Journal article
IL-27 Gene Therapy Ameliorates IPEX Syndrome Caused by Germline Mutation of Foxp3 Gene: A Major Role for Induction of IL-10
The Journal of immunology (1950), Vol.213(5), pp.559-566
07/08/2024
DOI: 10.4049/jimmunol.2400056
PMCID: PMC11333164
PMID: 38975727
Abstract
Inactivating mutations of Foxp3, the master regulator of regulatory T cell development and function, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in mice and humans. IPEX is a fatal autoimmune disease, with allogeneic stem cell transplant being the only available therapy. In this study, we report that a single dose of adeno-associated virus (AAV)-IL-27 to young mice with naturally occurring Foxp3 mutation (Scurfy mice) substantially ameliorates clinical symptoms, including growth retardation and early fatality. Correspondingly, AAV-IL-27 gene therapy significantly prevented naive T cell activation, as manifested by downregulation of CD62L and upregulation of CD44, and immunopathology typical of IPEX. Because IL-27 is known to induce IL-10, a key effector molecule of regulatory T cells, we evaluated the contribution of IL-10 induction by crossing IL-10-null allele to Scurfy mice. Although IL-10 deficiency does not affect the survival of Scurfy mice, it largely abrogated the therapeutic effect of AAV-IL-27. Our study revealed a major role for IL-10 in AAV-IL-27 gene therapy and demonstrated that IPEX is amenable to gene therapy.Inactivating mutations of Foxp3, the master regulator of regulatory T cell development and function, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in mice and humans. IPEX is a fatal autoimmune disease, with allogeneic stem cell transplant being the only available therapy. In this study, we report that a single dose of adeno-associated virus (AAV)-IL-27 to young mice with naturally occurring Foxp3 mutation (Scurfy mice) substantially ameliorates clinical symptoms, including growth retardation and early fatality. Correspondingly, AAV-IL-27 gene therapy significantly prevented naive T cell activation, as manifested by downregulation of CD62L and upregulation of CD44, and immunopathology typical of IPEX. Because IL-27 is known to induce IL-10, a key effector molecule of regulatory T cells, we evaluated the contribution of IL-10 induction by crossing IL-10-null allele to Scurfy mice. Although IL-10 deficiency does not affect the survival of Scurfy mice, it largely abrogated the therapeutic effect of AAV-IL-27. Our study revealed a major role for IL-10 in AAV-IL-27 gene therapy and demonstrated that IPEX is amenable to gene therapy.
Details
- Title: Subtitle
- IL-27 Gene Therapy Ameliorates IPEX Syndrome Caused by Germline Mutation of Foxp3 Gene: A Major Role for Induction of IL-10
- Creators
- Jin-Qing LiuAli Jabbari - University of IowaCho-Hao LinVenu AkkanapallyWendy L FrankelSujit BasuKai He - The Ohio State UniversityPan ZhengYang LiuXue-Feng Bai
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.213(5), pp.559-566
- DOI
- 10.4049/jimmunol.2400056
- PMID
- 38975727
- PMCID
- PMC11333164
- NLM abbreviation
- J Immunol
- ISSN
- 1550-6606
- eISSN
- 1550-6606
- Publisher
- AMER ASSOC IMMUNOLOGISTS
- Grant note
- National Institutes of Health: R01CA229254, R0 1AR077194
This work was supported by National Institutes of Health Grants R01CA229254 (to X.-F.B.) and R0 1AR077194 (to A.J.) .
- Language
- English
- Electronic publication date
- 07/08/2024
- Academic Unit
- Dermatology
- Record Identifier
- 9984656559202771
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