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

5Citations
Citations of this article
21Readers
Mendeley users who have this article in their library.

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.

Cite

CITATION STYLE

APA

Ghosh, S., Carmo, M., Calero-Garcia, M., Ricciardelli, I., Bustamante Ogando, J. C., Blundell, M. P., … Gaspar, H. B. (2018). T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations. Journal of Allergy and Clinical Immunology, 142(3), 904-913.e3. https://doi.org/10.1016/j.jaci.2017.11.050

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free