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Perforin Gene Transfer Into Hematopoietic Stem Cells Improves Immune Dysregulation in Murine Models of Perforin Deficiency
Defects in perforin lead to the failure of T and NK cell cytotoxicity, hypercytokinemia, and the immune dysregulatory condition known as familial hemophagocytic lymphohistiocytosis (FHL). The only curative treatment is allogeneic hematopoietic stem cell transplantation which carries substantial risk...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395774/ https://www.ncbi.nlm.nih.gov/pubmed/25523759 http://dx.doi.org/10.1038/mt.2014.242 |
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author | Carmo, Marlene Risma, Kimberly A Arumugam, Paritha Tiwari, Swati Hontz, Adrianne E Montiel-Equihua, Claudia A Alonso-Ferrero, Maria E Blundell, Michael P Schambach, Axel Baum, Christopher Malik, Punam Thrasher, Adrian J Jordan, Michael B Gaspar, H Bobby |
author_facet | Carmo, Marlene Risma, Kimberly A Arumugam, Paritha Tiwari, Swati Hontz, Adrianne E Montiel-Equihua, Claudia A Alonso-Ferrero, Maria E Blundell, Michael P Schambach, Axel Baum, Christopher Malik, Punam Thrasher, Adrian J Jordan, Michael B Gaspar, H Bobby |
author_sort | Carmo, Marlene |
collection | PubMed |
description | Defects in perforin lead to the failure of T and NK cell cytotoxicity, hypercytokinemia, and the immune dysregulatory condition known as familial hemophagocytic lymphohistiocytosis (FHL). The only curative treatment is allogeneic hematopoietic stem cell transplantation which carries substantial risks. We used lentiviral vectors (LV) expressing the human perforin gene, under the transcriptional control of the ubiquitous phosphoglycerate kinase promoter or a lineage-specific perforin promoter, to correct the defect in different murine models. Following LV-mediated gene transfer into progenitor cells from perforin-deficient mice, we observed perforin expression in mature T and NK cells, and there was no evidence of progenitor cell toxicity when transplanted into irradiated recipients. The resulting perforin-reconstituted NK cells showed partial recovery of cytotoxicity, and we observed full recovery of cytotoxicity in polyclonal CD8(+) T cells. Furthermore, reconstituted T cells with defined antigen specificity displayed normal cytotoxic function against peptide-loaded targets. Reconstituted CD8(+) lymphoblasts had reduced interferon-γ secretion following stimulation in vitro, suggesting restoration of normal immune regulation. Finally, upon viral challenge, mice with >30% engraftment of gene-modified cells exhibited reduction of cytokine hypersecretion and cytopenias. This study demonstrates the potential of hematopoietic stem cell gene therapy as a curative treatment for perforin-deficient FHL. |
format | Online Article Text |
id | pubmed-4395774 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-43957742015-04-21 Perforin Gene Transfer Into Hematopoietic Stem Cells Improves Immune Dysregulation in Murine Models of Perforin Deficiency Carmo, Marlene Risma, Kimberly A Arumugam, Paritha Tiwari, Swati Hontz, Adrianne E Montiel-Equihua, Claudia A Alonso-Ferrero, Maria E Blundell, Michael P Schambach, Axel Baum, Christopher Malik, Punam Thrasher, Adrian J Jordan, Michael B Gaspar, H Bobby Mol Ther Original Article Defects in perforin lead to the failure of T and NK cell cytotoxicity, hypercytokinemia, and the immune dysregulatory condition known as familial hemophagocytic lymphohistiocytosis (FHL). The only curative treatment is allogeneic hematopoietic stem cell transplantation which carries substantial risks. We used lentiviral vectors (LV) expressing the human perforin gene, under the transcriptional control of the ubiquitous phosphoglycerate kinase promoter or a lineage-specific perforin promoter, to correct the defect in different murine models. Following LV-mediated gene transfer into progenitor cells from perforin-deficient mice, we observed perforin expression in mature T and NK cells, and there was no evidence of progenitor cell toxicity when transplanted into irradiated recipients. The resulting perforin-reconstituted NK cells showed partial recovery of cytotoxicity, and we observed full recovery of cytotoxicity in polyclonal CD8(+) T cells. Furthermore, reconstituted T cells with defined antigen specificity displayed normal cytotoxic function against peptide-loaded targets. Reconstituted CD8(+) lymphoblasts had reduced interferon-γ secretion following stimulation in vitro, suggesting restoration of normal immune regulation. Finally, upon viral challenge, mice with >30% engraftment of gene-modified cells exhibited reduction of cytokine hypersecretion and cytopenias. This study demonstrates the potential of hematopoietic stem cell gene therapy as a curative treatment for perforin-deficient FHL. Nature Publishing Group 2015-04 2015-01-20 /pmc/articles/PMC4395774/ /pubmed/25523759 http://dx.doi.org/10.1038/mt.2014.242 Text en Copyright © 2015 The American Society of Gene & Cell Therapy http://creativecommons.org/licenses/by/3.0/ This work is licensed under a Creative Commons Attribution 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/ |
spellingShingle | Original Article Carmo, Marlene Risma, Kimberly A Arumugam, Paritha Tiwari, Swati Hontz, Adrianne E Montiel-Equihua, Claudia A Alonso-Ferrero, Maria E Blundell, Michael P Schambach, Axel Baum, Christopher Malik, Punam Thrasher, Adrian J Jordan, Michael B Gaspar, H Bobby Perforin Gene Transfer Into Hematopoietic Stem Cells Improves Immune Dysregulation in Murine Models of Perforin Deficiency |
title | Perforin Gene Transfer Into Hematopoietic Stem Cells Improves Immune Dysregulation in Murine Models of Perforin Deficiency |
title_full | Perforin Gene Transfer Into Hematopoietic Stem Cells Improves Immune Dysregulation in Murine Models of Perforin Deficiency |
title_fullStr | Perforin Gene Transfer Into Hematopoietic Stem Cells Improves Immune Dysregulation in Murine Models of Perforin Deficiency |
title_full_unstemmed | Perforin Gene Transfer Into Hematopoietic Stem Cells Improves Immune Dysregulation in Murine Models of Perforin Deficiency |
title_short | Perforin Gene Transfer Into Hematopoietic Stem Cells Improves Immune Dysregulation in Murine Models of Perforin Deficiency |
title_sort | perforin gene transfer into hematopoietic stem cells improves immune dysregulation in murine models of perforin deficiency |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395774/ https://www.ncbi.nlm.nih.gov/pubmed/25523759 http://dx.doi.org/10.1038/mt.2014.242 |
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