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Recombinant IFN-γ1b Treatment in a Patient with Inherited IFN-γ Deficiency

journal contribution
submitted on 2024-08-07, 06:35 and posted on 2024-08-07, 06:35 authored by Jérémie Rosain, Ayca Kiykim, Alexandre Michev, Yasemin Kendir-Demirkol, Darawan Rinchai, Jessica N. Peel, Hailun Li, Suheyla Ocak, Pinar Gokmirza Ozdemir, Tom Le Voyer, Quentin Philippot, Taushif Khan, Anna-Lena Neehus, Mélanie Migaud, Camille Soudée, Stéphanie Boisson-Dupuis, Nico Marr, Alessandro Borghesi, Jean-Laurent Casanova, Jacinta Bustamante

Purpose

Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Twenty-two genes with products involved in the production of, or response to, IFN-γ and variants of which underlie MSMD have been identified. However, pathogenic variants of IFNG encoding a defective IFN-γ have been described in only two siblings, who both underwent hematopoietic stem cell transplantation (HCST).

Methods

We characterized a new patient with MSMD by genetic, immunological, and clinical means. Therapeutic decisions were taken on the basis of these findings.

Results

The patient was born to consanguineous Turkish parents and developed bacillus Calmette-Guérin (BCG) disease following vaccination at birth. Whole-exome sequencing revealed a homozygous private IFNG variant (c.224 T > C, p.F75S). Upon overexpression in recipient cells or constitutive expression in the patient’s cells, the mutant IFN-γ was produced within the cells but was not correctly folded or secreted. The patient was treated for 6 months with two or three antimycobacterial drugs only and then for 30 months with subcutaneous recombinant IFN-γ1b plus two antimycobacterial drugs. Treatment with IFN-γ1b finally normalized all biological parameters. The patient presented no recurrence of mycobacterial disease or other related infectious diseases. The treatment was well tolerated, without the production of detectable autoantibodies against IFN-γ.

Conclusion

We describe a patient with a new form of autosomal recessive IFN-γ deficiency, with intracellular, but not extracellular IFN-γ. IFN-γ1b treatment appears to have been beneficial in this patient, with no recurrence of mycobacterial infection over a period of more than 30 months. This targeted treatment provides an alternative to HCST in patients with complete IFN-γ deficiency or at least an option to better control mycobacterial infection prior to HCST.

Other Information

Published in: Journal of Clinical Immunology
License: https://creativecommons.org/licenses/by/4.0
See article on publisher's website: https://dx.doi.org/10.1007/s10875-024-01661-5

Funding

Qatar National Research Fund (NPRP9-251–3-045), Human genetic susceptibility to severe viral infections in childhood.

History

Language

  • English

Publisher

Springer Nature

Publication Year

  • 2024

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU
  • Sidra Medicine
  • Clinical Research Centre - Sidra Medicine

Methodology

We characterized a new patient with MSMD by genetic, immunological, and clinical means. Therapeutic decisions were taken on the basis of these findings.

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