Research ExplorerPublicationsT-cell gene therapy for perforin deficiency corrects cytotox...

T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations

Standard

T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations. / Ghosh, Sujal; Carmo, Marlene; Calero-Garcia, Miguel; Ricciardelli, Ida; Bustamante Ogando, Juan Carlos; Blundell, Michael P; Schambach, Axel; Ashton-Rickardt, Philip G; Booth, Claire; Ehl, Stephan; Lehmberg, Kai; Thrasher, Adrian J; Gaspar, H Bobby.

In: J ALLERGY CLIN IMMUN, Vol. 142, No. 3, 09.2018, p. 904-913.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Ghosh, S, Carmo, M, Calero-Garcia, M, Ricciardelli, I, Bustamante Ogando, JC, Blundell, MP, Schambach, A, Ashton-Rickardt, PG, Booth, C, Ehl, S, Lehmberg, K, Thrasher, AJ & Gaspar, HB 2018, 'T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations', J ALLERGY CLIN IMMUN, vol. 142, no. 3, pp. 904-913. https://doi.org/10.1016/j.jaci.2017.11.050

APA

Ghosh, S., Carmo, M., Calero-Garcia, M., Ricciardelli, I., Bustamante Ogando, J. C., Blundell, M. P., Schambach, A., Ashton-Rickardt, P. G., Booth, C., Ehl, S., Lehmberg, K., Thrasher, A. J., & Gaspar, H. B. (2018). T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations. J ALLERGY CLIN IMMUN, 142(3), 904-913. https://doi.org/10.1016/j.jaci.2017.11.050

Vancouver

Ghosh S, Carmo M, Calero-Garcia M, Ricciardelli I, Bustamante Ogando JC, Blundell MP et al. T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations. J ALLERGY CLIN IMMUN. 2018 Sep;142(3):904-913. https://doi.org/10.1016/j.jaci.2017.11.050

Bibtex

@article{dc457573d8cd400188385115c587d7a5,
title = "T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations",
abstract = "BACKGROUND: Mutations in the perforin 1 (PRF1) gene account for up to 58% of familial hemophagocytic lymphohistiocytosis syndromes. The resulting defects in effector cell cytotoxicity lead to hypercytokinemia and hyperactivation with inflammation in various organs.OBJECTIVE: We sought to determine whether autologous gene-corrected T cells can restore cytotoxic function, reduce disease activity, and prevent hemophagocytic lymphohistiocytosis (HLH) symptoms in in vivo models.METHODS: We developed a gammaretroviral vector to transduce murine CD8 T cells in the Prf-/- mouse model. To verify functional correction of Prf-/- CD8 T cells in vivo, we used a lymphocytic choriomeningitis virus (LCMV) epitope-transfected murine lung carcinoma cell tumor model. Furthermore, we challenged gene-corrected and uncorrected mice with LCMV. One patient sample was transduced with a PRF1-encoding lentiviral vector to study restoration of cytotoxicity in human cells.RESULTS: We demonstrated efficient engraftment and functional reconstitution of cytotoxicity after intravenous administration of gene-corrected Prf-/- CD8 T cells into Prf-/- mice. In the tumor model infusion of Prf-/- gene-corrected CD8 T cells eliminated the tumor as efficiently as transplantation of wild-type CD8 T cells. Similarly, mice reconstituted with gene-corrected Prf-/- CD8 T cells displayed complete protection from the HLH phenotype after infection with LCMV. Patients' cells showed correction of cytotoxicity in human CD8 T cells after transduction.CONCLUSION: These data demonstrate the potential application of T-cell gene therapy in reconstituting cytotoxic function and protection against HLH in the setting of perforin deficiency.",
keywords = "Journal Article",
author = "Sujal Ghosh and Marlene Carmo and Miguel Calero-Garcia and Ida Ricciardelli and {Bustamante Ogando}, {Juan Carlos} and Blundell, {Michael P} and Axel Schambach and Ashton-Rickardt, {Philip G} and Claire Booth and Stephan Ehl and Kai Lehmberg and Thrasher, {Adrian J} and Gaspar, {H Bobby}",
note = "Copyright {\textcopyright} 2018 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = sep,
doi = "10.1016/j.jaci.2017.11.050",
language = "English",
volume = "142",
pages = "904--913",
journal = "J ALLERGY CLIN IMMUN",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "3",

}

RIS

TY - JOUR

T1 - T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations

AU - Ghosh, Sujal

AU - Carmo, Marlene

AU - Calero-Garcia, Miguel

AU - Ricciardelli, Ida

AU - Bustamante Ogando, Juan Carlos

AU - Blundell, Michael P

AU - Schambach, Axel

AU - Ashton-Rickardt, Philip G

AU - Booth, Claire

AU - Ehl, Stephan

AU - Lehmberg, Kai

AU - Thrasher, Adrian J

AU - Gaspar, H Bobby

N1 - Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2018/9

Y1 - 2018/9

N2 - BACKGROUND: Mutations in the perforin 1 (PRF1) gene account for up to 58% of familial hemophagocytic lymphohistiocytosis syndromes. The resulting defects in effector cell cytotoxicity lead to hypercytokinemia and hyperactivation with inflammation in various organs.OBJECTIVE: We sought to determine whether autologous gene-corrected T cells can restore cytotoxic function, reduce disease activity, and prevent hemophagocytic lymphohistiocytosis (HLH) symptoms in in vivo models.METHODS: We developed a gammaretroviral vector to transduce murine CD8 T cells in the Prf-/- mouse model. To verify functional correction of Prf-/- CD8 T cells in vivo, we used a lymphocytic choriomeningitis virus (LCMV) epitope-transfected murine lung carcinoma cell tumor model. Furthermore, we challenged gene-corrected and uncorrected mice with LCMV. One patient sample was transduced with a PRF1-encoding lentiviral vector to study restoration of cytotoxicity in human cells.RESULTS: We demonstrated efficient engraftment and functional reconstitution of cytotoxicity after intravenous administration of gene-corrected Prf-/- CD8 T cells into Prf-/- mice. In the tumor model infusion of Prf-/- gene-corrected CD8 T cells eliminated the tumor as efficiently as transplantation of wild-type CD8 T cells. Similarly, mice reconstituted with gene-corrected Prf-/- CD8 T cells displayed complete protection from the HLH phenotype after infection with LCMV. Patients' cells showed correction of cytotoxicity in human CD8 T cells after transduction.CONCLUSION: These data demonstrate the potential application of T-cell gene therapy in reconstituting cytotoxic function and protection against HLH in the setting of perforin deficiency.

AB - BACKGROUND: Mutations in the perforin 1 (PRF1) gene account for up to 58% of familial hemophagocytic lymphohistiocytosis syndromes. The resulting defects in effector cell cytotoxicity lead to hypercytokinemia and hyperactivation with inflammation in various organs.OBJECTIVE: We sought to determine whether autologous gene-corrected T cells can restore cytotoxic function, reduce disease activity, and prevent hemophagocytic lymphohistiocytosis (HLH) symptoms in in vivo models.METHODS: We developed a gammaretroviral vector to transduce murine CD8 T cells in the Prf-/- mouse model. To verify functional correction of Prf-/- CD8 T cells in vivo, we used a lymphocytic choriomeningitis virus (LCMV) epitope-transfected murine lung carcinoma cell tumor model. Furthermore, we challenged gene-corrected and uncorrected mice with LCMV. One patient sample was transduced with a PRF1-encoding lentiviral vector to study restoration of cytotoxicity in human cells.RESULTS: We demonstrated efficient engraftment and functional reconstitution of cytotoxicity after intravenous administration of gene-corrected Prf-/- CD8 T cells into Prf-/- mice. In the tumor model infusion of Prf-/- gene-corrected CD8 T cells eliminated the tumor as efficiently as transplantation of wild-type CD8 T cells. Similarly, mice reconstituted with gene-corrected Prf-/- CD8 T cells displayed complete protection from the HLH phenotype after infection with LCMV. Patients' cells showed correction of cytotoxicity in human CD8 T cells after transduction.CONCLUSION: These data demonstrate the potential application of T-cell gene therapy in reconstituting cytotoxic function and protection against HLH in the setting of perforin deficiency.

KW - Journal Article

U2 - 10.1016/j.jaci.2017.11.050

DO - 10.1016/j.jaci.2017.11.050

M3 - SCORING: Journal article

C2 - 29355678

VL - 142

SP - 904

EP - 913

JO - J ALLERGY CLIN IMMUN

JF - J ALLERGY CLIN IMMUN

SN - 0091-6749

IS - 3

ER -