{"id":114341,"date":"2018-03-11T10:42:15","date_gmt":"2018-03-11T10:42:15","guid":{"rendered":"https:\/\/www.deberes.net\/tesis\/sin-categoria\/gene-transfer-of-immunomodulatory-cytokines-biological-and-functional-characterization-of-adenoassociated-virus-expressing-interferon-alpha-and-interleukin-15-in-a-hbv-transgenic-mouse-model\/"},"modified":"2018-03-11T10:42:15","modified_gmt":"2018-03-11T10:42:15","slug":"gene-transfer-of-immunomodulatory-cytokines-biological-and-functional-characterization-of-adenoassociated-virus-expressing-interferon-alpha-and-interleukin-15-in-a-hbv-transgenic-mouse-model","status":"publish","type":"post","link":"https:\/\/www.deberes.net\/tesis\/inmunologia\/gene-transfer-of-immunomodulatory-cytokines-biological-and-functional-characterization-of-adenoassociated-virus-expressing-interferon-alpha-and-interleukin-15-in-a-hbv-transgenic-mouse-model\/","title":{"rendered":"Gene transfer of immunomodulatory cytokines: biological and functional characterization of adenoassociated virus expressing interferon-alpha and interleukin-15 in a hbv transgenic mouse model."},"content":{"rendered":"<h2>Tesis doctoral de <strong> Mar\u00eda nna Di Scala <\/strong><\/h2>\n<p>Worldwide 350 million people suffer from hbv infection and approximately 1 million people die annually because of hbv-induced liver pathologies. The host immune response to hbv antigens is a critical factor determining the outcome of the infection. In this thesis we have developed an immune-gene therapy strategy for the treatment of chb. As gene vehicle, we employed recombinant aav viruses and the expression of two immunostimulatory citokines, ifn-&#945; and il-15. In the first part, we tested the functionality of both virus in vivo and determine the optimal dosage. Next, we tested the antiviral activity of both vectors in a highly tolerant animal model of chb, hbv transgenic mice. we found that aavil-15 therapy increased serum levels of il-15 bound to il-15r&#945; leading to robust intrahepatic expansion of ifn-gamma-producing lymphocytes and increased hbv-specific cd8+ t-lymphocytes which, however, lacked cytolytic activity. Contrariwise, aavifn-&#945; stimulated cytotoxic functions of hbv-specific cd8+t-cells without increasing their number. Notably, administration of aavil-15+aavifn-&#945; to transgenic mice increased both the number and the cytolytic activity of anti-hbv cd8+t cells within the liver causing extensive hepatocellular necrosis and viral clearance. Aavil-15-treated transgenic mice showed ifn-gamma-dependent hepatic pd-l1 upregulation and a high proportion of pd-1+ intrahepatic t-cells. Combining aavifn-&#945; with aavil-15 reduced pd-1 and pd-l1 expression allowing hbv-specific t-lymphocytes to kill target cells. Accordingly, treatment of hbv transgenic mice with aavil-15 plus anti-pd-l1 antibody caused intense cytolysis and viral clearance.  Our study defines a potent new approach to break immune tolerance with broad applications in chronic viral infections and neoplastic conditions.  abbreviation:  aav: adeno-associated virus; chb: chronic hepatitis b; ifn-&#945;: interferon-alpha; il-15: interleukin-15; hbv: human hepatitis b virus; pd-1: programmed-death 1; pd-l1: programmed-death ligand 1.<\/p>\n<p>&nbsp;<\/p>\n<h3>Datos acad\u00e9micos de la tesis doctoral \u00ab<strong>Gene transfer of immunomodulatory cytokines: biological and functional characterization of adenoassociated virus expressing interferon-alpha and interleukin-15 in a hbv transgenic mouse model.<\/strong>\u00ab<\/h3>\n<ul>\n<li><strong>T\u00edtulo de la tesis:<\/strong>\u00a0 Gene transfer of immunomodulatory cytokines: biological and functional characterization of adenoassociated virus expressing interferon-alpha and interleukin-15 in a hbv transgenic mouse model. <\/li>\n<li><strong>Autor:<\/strong>\u00a0 Mar\u00eda nna Di Scala <\/li>\n<li><strong>Universidad:<\/strong>\u00a0 Navarra<\/li>\n<li><strong>Fecha de lectura de la tesis:<\/strong>\u00a0 21\/06\/2013<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<h3>Direcci\u00f3n y tribunal<\/h3>\n<ul>\n<li><strong>Director de la tesis<\/strong>\n<ul>\n<li>Gloria Gonzales Aseguinolaza<\/li>\n<\/ul>\n<\/li>\n<li><strong>Tribunal<\/strong>\n<ul>\n<li>Presidente del tribunal: Jes\u00fas m. Prieto valtue\u00f1a <\/li>\n<li>Jos\u00e9 Carlos Segovia sanz (vocal)<\/li>\n<li>jessica Fioravanti (vocal)<\/li>\n<li>Luis Alberto Anel bernal (vocal)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Tesis doctoral de Mar\u00eda nna Di Scala Worldwide 350 million people suffer from hbv infection and approximately 1 million people [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""}},"footnotes":""},"categories":[36483,1737,17749],"tags":[116473,219350,15059,84394,190288,226686],"class_list":["post-114341","post","type-post","status-publish","format-standard","hentry","category-biologia-molecular","category-inmunologia","category-navarra","tag-gloria-gonzales-aseguinolaza","tag-jessica-fioravanti","tag-jesus-m-prieto-valtuena","tag-jose-carlos-segovia-sanz","tag-luis-alberto-anel-bernal","tag-maria-nna-di-scala"],"_links":{"self":[{"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/posts\/114341","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/comments?post=114341"}],"version-history":[{"count":0,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/posts\/114341\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/media?parent=114341"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/categories?post=114341"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/tags?post=114341"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}