2.50
Hdl Handle:
http://hdl.handle.net/10033/621335
Title:
Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections.
Authors:
Hetzel, Miriam; Mucci, Adele; Blank, Patrick; Nguyen, Ariane Hai Ha; Schiller, Jan; Halle, Olga; Kühnel, Mark-Philipp; Billig, Sandra; Meineke, Robert; Brand, Daniel; Herder, Vanessa; Baumgärtner, Wolfgang; Bange, Franz-Christoph; Goethe, Ralph; Jonigk, Danny; Förster, Reinhold; Gentner, Bernhard; Casanova, Jean-Laurent; Bustamante, Jacinta; Schambach, Axel; Kalinke, Ulrich; Lachmann, Nico
Abstract:
Mendelian 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.
Affiliation:
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Citation:
Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections. 2018, 131 (5):533-545 Blood
Journal:
Blood
Issue Date:
1-Feb-2018
URI:
http://hdl.handle.net/10033/621335
DOI:
10.1182/blood-2017-10-812859
PubMed ID:
29233822
Type:
Article
Language:
en
ISSN:
1528-0020
Appears in Collections:
publications of the department of experimental infection research ([TC] EXPI)

Full metadata record

DC FieldValue Language
dc.contributor.authorHetzel, Miriamen
dc.contributor.authorMucci, Adeleen
dc.contributor.authorBlank, Patricken
dc.contributor.authorNguyen, Ariane Hai Haen
dc.contributor.authorSchiller, Janen
dc.contributor.authorHalle, Olgaen
dc.contributor.authorKühnel, Mark-Philippen
dc.contributor.authorBillig, Sandraen
dc.contributor.authorMeineke, Roberten
dc.contributor.authorBrand, Danielen
dc.contributor.authorHerder, Vanessaen
dc.contributor.authorBaumgärtner, Wolfgangen
dc.contributor.authorBange, Franz-Christophen
dc.contributor.authorGoethe, Ralphen
dc.contributor.authorJonigk, Dannyen
dc.contributor.authorFörster, Reinholden
dc.contributor.authorGentner, Bernharden
dc.contributor.authorCasanova, Jean-Laurenten
dc.contributor.authorBustamante, Jacintaen
dc.contributor.authorSchambach, Axelen
dc.contributor.authorKalinke, Ulrichen
dc.contributor.authorLachmann, Nicoen
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.en
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

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