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.
Preview |
Text
Thrasher VoR 1-s2.0-S0091674918300757-main.pdf - Published Version Download (3MB) | Preview |
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 |
Archive Staff Only
 |
View Item |
