Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections.
Hetzel et al final_print.pdf
Supp Fig 1.pdf
supplementary figure 1
Supp Fig 2.pdf
supplementary figure 2
Supp Fig 3.pdf
supplementary figure 3
Supp Fig 4.pdf
supplementary figure 4
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Nguyen, Ariane Hai Ha
MetadataShow full item record
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.
CitationHematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections. 2018, 131 (5):533-545 Blood
AffiliationTWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
The following license files are associated with this item:
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/
- Impaired IFNγ-Signaling and Mycobacterial Clearance in IFNγR1-Deficient Human iPSC-Derived Macrophages.
- Authors: Neehus AL, Lam J, Haake K, Merkert S, Schmidt N, Mucci A, Ackermann M, Schubert M, Happle C, Kühnel MP, Blank P, Philipp F, Goethe R, Jonigk D, Martin U, Kalinke U, Baumann U, Schambach A, Roesler J, Lachmann N
- Issue date: 2018 Jan 9
- Granulomatous skin lesions, severe scrotal and lower limb edema due to mycobacterial infections in a child with complete IFN-γ receptor-1 deficiency.
- Authors: Edeer Karaca N, Boisson-Dupuis S, Aksu G, Bustamante J, Kandiloglu G, Ozsan N, Hekimgil M, Casanova JL, Kutukculer N
- Issue date: 2012 Nov
- Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies.
- Authors: Dorman SE, Picard C, Lammas D, Heyne K, van Dissel JT, Baretto R, Rosenzweig SD, Newport M, Levin M, Roesler J, Kumararatne D, Casanova JL, Holland SM
- Issue date: 2004 Dec 11-17
- Impaired interferon gamma-mediated immunity and susceptibility to mycobacterial infection in childhood.
- Authors: Remus N, Reichenbach J, Picard C, Rietschel C, Wood P, Lammas D, Kumararatne DS, Casanova JL
- Issue date: 2001 Jul
- Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis.
- Authors: Jouanguy E, Lamhamedi-Cherradi S, Altare F, Fondanèche MC, Tuerlinckx D, Blanche S, Emile JF, Gaillard JL, Schreiber R, Levin M, Fischer A, Hivroz C, Casanova JL
- Issue date: 1997 Dec 1