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T cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents Haemophagocytic Lymphohistiocytosis manifestations

Ghosh, S; Carmo, M; Calero-Garcia, M; Ricciardelli, I; Bustamante Ogando, JC; Blundell, MP; Schambach, A; ... Gaspar, HB; + view all (2018) T cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents Haemophagocytic Lymphohistiocytosis manifestations. Journal of Allergy and Clinical Immunology , 142 (3) 904-913.e3. 10.1016/j.jaci.2017.11.050. Green open access

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Abstract

BACKGROUND: Mutations in the PRF1 gene account for up to 58% of familial haemophagocytic lymphohistiocytosis (FHL) syndromes. The resulting defects in effector cell cytotoxicity lead to hypercytokinaemia and hyperactivation with inflammation in various organs. OBJECTIVE: To determine whether autologous gene corrected T cells can restore cytotoxic function, reduce disease activity and prevent haemophagocytic 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 tumour model. Further, 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 tumour model, infusion of prf-/- gene corrected CD8-T cells eliminated the tumour as efficiently as the transplant 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. Patient 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 perforin deficiency.

Type: Article
Title: T cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents Haemophagocytic Lymphohistiocytosis manifestations
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jaci.2017.11.050
Publisher version: https://doi.org/10.1016/j.jaci.2017.11.050
Language: English
Additional information: © 2018 The Authors. Published by Elsevier Inc. on behalf of the American Academy ofAllergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: T cells, gene therapy, hemophagocytic lymphohistocytosis (HLH), perforin deficiency
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10041980
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