x53D7;&#x635F; Ly49 &#x7F3A;&#x9677;&#x5C0F;&#x9F20;&#x81EA;&#x7136;&#x6740;&#x4F24;&#x7EC6;&#x80DE;&#x81EA;&#x6211;&#x6559;&#x80B2;&#x548C;&quot;&#x7F3A;&#x5C11;&#x81EA;&#x6211;&quot;&#x53CD;&#x5E94;&#x3002;

Ly49-mediated recognition of MHC-I molecules on host cells is considered vital for natural killer (NK)-cell regulation and education; however, gene-deficient animal models are lacking because of the difficulty in deleting this large multigene family. Here, we describe NK gene complex knockdown (NKC(KD)) mice that lack expression of Ly49 and related MHC-I receptors on most NK cells. NKC(KD) NK cells exhibit defective killing of MHC-I-deficient, but otherwise normal, target cells, resulting in defective rejection by NKC(KD) mice of transplants from various types of MHC-I-deficient mice. Self-MHC-I immunosurveillance by NK cells in NKC(KD) mice can be rescued by self-MHC-I-specific Ly49 transgenes. Although NKC(KD) mice display defective recognition of MHC-I-deficient tumor cells, resulting in decreased in vivo tumor cell clearance, NKG2D- or antibody-dependent cell-mediated cytotoxicity-induced tumor cell cytotoxicity and cytokine production induced by activation receptors was efficient in Ly49-deficient NK cells, suggesting MHC-I education of NK cells is a single facet regulating their total potential. These results provide direct genetic evidence that Ly49 expression is necessary for NK-cell education to self-MHC-I molecules and that the absence of these receptors leads to loss of MHC-I-dependent "missing-self" immunosurveillance by NK cells.

Impaired natural killer cell self-education and "missing-self" responses in Ly49-deficient mice.

Ly49 induite par la reconnaissance du CMH-j&#39;ai des mol&eacute;cules sur les cellules de l&#39;h&ocirc;te est consid&eacute;r&eacute; comme vital pour natural killer (NK)-cellule de r&egrave;glement et l&#39;&eacute;ducation ; Cependant, le g&egrave;ne d&eacute;ficient des mod&egrave;les animaux manquent en raison de la difficult&eacute; &agrave; supprimer de cette grande famille multig&eacute;nique. Nous d&eacute;crivons ici le knockdown complexe de g&egrave;ne NK (souris NKC(KD)) qui manquent d&#39;expression Ly49 et connexe MHC-j&#39;ai des r&eacute;cepteurs sur la plupart des cellules NK. Exposition de cellules NK NKC(KD) d&eacute;fectueuse tuant de MHC I-d&eacute;ficient, mais normal, cibler les cellules, entra&icirc;nant rejet d&eacute;fectueux par des souris NKC(KD) de greffes de divers types de MHC-je souris d&eacute;ficientes. Immunosurveillance Self-MHC-I par les cellules NK chez la souris NKC(KD) peut &ecirc;tre sauv&eacute;e par soi-MHC-j&#39;ai sp&eacute;cifiques Ly49 transg&egrave;nes. Bien que NKC(KD) souris affichent d&eacute;fectueuse reconnaissance des cellules tumorales de MHC-I-deficient, aboutissant &agrave; la clairance de cellule tumorale in vivo une diminution, NKG2D ou anticorps-d&eacute;pendante cell-mediated de tumeur induite par la cytotoxicit&eacute; cellulaire cytotoxicit&eacute; et cytokine production induite par les r&eacute;cepteurs de l&#39;activation a &eacute;t&eacute; efficace dans les cellules NK Ly49 d&eacute;ficient, ce qui sugg&egrave;re de MHC-j&#39;ai l&#39;&eacute;ducation des cellules NK est une facette unique r&eacute;gissant leur total potentiel. Ces r&eacute;sultats constituent une preuve g&eacute;n&eacute;tique directe que Ly49 expression est n&eacute;cessaire pour l&#39;&eacute;ducation de NK-cellule aux mol&eacute;cules self-MHC-I et que l&#39;absence de ces r&eacute;cepteurs conduit &agrave; la perte de MHC-I-dependent &laquo; soi manquant &raquo; immunosurveillance par les cellules NK.

Avec facult&eacute;s affaiblies r&eacute;ponses auto-&eacute;ducation et &laquo; soi manquant &raquo; de cellule tueuse naturelle chez les souris d&eacute;ficientes en Ly49.

Ly49-vermittelte Anerkennung der MHC-ich Molek&uuml;len auf Wirtszellen gilt als entscheidend f&uuml;r nat&uuml;rliche Killer (NK)-Handy-Verordnung und Bildung; gen-defizienten Tiermodellen fehlen jedoch wegen der Schwierigkeit beim L&ouml;schen dieser gro&szlig;en multigene Familie. Hier beschreiben wir NK gen komplexe Niederschlag (NKC(KD))-M&auml;use, die Ausdruck der Ly49 und verwandte MHC fehlt-ich-Rezeptoren in den meisten NK-Zellen. Ausstellung-defekte NKC(KD) NK-Zellen t&ouml;ten von MHC-Mangel, aber ansonsten normalen, Zellen, was zu fehlerhaften Ablehnung von NKC(KD) M&auml;usen der Transplantationen von verschiedenen Typen von MHC-defizienten M&auml;usen Zielen. Selbst-MHC-I Immunosurveillance von NK-Zellen bei NKC(KD) M&auml;usen kann durch selbst-MHC-ich-spezifische Ly49 transgenen gerettet zu werden. Obwohl NKC(KD) M&auml;use mangelhafte Anerkennung der MHC-defizienten Tumorzellen anzeigen, was zu verringerter in-vivo Tumor Zelle Zollabwicklung, NKG2D oder Antik&ouml;rper-abh&auml;ngige zellvermittelte Zytotoxizit&auml;t induziert Tumor Zelle Zytotoxizit&auml;t und Cytokine Produktion durch Aktivierung von Rezeptoren induziert war effizient in Ly49-defizienten NK-Zellen, was darauf hindeutet MHC-ich Bildung von NK-Zellen ist eine einzige Facette regulieren ihren gesamten potenziellen. Diese Ergebnisse liefern direkte genetische Beweise, die Ly49 Ausdruck f&uuml;r NK-Zell-Bildung zu selbst-MHC-I Molek&uuml;len notwendig ist und die keine dieser Rezeptoren f&uuml;hrt zum Verlust von MHC-abh&auml;ngigen &quot;fehlt-selbst&quot; Immunosurveillance von NK-Zellen.

Natural Killer Cell Selbstbildung und &quot;missing-Self&quot; Antworten bei Ly49-defizienten M&auml;usen beeintr&auml;chtigt.

Riconoscimento Ly49-mediata di MHC-I molecole su cellule ospiti &egrave; considerato vitale per natural killer (NK)-cellula regolamento ed educazione; Tuttavia, a causa della difficolt&agrave; nell&#39;eliminazione di questa grande famiglia di multigene sono privi di modelli animali gene-carenti. Qui, descriviamo atterramento complesso NK gene (NKC(KD)) topi che mancano di espressione di Ly49 e correlati MHC-I recettori presenti sulla maggior parte delle cellule NK. Esposizione di cellule NK NKC(KD) difettoso uccisione di MHC-I-carenti, ma altrimenti normale, bersaglio le cellule, con conseguente rifiuto difettoso da topi NKC(KD) dei trapianti da vari tipi di mouse MHC-I-carenti. Auto-MHC-I immunosurveillance da parte delle cellule NK in topi NKC(KD) pu&ograve; essere salvato da auto-MHC-I-specific Ly49 transgeni. Anche se NKC(KD) topi display difettoso riconoscimento delle cellule tumorali di MHC-I-carenti, con conseguente liquidazione cellula tumorale in vivo &egrave; diminuito, NKG2D - o anticorpo-dipendente cellulo-mediata citotossicit&agrave; indotta da tumore delle cellule citotossicit&agrave; e cytokine produzione indotta dai recettori attivazione era efficiente nelle cellule NK Ly49-carenti, suggerendo MHC-I formazione delle cellule NK &egrave; una sfaccettatura singola regolazione della loro potenziale totale. Questi risultati forniscono la prova genetica diretta che Ly49 espressione &egrave; necessario per la formazione di cellule NK alle molecole di auto-MHC-I e che l&#39;assenza di questi recettori porta alla perdita di MHC-I-dipendente immunosurveillance &quot;missing-self&quot; da parte delle cellule NK.

Alterata delle cellule killer naturali autoformazione e &quot;missing-self&quot; risposte nei topi deficienti Ly49.

Ly49 &#x3092;&#x4ECB;&#x3057;&#x305F;&#x8A8D;&#x8B58; MHC &#x306E;-&#x79C1;&#x306F;&#x5206;&#x5B50;&#x306E;&#x30DB;&#x30B9;&#x30C8;&#x7D30;&#x80DE;&#x306F;&#x30CA;&#x30C1;&#x30E5;&#x30E9;&#x30EB; &#x30AD;&#x30E9;&#x30FC; (NK) &#x91CD;&#x8981;&#x3068;&#x898B;&#x306A;&#x3055;&#x308C;&#x307E;&#x3059;-&#x7D30;&#x80DE;&#x306E;&#x898F;&#x5236;&#x3068;&#x6559;&#x80B2;;&#x305F;&#x3060;&#x3057;&#x3001;&#x907A;&#x4F1D;&#x5B50;&#x6B20;&#x640D;&#x52D5;&#x7269;&#x30E2;&#x30C7;&#x30EB;&#x306F;&#x3053;&#x306E;&#x5927;&#x898F;&#x6A21;&#x306A;&#x591A;&#x91CD;&#x907A;&#x4F1D;&#x5B50;&#x65CF;&#x306E;&#x524A;&#x9664;&#x96E3;&#x3057;&#x3055;&#x306E;&#x305F;&#x3081;&#x306B;&#x6B20;&#x3051;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x6211;&#x3005; &#x306F; NK &#x907A;&#x4F1D;&#x5B50;&#x306E;&#x8907;&#x96D1;&#x306A;&#x6253;&#x6483;&#x3092;&#x8A18;&#x8FF0;&#x3059;&#x308B; (Ly49 &#x304A;&#x3088;&#x3073; mhc &#x95A2;&#x9023;&#x5206;&#x5B50;&#x306E;&#x767A;&#x73FE;&#x3092;&#x6B20;&#x3044;&#x3066;&#x3044;&#x308B; NKC(KD)) &#x30DE;&#x30A6;&#x30B9;-&#x79C1;&#x306F;&#x307B;&#x3068;&#x3093;&#x3069; NK &#x7D30;&#x80DE;&#x53D7;&#x5BB9;&#x4F53;&#x3002;NKC(KD) NK &#x7D30;&#x80DE;&#x5C55;&#x793A;&#x6B20;&#x9665;&#x6B20;&#x9665;&#x62D2;&#x7D76;&#x53CD;&#x5FDC;&#x306E; NKC(KD) &#x30DE;&#x30A6;&#x30B9;&#x306E; MHC &#x6B20;&#x640D;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x69D8;&#x3005; &#x306A;&#x7A2E;&#x985E;&#x306E;&#x79FB;&#x690D;&#x306B;&#x3088;&#x308B;&#x7D50;&#x679C;&#x306E;&#x30BB;&#x30EB;&#x3092;&#x5BFE;&#x8C61;&#x306B; MHC-&#x79C1;&#x306F;-&#x6B20;&#x4E4F;&#x3001;&#x3057;&#x304B;&#x3057;&#x3001;&#x305D;&#x308C;&#x4EE5;&#x5916;&#x306E;&#x5834;&#x5408;&#x901A;&#x5E38;&#x306E;&#x6BBA;&#x5BB3;&#x3057;&#x307E;&#x3059;&#x3002;&#x81EA;&#x5DF1; MHC &#x79C1;&#x306F;&#x98DF;&#x990C; NKC(KD) &#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B; NK &#x7D30;&#x80DE;&#x306B;&#x3088;&#x308B;&#x81EA;&#x5DF1; MHC-&#x79C1;&#x306F;-&#x56FA;&#x6709; Ly49 transgenes &#x306B;&#x3088;&#x3063;&#x3066;&#x6551;&#x51FA;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x3002;NKC(KD) &#x30DE;&#x30A6;&#x30B9;&#x6E1B;&#x5C11; in vivo &#x304C;&#x3093;&#x7D30;&#x80DE;&#x306E;&#x30AF;&#x30EA;&#x30A2;&#x30E9;&#x30F3;&#x30B9;&#x3092;&#x751F;&#x3058;&#x308B; MHC &#x6B20;&#x640D;&#x816B;&#x760D;&#x7D30;&#x80DE;&#x306E;&#x6B20;&#x9665;&#x8A8D;&#x8B58;&#x8868;&#x793A;&#x304C; NKG2D &#x307E;&#x305F;&#x306F;&#x6297;&#x4F53;&#x4F9D;&#x5B58;&#x306E;&#x7D30;&#x80DE;&#x5A92;&#x4ECB;&#x6027;&#x7D30;&#x80DE;&#x6BD2;&#x6027;&#x8A98;&#x767A;&#x816B;&#x760D;&#x7D30;&#x80DE;&#x306E;&#x7D30;&#x80DE;&#x6BD2;&#x6027;&#x3068;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x306E;&#x751F;&#x7523;&#x8A98;&#x5C0E;&#x306B;&#x3088;&#x308B;&#x6D3B;&#x6027;&#x5316;&#x53D7;&#x5BB9;&#x4F53;&#x306F; MHC &#x3092;&#x793A;&#x5506; Ly49 &#x6B20;&#x640D; NK &#x7D30;&#x80DE;&#x306E;&#x52B9;&#x7387;&#x7684;&#x3060;&#x3063;&#x305F;-&#x79C1;&#x306F; NK &#x7D30;&#x80DE;&#x306E;&#x6559;&#x80B2;&#x3067;&#x3042;&#x308B;&#x6F5C;&#x5728;&#x7684;&#x306A;&#x305D;&#x308C;&#x305E;&#x308C;&#x306E;&#x5408;&#x8A08;&#x3092;&#x898F;&#x5236;&#x3059;&#x308B; 1 &#x3064;&#x306E;&#x30D5;&#x30A1;&#x30BB;&#x30C3;&#x30C8;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x7D50;&#x679C;&#x306F; Ly49 &#x5F0F;&#x304C; NK &#x7D30;&#x80DE;&#x6559;&#x80B2;&#x81EA;&#x5DF1; MHC &#x79C1;&#x306F;&#x5206;&#x5B50;&#x306B;&#x5FC5;&#x8981;&#x3067;&#x3042;&#x308A;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x53D7;&#x5BB9;&#x4F53;&#x306E;&#x4E0D;&#x5728; MHC &#x4F9D;&#x5B58;&#x300C;&#x884C;&#x65B9;&#x4E0D;&#x660E;&#x81EA;&#x5DF1;&#x300D;&#x98DF;&#x990C;&#x306E;&#x640D;&#x5931;&#x306B;&#x3064;&#x306A;&#x304C;&#x308B; NK &#x7D30;&#x80DE;&#x306B;&#x3088;&#x308B;&#x76F4;&#x63A5;&#x306E;&#x907A;&#x4F1D;&#x5B66;&#x7684;&#x8A3C;&#x62E0;&#x3092;&#x63D0;&#x4F9B;&#x3057;&#x307E;&#x3059;&#x3002;

&#x30CA;&#x30C1;&#x30E5;&#x30E9;&#x30EB; &#x30AD;&#x30E9;&#x30FC;&#x7D30;&#x80DE;&#x306E;&#x81EA;&#x5DF1;&#x6559;&#x80B2;&#x3068;&#x300C;&#x4E0D;&#x8DB3;&#x3057;&#x3066;&#x3044;&#x308B;&#x81EA;&#x5DF1;&#x300D;&#x306E;&#x5FDC;&#x7B54; Ly49 &#x6B20;&#x640D;&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x969C;&#x5BB3;&#x8005;&#x3002;

MHC&#xC758; &#xC778;&#xC2DD; Ly49-&#xC911;&#xC7AC;-&#xB0B4;&#xAC00; &#xD638;&#xC2A4;&#xD2B8; &#xC140;&#xC5D0; &#xBD84;&#xC790; &#xC790;&#xC5F0; &#xD0AC;&#xB7EC; (NK)&#xC5D0; &#xB300; &#xD55C; &#xC911;&#xC694; &#xD55C; &#xAC83;&#xC73C;&#xB85C; &#xAC04;&#xC8FC; &#xB429;&#xB2C8;&#xB2E4;-&#xC140; &#xB808; &#xADE4; &#xB808;&#xC774; &#xC158; &#xBC0F; &#xAD50;&#xC721;; &#xADF8;&#xB7EC;&#xB098;, &#xC720;&#xC804;&#xC790; &#xBD88;&#xCDA9;&#xBD84; &#xD55C; &#xB3D9;&#xBB3C; &#xBAA8;&#xB378; multigene &#xAC00;&#xC871;&#xC774; &#xC0AD;&#xC81C;&#xC758; &#xC5B4;&#xB824;&#xC6C0; &#xB54C;&#xBB38;&#xC5D0; &#xACB0;&#xC5EC; &#xB418; &#xACE0; &#xC788;&#xB2E4;. &#xC5EC;&#xAE30;, &#xC6B0;&#xB9AC; NK &#xC9C4; &#xBCF5;&#xC7A1; &#xD55C; &#xCD5C;&#xC800;&#xC758; &#xC124;&#xBA85; (ly49&#xACFC; &#xAD00;&#xB828; &#xB41C; MHC&#xC758; &#xD45C;&#xD604; &#xBD80;&#xC871; NKC(KD)) &#xB9C8;&#xC6B0;&#xC2A4;-&#xB09C; &#xB300;&#xBD80;&#xBD84;&#xC758; NK &#xC138;&#xD3EC;&#xC5D0; &#xC218;&#xC6A9; &#xCCB4;. NKC(KD) NK &#xC138;&#xD3EC; &#xC804;&#xC2DC; &#xACB0;&#xD568;&#xC774; &#xC788;&#xB294; &#xC140;, &#xB2E4;&#xC591; &#xD55C; &#xC885;&#xB958;&#xC758; MHC-&#xB09C;-&#xACB0;&#xD54D; &#xC950;&#xC5D0;&#xC11C; &#xC774;&#xC2DD; NKC(KD) &#xB9C8;&#xC6B0;&#xC2A4;&#xC5D0; &#xC758;&#xD574; &#xACB0;&#xD568;&#xC774; &#xAC70;&#xBD80;&#xC5D0; &#xB530;&#xB978; &#xB300;&#xC0C1; MHC-&#xB09C;-&#xACB0;&#xD54D;, &#xD558;&#xC9C0;&#xB9CC; &#xADF8;&#xB807;&#xC9C0; &#xC54A;&#xC73C;&#xBA74; &#xC815;&#xC0C1;&#xC758; &#xC0B4;&#xC778;. &#xC140;&#xD504;-MHC-&#xB09C; immunosurveillance NKC(KD) &#xC0DD;&#xC950;&#xC5D0;&#xC11C; NK &#xC138;&#xD3EC; &#xC790;&#xAE30;-MHC-&#xB09C; &#xAD00;&#xB828; Ly49 transgenes&#xC5D0; &#xC758;&#xD574; &#xAD6C;&#xCD9C; &#xB420; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. NKC(KD) &#xB9C8;&#xC6B0;&#xC2A4; &#xD45C;&#xC2DC; &#xAC10;&#xC18C; vivo&#xC5D0;&#xC11C; &#xC885;&#xC591; &#xC138;&#xD3EC; &#xD074;&#xB9AC;&#xC5B4;&#xB7F0;&#xC2A4;&#xC758; &#xACB0;&#xACFC;&#xB85C; MHC-&#xB09C; &#xBD88;&#xCDA9;&#xBD84; &#xC885;&#xC591; &#xC138;&#xD3EC;&#xC758; &#xACB0;&#xD568;&#xC774; &#xC778;&#xC815; NKG2D &#xB610;&#xB294; &#xD56D; &#xCCB4; &#xC885;&#xC18D;&#xC801; &#xD65C;&#xC131;&#xD654; &#xC218;&#xC6A9; &#xCCB4;&#xC5D0; &#xC758;&#xD574; &#xC720;&#xB3C4; &#xB41C; &#xC138;&#xD3EC; &#xB3C5;&#xC131; &#xC720;&#xBC1C; &#xB41C; &#xC885;&#xC591; &#xC138;&#xD3EC; &#xC911;&#xC7AC; &#xC140; &#xC138;&#xD3EC; &#xB3C5;&#xC131; &#xBC0F; cytokine &#xC0DD;&#xC0B0; Ly49 &#xBD88;&#xCDA9;&#xBD84; &#xD55C; NK &#xC138;&#xD3EC;, MHC &#xC81C;&#xC548;&#xC5D0; &#xD6A8;&#xC728;&#xC801; &#xC774;&#xC5C8;&#xB2E4;-&#xB098; NK &#xC138;&#xD3EC;&#xC758; &#xAD50;&#xC721; &#xADF8;&#xB4E4;&#xC758; &#xCD1D; &#xC7A0;&#xC7AC; &#xADDC;&#xC81C; &#xD558;&#xB098;&#xC758; &#xC77C; &#xBA74; &#xC774;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xACB0;&#xACFC; Ly49 &#xC2DD; &#xC790;&#xAE30;-MHC-&#xB09C; &#xBD84;&#xC790;&#xC5D0; NK &#xC138;&#xD3EC; &#xAD50;&#xC721;&#xC5D0; &#xD544;&#xC694; &#xD558;&#xB2E4; &#xACE0; &#xC774;&#xB4E4; &#xC218;&#xC6A9;&#xC774; &#xCCB4;&#xC758; &#xBD80;&#xC7AC; NK &#xC138;&#xD3EC; MHC &#xC885;&#xC18D;&#xC801; &quot;&#xB204;&#xB77D; &#xC790;&#xAC00;&quot; immunosurveillance&#xC758; &#xC190;&#xC2E4;&#xB85C; &#xC5F0;&#xACB0; &#xC9C1;&#xC811; &#xC720;&#xC804;&#xC790; &#xC99D;&#xAC70;&#xB97C; &#xC81C;&#xACF5; &#xD569;&#xB2C8;&#xB2E4;.

&#xC790;&#xC5F0; &#xD0AC;&#xB7EC; &#xC138;&#xD3EC; &#xC790;&#xCCB4; &#xAD50;&#xC721; &#xBC0F; &quot;&#xB204;&#xB77D; &#xC790;&#xAC00;&quot; &#xC751;&#xB2F5; Ly49 &#xBD88;&#xCDA9;&#xBD84; &#xD55C; &#xB9C8;&#xC6B0;&#xC2A4;&#xC5D0; &#xC7A5;&#xC560;.

Reconocimiento de Ly49-mediada de MHC-I mol&eacute;culas en las c&eacute;lulas del hu&eacute;sped se considera vital para natural killer (NK)-celular regulaci&oacute;n y educaci&oacute;n; sin embargo, se carecen de modelos animales del gen deficiente debido a la dificultad en la eliminaci&oacute;n de esta gran familia multig&eacute;nica. Aqu&iacute;, describimos ca&iacute;da complejo de NK gene (NKC(KD)) ratones que carecen de la expresi&oacute;n de Ly49 y relacionados con MHC-I receptores en la mayor&iacute;a de las c&eacute;lulas NK. Exposici&oacute;n de las c&eacute;lulas NK NKC(KD) defectuoso matanza de MHC-I-deficiente, pero normales, apuntar c&eacute;lulas, dando por resultado defectuoso rechazo por NKC(KD) ratones de trasplantes de varios tipos de ratones MHC--deficientes. Uno mismo-MHC-I ataque por las c&eacute;lulas NK en ratones NKC(KD) puede ser rescatado por los transgenes de Ly49 uno mismo-MHC--espec&iacute;fico. Aunque los ratones NKC(KD) Mostrar reconocimiento defectuoso de las c&eacute;lulas tumorales de MHC--deficientes, dando por resultado la separaci&oacute;n de la c&eacute;lula disminuido tumor in vivo, NKG2D - o anticuerpo-dependiente producci&oacute;n de citotoxicidad y citoquinas de c&eacute;lulas de tumor de inducida por citotoxicidad mediada por c&eacute;lulas inducida por receptores de activaci&oacute;n fue eficiente en c&eacute;lulas NK Ly49 deficientes, sugiriendo MHC-I la educaci&oacute;n de las c&eacute;lulas NK es una sola faceta regulando su total potencial. Estos resultados proporcionan evidencia gen&eacute;tica directa que expresi&oacute;n de Ly49 es necesario para la educaci&oacute;n de c&eacute;lulas NK a las mol&eacute;culas de uno mismo-MHC-I y que la ausencia de estos receptores lleva a p&eacute;rdida de MHC--dependiente &quot;mismo que faltan&quot; ataque por las c&eacute;lulas NK.

Deteriorada la c&eacute;lula de asesino natural autoeducaci&oacute;n y &quot;mismo que faltan&quot; respuestas en ratones deficientes en Ly49.

Natural killer (NK) cell clearance of tumor cell emboli following surgery is thought to be vital in preventing postoperative metastases. Using a mouse model of surgical stress, we transferred surgically stressed NK cells into NK-deficient mice and observed enhanced lung metastases in tumor-bearing mice as compared with mice that received untreated NK cells. These results establish that NK cells play a crucial role in mediating tumor clearance following surgery. Surgery markedly reduced NK cell total numbers in the spleen and affected NK cell migration. Ex vivo and in vivo tumor cell killing by NK cells were significantly reduced in surgically stressed mice. Furthermore, secreted tissue signals and myeloid-derived suppressor cell populations were altered in surgically stressed mice. Significantly, perioperative administration of oncolytic parapoxvirus ovis (ORFV) and vaccinia virus can reverse NK cell suppression, which correlates with a reduction in the postoperative formation of metastases. In human studies, postoperative cancer surgery patients had reduced NK cell cytotoxicity, and we show for the first time that oncolytic vaccinia virus markedly increases NK cell activity in patients with cancer. These data provide direct in vivo evidence that surgical stress impairs global NK cell function. Perioperative therapies aimed at enhancing NK cell function will reduce metastatic recurrence and improve survival in surgical cancer patients.

Preventing postoperative metastatic disease by inhibiting surgery-induced dysfunction in natural killer cells.

To determine whether the postoperative hypercoagulable state is responsible for the increase in metastases observed after surgery.

Surgical stress promotes the development of cancer metastases by a coagulation-dependent mechanism involving natural killer cells in a murine model.

Plasmacytoid dendritic cells (pDC) are the major producers of type I IFN during the initial immune response to viral infection. Ly49Q, a C-type lectin-like receptor specific for MHC-I, possesses a cytoplasmic ITIM and is highly expressed on murine pDC. Using Ly49Q-deficient mice, we show that, regardless of strain background, this receptor is required for maximum IFN-α production by pDC. Furthermore, Ly49Q expression on pDC, but not myeloid dendritic cells, is necessary for optimal IL-12 secretion, MHC-II expression, activation of CD4(+) T cell proliferation, and nuclear translocation of the master IFN-α regulator IFN regulatory factor 7 in response to TLR9 agonists. In contrast, the absence of Ly49Q did not affect plasmacytoid dendritic cell-triggering receptor expressed on myeloid cells expression or pDC viability. Genetic complementation revealed that IFN-α production by pDC is dependent on an intact tyrosine residue in the Ly49Q cytoplasmic ITIM. However, pharmacological inhibitors and phosphatase-deficient mice indicate that Src homology 2 domain-containing phosphatase 1 (SHP)-1, SHP-2, and SHIP phosphatase activity is dispensable for this function. Finally, we observed that Ly49Q itself is downregulated on pDC in response to CpG exposure in an ITIM-independent manner. In conclusion, Ly49Q enhances TLR9-mediated signaling events, leading to IFN regulatory factor 7 nuclear translocation and expression of IFN-I genes in an ITIM-dependent manner that can proceed without the involvement of SHP-1, SHP-2, and SHIP.

Ly49Q positively regulates type I IFN production by plasmacytoid dendritic cells in an immunoreceptor tyrosine-based inhibitory motif-dependent manner.

Surgical removal of solid primary tumors is an essential component of cancer treatment. Surgery-induced dysfunction in natural killer (NK) cells has been linked to the development of metastases in animal models and patients with cancer. We investigated the activation of NK cells using influenza vaccine in the perioperative period to eradicate micrometastatic disease.

Perioperative influenza vaccination reduces postoperative metastatic disease by reversing surgery-induced dysfunction in natural killer cells.

Murine Ly49 receptors, which are expressed mainly on NK and NKT cells, interact with MHC class I (MHC-I) molecules with varying specificity. Differing reports of Ly49/MHC binding affinities may be affected by multiple factors, including cis versus trans competition and species origin of the MHC-I L chain (β2-microglobulin). To determine the contribution of each of these factors, Ly49G, Ly49I, Ly49O, Ly49V, and Ly49Q receptors from the 129 mouse strain were expressed individually on human 293T cells or the mouse cell lines MHC-I-deficient C1498, H-2(b)-expressing MC57G, and H-2(k)-expressing L929. The capacity to bind to H-2D(b)- and H-2K(b)-soluble MHC-I tetramers containing either human or murine β2-microglobulin L chains was tested for all five Ly49 receptors in all four cell lines. We found that most of these five inhibitory Ly49 receptors show binding for one or both self-MHC-I molecules in soluble tetramer binding assays when three conditions are fulfilled: 1) lack of competing cis interactions, 2) tetramer L chain is of mouse origin, and 3) Ly49 is expressed in mouse and not human cell lines. Furthermore, Ly49Q, the single known MHC-I receptor on plasmacytoid dendritic cells, was shown to bind H-2D(b) in addition to H-2K(b) when the above conditions were met, suggesting that Ly49Q functions as a pan-MHC-Ia receptor on plasmacytoid dendritic cells. In this study, we have optimized the parameters for soluble tetramer binding analyses to enhance future Ly49 ligand identification and to better evaluate specific contributions by different Ly49/MHC-I pairs to NK cell education and function.

Optimized tetramer analysis reveals Ly49 promiscuity for MHC ligands.

Surgical resection is the mainstay of treatment for solid tumors, but the postoperative period is uniquely inclined to the formation of metastases, largely due to the suppression of natural killer (NK) cells. We found that preoperative influenza vaccination prevents postoperative NK-cell dysfunction, attenuating tumor dissemination in murine models and promoting the activation of NK cells in cancer patients.

Article	Year
Molecular and genetic basis for strain-dependent NK1.1 alloreactivity of mouse NK cells. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 16751398	2006
Recognition of H-2K(b) by Ly49Q suggests a role for class Ia MHC regulation of plasmacytoid dendritic cell function. Molecular immunology\| PubMed ID: 17240452	2007
Translational control of the innate immune response through IRF-7. Nature\| PubMed ID: 18272964	2008
Evolution of the Ly49 and Nkrp1 recognition systems. Seminars in immunology\| PubMed ID: 18595730	2008
Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC. The Journal of experimental medicine\| PubMed ID: 19075287	2008
Effect of Ly49 haplotype variance on NK cell function and education. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 20855875	2010
ORFV: A Novel Oncolytic and Immune Stimulating Parapoxvirus Therapeutic. Molecular therapy : the journal of the American Society of Gene Therapy\| PubMed ID: 22273579	2012
Impaired natural killer cell self-education and "missing-self" responses in Ly49-deficient mice. Blood\| PubMed ID: 22661698	2012
Preventing postoperative metastatic disease by inhibiting surgery-induced dysfunction in natural killer cells. Cancer research\| PubMed ID: 23090117	2013
Surgical stress promotes the development of cancer metastases by a coagulation-dependent mechanism involving natural killer cells in a murine model. Annals of surgery\| PubMed ID: 23108132	2013
Ly49Q positively regulates type I IFN production by plasmacytoid dendritic cells in an immunoreceptor tyrosine-based inhibitory motif-dependent manner. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 23479228	2013
Perioperative influenza vaccination reduces postoperative metastatic disease by reversing surgery-induced dysfunction in natural killer cells. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 23881927	2013
Optimized tetramer analysis reveals Ly49 promiscuity for MHC ligands. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 24154624	2013
Preventing surgery-induced NK cell dysfunction and cancer metastases with influenza vaccination. Oncoimmunology\| PubMed ID: 24404430	2013

Lee-Hwa Tai

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