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dc.contributor.authorHetzel, Miriam
dc.contributor.authorMucci, Adele
dc.contributor.authorBlank, Patrick
dc.contributor.authorNguyen, Ariane Hai Ha
dc.contributor.authorSchiller, Jan
dc.contributor.authorHalle, Olga
dc.contributor.authorKühnel, Mark-Philipp
dc.contributor.authorBillig, Sandra
dc.contributor.authorMeineke, Robert
dc.contributor.authorBrand, Daniel
dc.contributor.authorHerder, Vanessa
dc.contributor.authorBaumgärtner, Wolfgang
dc.contributor.authorBange, Franz-Christoph
dc.contributor.authorGoethe, Ralph
dc.contributor.authorJonigk, Danny
dc.contributor.authorFörster, Reinhold
dc.contributor.authorGentner, Bernhard
dc.contributor.authorCasanova, Jean-Laurent
dc.contributor.authorBustamante, Jacinta
dc.contributor.authorSchambach, Axel
dc.contributor.authorKalinke, Ulrich
dc.contributor.authorLachmann, Nico
dc.date.accessioned2018-04-03T14:07:47Z
dc.date.available2018-04-03T14:07:47Z
dc.date.issued2018-02-01
dc.identifier.citationHematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections. 2018, 131 (5):533-545 Blooden
dc.identifier.issn1528-0020
dc.identifier.pmid29233822
dc.identifier.doi10.1182/blood-2017-10-812859
dc.identifier.urihttp://hdl.handle.net/10033/621335
dc.description.abstractMendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by severe infections caused by weakly virulent mycobacteria. Biallelic null mutations in genes encoding interferon gamma receptor 1 or 2 (IFNGR1orIFNGR2) result in a life-threatening disease phenotype in early childhood. Recombinant interferon γ (IFN-γ) therapy is inefficient, and hematopoietic stem cell transplantation has a poor prognosis. Thus, we developed a hematopoietic stem cell (HSC) gene therapy approach using lentiviral vectors that expressIfnγr1either constitutively or myeloid specifically. Transduction of mouseIfnγr1 -/- HSCs led to stable IFNγR1 expression on macrophages, which rescued their cellular responses to IFN-γ. As a consequence, genetically corrected HSC-derived macrophages were able to suppress T-cell activation and showed restored antimycobacterial activity againstMycobacterium aviumandMycobacterium bovisBacille Calmette-Guérin (BCG) in vitro. Transplantation of genetically corrected HSCs intoIfnγr1-/-mice before BCG infection prevented manifestations of severe BCG disease and maintained lung and spleen organ integrity, which was accompanied by a reduced mycobacterial burden in lung and spleen and a prolonged overall survival in animals that received a transplant. In summary, we demonstrate an HSC-based gene therapy approach for IFNγR1 deficiency, which protects mice from severe mycobacterial infections, thereby laying the foundation for a new therapeutic intervention in corresponding human patients.
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleHematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections.en
dc.typeArticleen
dc.contributor.departmentTWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.en
dc.identifier.journalBlooden
html.description.abstractMendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by severe infections caused by weakly virulent mycobacteria. Biallelic null mutations in genes encoding interferon gamma receptor 1 or 2 (IFNGR1orIFNGR2) result in a life-threatening disease phenotype in early childhood. Recombinant interferon γ (IFN-γ) therapy is inefficient, and hematopoietic stem cell transplantation has a poor prognosis. Thus, we developed a hematopoietic stem cell (HSC) gene therapy approach using lentiviral vectors that expressIfnγr1either constitutively or myeloid specifically. Transduction of mouseIfnγr1 -/- HSCs led to stable IFNγR1 expression on macrophages, which rescued their cellular responses to IFN-γ. As a consequence, genetically corrected HSC-derived macrophages were able to suppress T-cell activation and showed restored antimycobacterial activity againstMycobacterium aviumandMycobacterium bovisBacille Calmette-Guérin (BCG) in vitro. Transplantation of genetically corrected HSCs intoIfnγr1-/-mice before BCG infection prevented manifestations of severe BCG disease and maintained lung and spleen organ integrity, which was accompanied by a reduced mycobacterial burden in lung and spleen and a prolonged overall survival in animals that received a transplant. In summary, we demonstrate an HSC-based gene therapy approach for IFNγR1 deficiency, which protects mice from severe mycobacterial infections, thereby laying the foundation for a new therapeutic intervention in corresponding human patients.


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