Evaluation of the Efficacy of the <em>H. pylori</em> Protein HP-NAP as a Therapeutic Tool for Treatment of Bladder Cancer in an Orthotopic Murine Model

Bladder cancer is one of the most common malignancies of the urogenital tract. Intravesical injection of Bacillus Calmette-Gu&#233;rin (BCG) is the gold ...

University of Padua

Lymphoid hyperplasia of gastric mucosa associated with Helicobacter pylori (HP) infection represents a preneoplastic condition of the mucosa associated lymphoid tissue (MALT), which may evolve to a B-cell lymphoma. While it is well established that the initial neoplastic proliferation of B cells is antigen-driven and dependent on the helper activity of HP-specific T cells, it needs to be elucidated which cytokine or soluble factor(s) promote B-cell activation and lymphomagenesis. Herein, we originally report that gastric MALT lymphoma express high levels of a proliferation inducing ligand (APRIL), a novel cytokine crucial in sustaining B-cell proliferation. By immunohistochemistry, we demonstrate that APRIL is produced almost exclusively by gastric lymphoma-infiltrating macrophages located in close proximity to neoplastic B cells. We also show that macrophages produce APRIL on direct stimulation with both HP and HP-specific T cells. Collectively, our results represent the first evidence for an involvement of APRIL in gastric MALT lymphoma development in HP-infected patients.

Tumor-associated macrophages as major source of APRIL in gastric MALT lymphoma.

Intravesical Bacillus Calmette-Guérin (BCG) is the gold standard treatment for intermediate and high-risk non-muscle-invasive bladder cancer. BCG therapy is the most successful example of immunotherapy in cancer. Unfortunately, the treatment-related side effects are still relevant. Furthermore, non-responder patients are candidate to radical cystectomy in the absence of valuable alternative options. These aspects have prompted the search for newer biological response modifiers (BRM) with a better benefit/side effects ratio. The toll-like receptor (TLR) 2 ligand, Helicobacter pylori protein HP-NAP, has been shown to deserve a potential role as BRM. HP-NAP is capable of driving the differentiation of T helper (Th) 1 cells, both in vitro and in vivo, because of its ability to create an IL-12-enriched milieu. Herein, we report that local administration of HP-NAP decreases tumour growth by triggering tumour necrosis in a mouse model of bladder cancer implant. The effect is accompanied by a significant accumulation of both CD4+ and CD8+ IFN-γ-secreting cells, within tumour and regional lymph nodes. Noteworthy, HP-NAP-treated tumours show also a reduced vascularization due to the anti-angiogenic activity of IFN-γ induced by HP-NAP. Our findings strongly indicate that HP-NAP might become a novel therapeutic "bullet" for the cure of bladder tumours.

HP-NAP inhibits the growth of bladder cancer in mice by activating a cytotoxic Th1 response.

&#x78F7;&#x8102;&#x9176;&#x88AB;&#x4EA7;&#x751F;&#x7684;&#x7EC6;&#x83CC;&#x75C5;&#x539F;&#x975E;&#x5E38;&#x4E0D;&#x540C;&#x7684;&#x75BE;&#x75C5;&#x3002;&#x6700;&#x8010;&#x4EBA;&#x5BFB;&#x5473;&#x7684;&#x78F7;&#x8102;&#x9176;&#x7684;&#x65B9;&#x9762;&#x4E4B;&#x4E00;&#x662F;&#x5176;&#x5E72;&#x6270;&#x7EC6;&#x80DE;&#x4FE1;&#x53F7;&#x8F6C;&#x5BFC;&#x53F6;&#x6805;&#xFF0C;&#x5E76;&#x8C03;&#x8282;&#x5BBF;&#x4E3B;&#x514D;&#x75AB;&#x53CD;&#x5E94;&#x7684;&#x6F5C;&#x529B;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x8C03;&#x67E5;&#x8BF1;&#x53D1;&#x80BA;&#x708E;&#x78F7;&#x8102;&#x9176; Chlamydophila D (CpPLD) &#x5728;&#x52A8;&#x8109;&#x7CA5;&#x6837;&#x786C;&#x5316;&#x53D1;&#x75C5;&#x4E2D;&#x7684;&#x5148;&#x5929;&#x548C;&#x540E;&#x5929;&#x514D;&#x75AB;&#x53CD;&#x5E94;&#x7684;&#x4F5C;&#x7528;&#x3002;&#x6211;&#x4EEC;&#x8BC4;&#x4F30; CpPLD &#x4E3A;&#x6E17;&#x900F; C.&#x80BA;&#x708E;&#x6297;&#x4F53;&#x60A3;&#x8005;&#x52A8;&#x8109;&#x7CA5;&#x6837;&#x786C;&#x5316;&#x75C5;&#x53D8;&#x7684; CpPLD &#x5728;&#x5065;&#x5EB7;&#x6350;&#x52A9;&#x8005;&#x5355;&#x6838;&#x7EC6;&#x80DE;&#x548C;&#x4F53;&#x5185;&#x6D3B;&#x5316;&#x7684; T &#x7EC6;&#x80DE;&#x7684;&#x7279;&#x5B9A;&#x8BF1;&#x5BFC;&#x7EC6;&#x80DE;&#x56E0;&#x5B50;&#x548C;&#x8D8B;&#x5316;&#x56E0;&#x5B50;&#x7684;&#x751F;&#x4EA7;&#x3002;&#x6211;&#x4EEC;&#x8FD8;&#x5BA1;&#x67E5;&#x4E86;&#x7279;&#x5B9A;&#x4E8E; CpPLD &#x7684; T &#x7EC6;&#x80DE;&#x5355;&#x6838;&#x7EC6;&#x80DE;&#x57FA;&#x8D28;&#x91D1;&#x5C5E;&#x86CB;&#x767D;&#x9176; &#xFF08;MMP&#xFF09;-9 &#x548C;&#x7EC4;&#x7EC7;&#x56E0;&#x5B50; (TF) &#x751F;&#x4EA7;&#x7684; helper &#x51FD;&#x6570;&#xFF0C;&#x4EE5;&#x53CA;&#x7531;&#x5FAE;&#x5185;&#x76AE;&#x7EC6;&#x80DE; (&#x8110;) CpPLD &#x8BF1;&#x5BFC;&#x8D8B;&#x5316;&#x56E0;&#x5B50;&#x8868;&#x8FBE;&#x3002;&#x6211;&#x4EEC;&#x5728;&#x8FD9;&#x91CC;&#x62A5;&#x544A; CpPLD &#x662F; TLR4 &#x6FC0;&#x52A8;&#x5242;&#x80FD;&#x8BF1;&#x5BFC;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-23&#xFF0C;&#x8868;&#x8FBE;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-6&#x3001; &#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-1&beta;&#x3001; TGF-&beta;&#xFF0C;CCL-20 &#x5355;&#x6838;&#x7EC6;&#x80DE;&#xFF0C;&#x4EE5;&#x53CA; CXCL 9&#x3001; CCL 20&#x3001; CCL 4&#x3001; &#x8986;&#x94DC;&#x677F; 2&#x3001; &#x7EC6;&#x80DE;&#x95F4;&#x7C98;&#x9644;&#x5206;&#x5B50;-1 &#x548C;&#x8840;&#x7BA1;&#x7EC6;&#x80DE;&#x9ECF;&#x9644;&#x5206;&#x5B50;-1 &#x5728;&#x8110;&#x4E2D;&#x3002;&#x6591; T &#x7EC6;&#x80DE;&#x4EA7;&#x751F;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-17 CpPLD &#x54CD;&#x5E94;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x7279;&#x5B9A;&#x4E8E; CpPLD &#x7684; CD4(+) T &#x6DCB;&#x5DF4;&#x7EC6;&#x80DE;&#x663E;&#x793A;&#x4E3A;&#x5355;&#x6838;&#x7EC6;&#x80DE;&#x57FA;&#x8D28;&#x91D1;&#x5C5E;&#x86CB;&#x767D;&#x9176;-9 &#x548C; TF &#x751F;&#x4EA7;&#x7684; helper &#x51FD;&#x6570;&#x3002;CpPLD &#x4FC3;&#x8FDB; Th17 &#x7EC6;&#x80DE;&#x8FC1;&#x79FB;&#x901A;&#x8FC7;&#x8BF1;&#x5BFC;&#x7684;&#x5185;&#x76AE;&#x7EC6;&#x80DE;&#x7684;&#x8D8B;&#x5316;&#x56E0;&#x5B50;&#x5206;&#x6CCC;&#x548C;&#x7C98;&#x9644;&#x5206;&#x5B50;&#x7684;&#x8868;&#x8FBE;&#x3002;&#x8FD9;&#x4E9B;&#x7ED3;&#x679C;&#x8868;&#x660E; CpPLD &#x662F;&#x53EF;&#x4EE5;&#x9A71;&#x52A8;&#x7684;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-23&#xFF0C;&#x8868;&#x8FBE;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-6&#x3001; &#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-1&beta;&#x3001; TGF-&beta;&#xFF0C;CCL-20 &#x5355;&#x6838;&#x7EC6;&#x80DE;&#xFF0C;&#x5F15;&#x8D77;&#x52A8;&#x8109;&#x7CA5;&#x6837;&#x786C;&#x5316;&#x7684;&#x6210;&#x56E0;&#x4E2D;&#x53D1;&#x6325;&#x7740;&#x5173;&#x952E;&#x4F5C;&#x7528;&#x7684; Th17 &#x514D;&#x75AB;&#x53CD;&#x5E94;&#x3002;

Chlamydophila &#x80BA;&#x708E;&#x78F7;&#x8102;&#x9176; D (CpPLD) &#x5728;&#x4EBA;&#x7C7B;&#x52A8;&#x8109;&#x7CA5;&#x6837;&#x786C;&#x5316;&#x9A71;&#x52A8;&#x5668; Th17 &#x708E;&#x75C7;&#x3002;

Phospholipases are produced from bacterial pathogens causing very different diseases. One of the most intriguing aspects of phospholipases is their potential to interfere with cellular signaling cascades and to modulate the host-immune response. Here, we investigated the role of the innate and acquired immune responses elicited by Chlamydophila pneumoniae phospholipase D (CpPLD) in the pathogenesis of atherosclerosis. We evaluated the cytokine and chemokine production induced by CpPLD in healthy donors' monocytes and in vivo activated T cells specific for CpPLD that infiltrate atherosclerotic lesions of patients with C. pneumoniae antibodies. We also examined the helper function of CpPLD-specific T cells for monocyte matrix metalloproteinase (MMP)-9 and tissue factor (TF) production as well as the CpPLD-induced chemokine expression by human venular endothelial cells (HUVECs). We report here that CpPLD is a TLR4 agonist able to induce the expression of IL-23, IL-6, IL-1Î², TGF-Î², and CCL-20 in monocytes, as well as CXCL-9, CCL-20, CCL-4, CCL-2, ICAM-1, and VCAM-1 in HUVECs. Plaque-derived T cells produce IL-17 in response to CpPLD. Moreover, CpPLD-specific CD4(+) T lymphocytes display helper function for monocyte MMP-9 and TF production. CpPLD promotes Th17 cell migration through the induction of chemokine secretion and adhesion molecule expression on endothelial cells. These findings indicate that CpPLD is able to drive the expression of IL-23, IL-6, IL-1Î², TGF-Î², and CCL-20 by monocytes and to elicit a Th17 immune response that plays a key role in the genesis of atherosclerosis.

Chlamydophila pneumoniae phospholipase D (CpPLD) drives Th17 inflammation in human atherosclerosis.

Phospholipases sont produites &agrave; partir de bact&eacute;ries pathog&egrave;nes responsables de maladies tr&egrave;s diff&eacute;rentes. Un des aspects plus intrigants de phospholipases est leur potentiel d&#39;interf&eacute;rer avec le cellulaire cascades de signalisation et de moduler la r&eacute;ponse immunitaire-h&ocirc;te. Ici, nous avons examin&eacute; le r&ocirc;le des r&eacute;actions immunitaires inn&eacute;es et acquises par Chlamydophila pneumoniae phospholipase D (CpPLD) dans la pathogen&egrave;se de l&#39;ath&eacute;roscl&eacute;rose. Nous avons &eacute;valu&eacute; la production de cytokines et de chimiokines induite par CpPLD dans les monocytes et les lymphocytes T activ&eacute;s in vivo sp&eacute;cifiques des donneurs sains pour CpPLD qui infiltrent les l&eacute;sions ath&eacute;roscl&eacute;reuses des patients pr&eacute;sentant des anticorps c. pneumoniae. Nous avons aussi examin&eacute; la fonction d&#39;assistance de cellules T CpPLD sp&eacute;cifiques pour la production de facteur (TF) de tissu et de monocyte matrix m&eacute;talloprot&eacute;inases (MMP) -9 ainsi que l&#39;expression de chemokine induite par le CpPLD par les cellules endoth&eacute;liales humaines veinules (HUVEC). Nous rapportons ici que CpPLD est un agoniste de TLR4 capable d&#39;induire l&#39;expression d&#39;IL-23, IL-6, IL-1&beta;, TGF-&beta; et CCL-20 dans les monocytes, mais aussi CXCL-9, CCL-20, CCL-4, CCL-2, ICAM-1 et VCAM-1 dans les HUVECs. Plaque d&eacute;riv&eacute;es des cellules T produisent l&#39;IL-17 en r&eacute;ponse &agrave; CpPLD. En outre, les lymphocytes T CD4 + sp&eacute;cifique CpPLD affichent la fonction d&#39;assistance pour les monocytes production de MMP-9 et TF. CpPLD favorise la migration des cellules Th17 par l&#39;induction de l&#39;expression du chemokine la s&eacute;cr&eacute;tion et l&#39;adh&eacute;rence de la mol&eacute;cule sur les cellules endoth&eacute;liales. Ces r&eacute;sultats indiquent que la CpPLD est capable de conduire l&#39;expression d&#39;IL-23, IL-6, IL-1&beta;, TGF-&beta; et CCL-20 de monocytes et de d&eacute;clencher une r&eacute;ponse immunitaire Th17 qui joue un r&ocirc;le cl&eacute; dans la gen&egrave;se de l&#39;ath&eacute;roscl&eacute;rose.

Chlamydophila pneumoniae phospholipase D (CpPLD) disques Th17 inflammation dans l&#39;ath&eacute;roscl&eacute;rose humaine.

Phospholipases werden aus bakteriellen Erreger sehr unterschiedliche Krankheiten erzeugt. Einer der faszinierendsten Aspekte der Phospholipases ist ihr Potenzial zu st&ouml;ren zellular signalisieren Kaskaden und die Host-Immunantwort modulieren. Hier untersuchten wir die Rolle der angeborenen und erworbenen Immunantworten, hervorgerufen durch Chlamydophila Pneumoniae Phospholipase D (CpPLD) in der Pathogenese der Atherosklerose. Wir evaluieren die Herstellung Zytokine und Chemokine induziert durch CpPLD in Monozyten und in-vivo aktivierte T-Zellen, die bestimmte gesunde Geber f&uuml;r CpPLD, die atherosklerotische L&auml;sionen von Patienten mit Chlamydophila Pneumoniae-Antik&ouml;rper zu infiltrieren. Wir untersuchen auch die Hilfsfunktion CpPLD-spezifische T-Zellen f&uuml;r Monozyte-Matrix-Metalloproteasen (MMP)-9 und Gewebe-Faktor (TF)-Produktion sowie der CpPLD-induzierten Chemokin-Ausdruck von menschlichen venular Endothelzellen (HUVECs). Wir berichten hier, dass CpPLD ein TLR4-Agonist, der in der Lage, den Ausdruck der IL-23, induzieren IL-6, IL-1&beta;, TGF-&beta; und CCL-20 in Monozyten, sowie CXCL-9, CCL-20, CCL-4, CCL-2, ICAM-1 und VCAM-1 in HUVECs. Plakette abgeleiteten T-Zellen produzieren IL-17 als Antwort auf CpPLD. Dar&uuml;ber hinaus zeigen CpPLD-spezifischen CD4(+) T-Lymphozyten Hilfsfunktion f&uuml;r Monozyte MMP-9 und TF-Produktion. CpPLD f&ouml;rdert Th17 Zellmigration durch die Induktion von Chemokine Sekretion und Adh&auml;sion Molek&uuml;l Ausdruck in Endothelzellen. Diese Befunde zeigen, dass CpPLD in der Lage ist, den Ausdruck der IL-23, IL-6, IL-1&beta;, TGF-&beta; und CCL-20 von Monozyten und eine Th17-Immunantwort ausl&ouml;sen, die eine Schl&uuml;sselrolle bei der Entstehung der Arteriosklerose spielt.

Chlamydophila Pneumoniae Phospholipase D (CpPLD) Laufwerke Th17 Entz&uuml;ndung in menschlichen Arteriosklerose.

Phospholipases sono prodotte da agenti patogeni batterici che causano malattie molto diverse. Uno degli aspetti pi&ugrave; intriganti della phospholipases &egrave; la loro potenziale interferire con cascate di segnalazione cellulare e modulano la risposta immunitaria ospite. Qui, abbiamo studiato il ruolo della risposta immunitaria innata ed acquisita elicitata da Chlamydophila pneumoniae fosfolipasi D (CpPLD) nella patogenesi dell&#39;aterosclerosi. Abbiamo valutato la produzione di citochine e chemochine indotta da CpPLD nei monociti dei donatori sani e in vivo cellule T attivate specifiche per CpPLD che si infiltrano lesioni aterosclerotiche dei pazienti con anticorpi anti-c. pneumoniae. Abbiamo anche esaminato la funzione di supporto delle cellule T CpPLD-specifico per monociti matrix metalloproteinase (MMP) -9 e la produzione di tissue factor (TF) cos&igrave; come l&#39;espressione di chemochine CpPLD-indotta da cellule endoteliali umane venular (HUVECs). Segnaliamo qui che CpPLD &egrave; un agonista TLR4 in grado di indurre l&#39;espressione di IL-23, IL-6, IL-1 &beta;, TGF-&beta; e CCL-20 nei monociti, come pure CXCL-9, CCL-20, CCL-4, CCL-2, ICAM-1 e VCAM-1 in HUVECs. Placca-derivato T cellule producono IL-17 in risposta a CpPLD. Inoltre, i linfociti T CD4(+) CpPLD-specifiche display funzione helper per monociti produzione di MMP-9 e TF. CpPLD promuove la migrazione delle cellule Th17 attraverso l&#39;induzione dell&#39;espressione di chemochine secrezione e adesione molecola sulle cellule endoteliali. Questi risultati indicano che CpPLD &egrave; in grado di guidare l&#39;espressione di IL-23, IL-6, IL-1 &beta;, TGF-&beta; e CCL-20 di monociti e di suscitare una risposta immunitaria Th17 che gioca un ruolo chiave nella genesi dell&#39;aterosclerosi.

Chlamydophila pneumoniae fosfolipasi D (CpPLD) unit&agrave; Th17 infiammazione nell&#39;aterosclerosi umana.

&#x30DB;&#x30B9;&#x30DB;&#x30EA;&#x30D1;&#x30FC;&#x30BC;&#x306F;&#x975E;&#x5E38;&#x306B;&#x3055;&#x307E;&#x3056;&#x307E;&#x306A;&#x75C5;&#x6C17;&#x3092;&#x5F15;&#x304D;&#x8D77;&#x3053;&#x3059;&#x7D30;&#x83CC;&#x306E;&#x75C5;&#x539F;&#x4F53;&#x304B;&#x3089;&#x751F;&#x7523;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x30DB;&#x30B9;&#x30DB;&#x30EA;&#x30D1;&#x30FC;&#x30BC;&#x306E;&#x6700;&#x3082;&#x9B45;&#x529B;&#x7684;&#x306A;&#x5074;&#x9762;&#x306E; 1 &#x3064;&#x306F;&#x3001;&#x305D;&#x306E;&#x6F5C;&#x5728;&#x7684;&#x306A;&#x7D30;&#x80DE;&#x3068;&#x30AB;&#x30B9;&#x30B1;&#x30FC;&#x30C9;&#x5185;&#x30B7;&#x30B0;&#x30CA;&#x30EA;&#x30F3;&#x30B0;&#x3092;&#x59A8;&#x5BB3;&#x3057;&#x3066;&#x3001;&#x30DB;&#x30B9;&#x30C8;&#x514D;&#x75AB;&#x5FDC;&#x7B54;&#x3092;&#x8ABF;&#x7BC0;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;Chlamydophila &#x80BA;&#x708E;&#x30DB;&#x30B9;&#x30DB;&#x30EA;&#x30D1;&#x30FC;&#x30BC; D (CpPLD) &#x306E;&#x30A2;&#x30C6;&#x30ED;&#x30FC;&#x30E0;&#x6027;&#x52D5;&#x8108;&#x786C;&#x5316;&#x306E;&#x75C5;&#x614B;&#x306B;&#x3088;&#x3063;&#x3066;&#x8A98;&#x767A;&#x3055;&#x308C;&#x308B;&#x81EA;&#x7136;&#x514D;&#x75AB;&#x3068;&#x7372;&#x5F97;&#x514D;&#x75AB;&#x5FDC;&#x7B54;&#x306E;&#x5F79;&#x5272;&#x3092;&#x691C;&#x8A0E;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x6211;&#x3005; &#x306F;&#x3001;CpPLD &#x306B;&#x3088;&#x3063;&#x3066;&#x5065;&#x5EB7;&#x306A;&#x30C9;&#x30CA;&#x30FC;&#x5358;&#x7403;&#x304A;&#x3088;&#x3073; in vivo &#x6D3B;&#x6027;&#x5316; T &#x7D30;&#x80DE;&#x7279;&#x5B9A;&#x306E;&#x6297;&#x4F53; C. &#x80BA;&#x708E;&#x60A3;&#x8005;&#x306E;&#x52D5;&#x8108;&#x786C;&#x5316;&#x75C5;&#x5909;&#x306B;&#x6F5C;&#x5165; CpPLD &#x306E;&#x8A98;&#x5C0E;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x3068;&#x30B1;&#x30E2;&#x30AB;&#x30A4;&#x30F3;&#x306E;&#x751F;&#x7523;&#x3092;&#x8A55;&#x4FA1;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x307E;&#x305F; CpPLD &#x7279;&#x7570;&#x7684; T &#x7D30;&#x80DE;&#x5358;&#x7403;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x30E1;&#x30BF;&#x30ED;&#x30D7;&#x30ED;&#x30C6;&#x30A4;&#x30CA;&#x30FC;&#x30BC; (MMP)-9 &#x3068;&#x7D44;&#x7E54;&#x56E0;&#x5B50; (TF) &#x751F;&#x7523;&#x306E;&#x305F;&#x3081;&#x306E;&#x30D8;&#x30EB;&#x30D1;&#x30FC;&#x95A2;&#x6570;&#x3068;&#x3057;&#x3066; CpPLD &#x8A98;&#x8D77;&#x30B1;&#x30E2;&#x30AB;&#x30A4;&#x30F3;&#x306E;&#x767A;&#x73FE;&#x306B;&#x3088;&#x3063;&#x3066;&#x4EBA;&#x9593;&#x6C34;&#x816B;&#x5185;&#x76AE;&#x7D30;&#x80DE;) &#x3092;&#x8ABF;&#x3079;&#x305F;&#x3002;&#x6211;&#x3005; &#x306F;&#x3053;&#x3053;&#x3067; CpPLD IL 23 &#x306E;&#x767A;&#x73FE;&#x3092;&#x8A98;&#x5C0E;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x308B; TLR4 &#x30A2;&#x30B4;&#x30CB;&#x30B9;&#x30C8;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x5831;&#x544A; il-6, il-1&#x3001;TGF-&beta; &#x304A;&#x3088;&#x3073; CCL-20 &#x306E;&#x5358;&#x7403;&#x3068;&#x540C;&#x69D8; CXCL 9&#x3001;CCL 20&#x3001;CCL 4&#x3001;CCL 2&#x3001;ICAM-1 VCAM-1 &#x6BD4;&#x8F03;&#x3067;&#x3002;&#x6B6F;&#x57A2;&#x7531;&#x6765; T &#x7D30;&#x80DE; IL 17 &#x306E;&#x5FDC;&#x7B54; CpPLD &#x3092;&#x751F;&#x6210;&#x3057;&#x307E;&#x3059;&#x3002;&#x307E;&#x305F;&#x3001;&#x7279;&#x5B9A;&#x306E; CpPLD CD4(+) T &#x30EA;&#x30F3;&#x30D1;&#x7403;&#x5358;&#x7403; mmp-9 &#x3068; TF &#x751F;&#x7523;&#x7528;&#x306E;&#x30D8;&#x30EB;&#x30D1;&#x30FC;&#x95A2;&#x6570;&#x3092;&#x8868;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;CpPLD &#x30B1;&#x30E2;&#x30AB;&#x30A4;&#x30F3;&#x5206;&#x6CCC;&#x3068;&#x63A5;&#x7740;&#x5206;&#x5B50;&#x306E;&#x767A;&#x73FE;&#x5185;&#x76AE;&#x7D30;&#x80DE;&#x306E;&#x8A98;&#x5C0E;&#x3092;&#x4ECB;&#x3057;&#x3066; Th17 &#x7D30;&#x80DE;&#x904A;&#x8D70;&#x3092;&#x4FC3;&#x9032;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x8ABF;&#x67FB;&#x7D50;&#x679C; CpPLD &#x304C; IL 23 &#x306E;&#x767A;&#x73FE;&#x3092;&#x30C9;&#x30E9;&#x30A4;&#x30D6;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3059; IL 6&#x3001;il-1, TGF-&beta; &#x3068; CCL-20 &#x5358;&#x7403;&#x3068;&#x30A2;&#x30C6;&#x30ED;&#x30FC;&#x30E0;&#x6027;&#x52D5;&#x8108;&#x786C;&#x5316;&#x306E;&#x6210;&#x56E0;&#x3067;&#x91CD;&#x8981;&#x306A;&#x5F79;&#x5272;&#x3092;&#x679C;&#x305F;&#x3057;&#x3066;&#x3044;&#x308B; th17 &#x7D30;&#x80DE;&#x514D;&#x75AB;&#x53CD;&#x5FDC;&#x3092;&#x5F15;&#x304D;&#x51FA;&#x3059;&#x305F;&#x3081;&#x306B;&#x3002;

Chlamydophila &#x80BA;&#x708E;&#x30DB;&#x30B9;&#x30DB;&#x30EA;&#x30D1;&#x30FC;&#x30BC; D (CpPLD) th17 &#x7D30;&#x80DE;&#x708E;&#x75C7;&#x306B;&#x304A;&#x3051;&#x308B;&#x30D2;&#x30C8;&#x306E;&#x52D5;&#x8108;&#x786C;&#x5316;&#x3092;&#x99C6;&#x52D5;&#x3057;&#x307E;&#x3059;&#x3002;

Phospholipases&#xB294; &#xB9E4;&#xC6B0; &#xB2E4;&#xB978; &#xC9C8;&#xBCD1;&#xC744; &#xC77C;&#xC73C;&#xD0A4;&#xB294; &#xC138;&#xADE0; &#xBCD1;&#xC6D0; &#xADE0;&#xC5D0;&#xC11C; &#xC0DD;&#xC0B0; &#xB429;&#xB2C8;&#xB2E4;. Phospholipases&#xC758; &#xAC00;&#xC7A5; &#xD765;&#xBBF8;&#xB85C;&#xC6B4; &#xCE21;&#xBA74; &#xC911; &#xD558;&#xB098;&#xB294; &#xADF8;&#xB4E4;&#xC758; &#xC7A0;&#xC7AC;&#xB825;&#xC744; &#xD734;&#xB300; &#xACC4;&#xACE1; &#xC2E0;&#xD638;&#xB97C; &#xBC29;&#xD574; &#xD558; &#xACE0; &#xD638;&#xC2A4;&#xD2B8; &#xBA74;&#xC5ED; &#xBC18;&#xC751;&#xC744; &#xC870;&#xC808;. &#xC5EC;&#xAE30;, &#xC6B0;&#xB9AC;&#xB294; Chlamydophila &#xADE0; phospholipase D (CpPLD) &#xB3D9;&#xB9E5; &#xACBD;&#xD654; &#xC99D;&#xC758; &#xBCD1; &#xC778;&#xC5D0;&#xB85C; elicited &#xD0C0;&#xACE0; &#xB09C;&#xACFC; &#xD68D;&#xB4DD; &#xBA74;&#xC5ED; &#xBC18;&#xC751;&#xC758; &#xC5ED;&#xD560;&#xC744; &#xC870;&#xC0AC; &#xD588;&#xB2E4;. C. &#xADE0; &#xD56D; &#xCCB4; &#xD658;&#xC790;&#xC758; &#xB3D9;&#xB9E5; &#xACBD; &#xD654;&#xC131; &#xBCD1; &#xBCC0; &#xCE68;&#xD22C; Cppld&#xC5D0; &#xB300; &#xD55C; &#xAC74;&#xAC15; &#xD55C; &#xAE30;&#xC99D;&#xC790; monocytes &#xADF8;&#xB9AC;&#xACE0; vivo&#xC5D0;&#xC11C; &#xD65C;&#xC131;&#xD654; &#xB41C; T &#xC138;&#xD3EC; &#xD2B9;&#xC815;&#xC5D0; Cppld&#xC5D0; &#xC758;&#xD574; &#xC720;&#xB3C4; &#xB41C; &#xC0AC;&#xC774;&#xD1A0;&#xCE74;&#xC778; &#xBC0F; chemokine &#xC0DD;&#xC0B0;&#xC744; &#xD3C9;&#xAC00; &#xD588;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; &#xB610;&#xD55C; &#xC778;&#xAC04;&#xC758; venular &#xB0B4; &#xD53C; &#xC138;&#xD3EC; (HUVECs)&#xC5D0; &#xC758;&#xD574; CpPLD &#xC720;&#xB3C4; &#xB41C; chemokine &#xC2DD;&#xC73C;&#xB85C; monocyte &#xB9E4;&#xD2B8;&#xB9AD;&#xC2A4; metalloproteinase (MMP)-9 &#xBC0F; &#xC870;&#xC9C1; &#xC778;&#xC790; (TF) &#xC0DD;&#xC0B0;&#xC744; &#xC704;&#xD55C; CpPLD &#xAD00;&#xB828; T &#xC138;&#xD3EC;&#xC758; &#xB3C4;&#xC6B0;&#xBBF8; &#xAE30;&#xB2A5;&#xC744; &#xC870;&#xC0AC; &#xD588;&#xB2E4;. &#xC6B0;&#xB9AC; &#xBCF4;&#xACE0; &#xC5EC;&#xAE30; Cppld&#xC740; IL 23&#xC758; &#xD45C;&#xD604;&#xC744; &#xC720;&#xB3C4; &#xC218; TLR4 &#xAE38; &#xD56D; &#xC81C;&#xB294; &#xC77C;&#xB9AC;&#xB178;&#xC774;-6, IL 1&beta;, TGF-&beta;, &#xBC0F; CCL-20 monocytes&#xB85C; CXCL-9, CCL 20, CCL 4, CCL 2, ICAM-1, VCAM-1 HUVECs. &#xD328; &#xC720;&#xB798; T &#xC138;&#xD3EC; Cppld&#xC5D0; &#xB300; &#xD55C; &#xC751;&#xB2F5;&#xC5D0;&#xC11C; IL-17&#xC744; &#xC0DD;&#xC0B0;. &#xB610;&#xD55C;, CpPLD &#xAD00;&#xB828; CD4(+) T &#xB9BC;&#xD504; &#xD1A8; monocyte MMP 9 &#xBC0F; TF &#xC0DD;&#xC0B0;&#xC5D0; &#xB300; &#xD55C; &#xB3C4;&#xC6B0;&#xBBF8; &#xD568;&#xC218;&#xB97C; &#xD45C;&#xC2DC;&#xD569;&#xB2C8;&#xB2E4;. CpPLD &#xB0B4; &#xD53C; &#xC138;&#xD3EC;&#xC5D0; chemokine&#xC758; &#xBD84; &#xBE44;&#xC640; &#xC811;&#xCC29; &#xBD84;&#xC790; &#xC2DD;&#xC758; &#xC720;&#xB3C4; &#xD1B5;&#xD574; Th17 &#xC138;&#xD3EC; &#xB9C8;&#xC774;&#xADF8;&#xB808;&#xC774;&#xC158; &#xCD94;&#xC9C4;. &#xC774;&#xB7EC;&#xD55C; &#xC5F0;&#xAD6C; &#xACB0;&#xACFC; &#xD45C;&#xC2DC; CpPLD IL 23 &#xC2DD; &#xAD6C;&#xB3D9;&#xD560; &#xC218; &#xC77C;&#xB9AC;&#xB178;&#xC774;-6, IL 1&beta;, TGF-&beta;, &#xBC0F; CCL-20&#xC5D0; &#xC758;&#xD574; monocytes &#xADF8;&#xB9AC;&#xACE0; &#xB3D9;&#xB9E5; &#xACBD;&#xD654; &#xC99D;&#xC758; &#xCC3D;&#xC138;&#xAE30;&#xC5D0;&#xC11C; &#xD575;&#xC2EC; &#xC5ED;&#xD560;&#xC744; Th17 &#xBA74;&#xC5ED; &#xBC18;&#xC751;&#xC744; &#xC720;&#xB3C4; &#xD569;&#xB2C8;&#xB2E4;.

Chlamydophila &#xADE0; phospholipase D (CpPLD) &#xC778;&#xAC04;&#xC758; &#xB3D9;&#xB9E5; &#xACBD;&#xD654;&#xC5D0;&#xC11C; Th17 &#xC5FC;&#xC99D; &#xB4DC;&#xB77C;&#xC774;&#xBE0C;.

Se producen las fosfolipasas de pat&oacute;genos bacterianos que causan enfermedades muy diferentes. Uno de los aspectos m&aacute;s fascinantes de las fosfolipasas es su potencial para interferir con celular cascadas de se&ntilde;alizaci&oacute;n y modulan la inmunorespuesta del anfitri&oacute;n. Aqu&iacute;, hemos investigado el papel de la respuesta inmune innata y adquirida sacados por Chlamydophila pneumoniae fosfolipasa D (CpPLD) en la patogenia de la aterosclerosis. Se evalu&oacute; la producci&oacute;n de citoquinas y quimioquinas inducida por CpPLD en donantes sanos monocitos y c&eacute;lulas activadas en vivo T espec&iacute;ficas para CpPLD que se infiltran las lesiones ateroscler&oacute;ticas de pacientes con C. pneumoniae anticuerpos. Tambi&eacute;n examinamos la funci&oacute;n auxiliar de c&eacute;lulas T CpPLD espec&iacute;ficos para monocitos metaloproteinasa de la matriz (MMP) -9 y la producci&oacute;n del factor (TF) del tejido as&iacute; como la expresi&oacute;n de la Quimiocina CpPLD-inducida por las c&eacute;lulas endoteliales venulares humanas (HUVECs). Divulgamos aqu&iacute; que CpPLD es un agonista de TLR4 capaces de inducir la expresi&oacute;n de IL-23, IL-6, IL-1&beta;, TGF-&beta; y CCL-20 en monocitos, as&iacute; como CXCL-9, CCL-20, CCL-4, 2-CCL, ICAM-1 y VCAM-1 en HUVECs. Placa-producidas por c&eacute;lulas T producen IL-17 en respuesta a CpPLD. Por otra parte, los linfocitos T CD4 de CpPLD espec&iacute;ficos Mostrar la funci&oacute;n auxiliar para monocitos producci&oacute;n de MMP-9 y TF. CpPLD promueve la migraci&oacute;n de c&eacute;lulas Th17 a trav&eacute;s de la inducci&oacute;n de la expresi&oacute;n de quimiocina secreci&oacute;n y adherencia de mol&eacute;cula en las c&eacute;lulas endoteliales. Estos resultados indican que la CpPLD es capaz de conducir la expresi&oacute;n de IL-23, IL-6, IL-1&beta;, TGF-&beta; y CCL-20 por los monocitos y provocar una respuesta inmune de Th17 que juega un papel clave en la g&eacute;nesis de la aterosclerosis.

Chlamydophila pneumoniae fosfolipasa D (CpPLD) unidades de inflamaci&oacute;n Th17 en la aterosclerosis humana.

Patients with non-muscle invasive bladder cancer recurrence after 2 induction courses of BCG are eligible for radical cystectomy. So, in the last years research to discover new drugs for the management of non-muscle invasive bladder cancer recurrence after failure of first and second line therapy is ongoing. In accordance to the results obtained with BCG, whose mechanism depends on the induction of the T helper 1 (TH1) immune response, we investigated the activity of a Toll-like receptor (TLR) 2 ligand, named Helicobacter Pylori Neutrophil Activating Protein (HP-NAP), that we recently demonstrated being able of enhancing the differentiation of Th1 cells, both in vitro and in vivo, because of its ability to create an IL-12 enriched milieu.

[Therapy for non-muscle invasive bladder cancer: HP-NAP].

Helicobacter pylori infection is characterized by an inflammatory infiltrate, consisting mainly of neutrophils and T cells. This study was undertaken to evaluate the type of gastric T cell response elicited by the secreted peptidyl prolyl cis, trans-isomerase of H. pylori (HP0175) in patients with distal gastric adenocarcinoma. The cytokine profile and the effector functions of gastric tumor-infiltrating lymphocytes (TILs) specific for HP0175 was investigated in 20 patients with distal gastric adenocarcinoma and H. pylori infection. The helper function of HP0175-specific TILs for monocyte MMP-2, MMP-9, and VEGF production was also investigated. TILs cells from H. pylori infected patients with distal gastric adenocarcinoma produced Interleukin (IL)-17 and IL-21 in response to HP0175. HP0175-specific TILs showed poor cytolytic activity while expressing helper activity for monocyte MMP-2, MMP-9 and VEGF production. These findings indicate that HP0175 is able to drive gastric Th17 response. Thus, HP0175, by promoting pro-inflammatory low cytotoxic TIL response, matrix degradation and pro-angiogenic pathways, may provide a link between H. pylori and gastric cancer.

Helicobacter pylori secreted peptidyl prolyl cis, trans-isomerase drives Th17 inflammation in gastric adenocarcinoma.

BAFF is a crucial cytokine that affects the activity of both innate and adaptive immune cells. It promotes the expansion of Th17 cells in autoimmune disorders. With this study, we investigated the BAFF/Th17 responses in Helicobacter pylori-induced gastritis in humans. Our results show that the mucosa from Helicobacter(+) patients with chronic gastritis is enriched in IL-17 and BAFF, whereas the two cytokines are weakly expressed in Helicobacter(-) patients with chronic gastritis; moreover, the expression of both BAFF and IL-17 decreases after bacteria eradication. We demonstrate that BAFF accumulates in macrophages in vivo and that it is produced by monocyte-derived macrophages in vitro, after Helicobacter stimulation. Application of BAFF on monocytes triggers the accumulation of reactive oxygen species that are crucial for the release of pro-Th17 cytokines, such as IL-23, IL-1β, and TGF-β. Moreover, BAFF directly promotes the differentiation of Th17 cells. In conclusion, our results support the notion that an axis BAFF/Th17 exists in chronic gastritis of Helicobacter(+) patients and that its presence strictly depends on the bacterium. Moreover, we demonstrated that BAFF is able to drive Th17 responses both indirectly, by creating a pro-Th17 cytokine milieu through the involvement of innate immune cells, and directly, via the differentiation of T cells toward the specific profile. The results obtained in this study are of great interest for Helicobacter-related diseases and the development of novel therapeutic strategies based on the inhibition of the BAFF/IL-17 response.

Fabio Munari

Department of Biology

University of Padua

Evaluation of the Efficacy of the H. pylori Protein HP-NAP as a Therapeutic Tool for Treatment of Bladder Cancer in an Orthotopic Murine Model

Fabio Munari

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Biology

University of Padua

Evaluation of the Efficacy of the H. pylori Protein HP-NAP as a Therapeutic Tool for Treatment of Bladder Cancer in an Orthotopic Murine Model

Department of Biology