T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations
| Autor: | Sujal, Ghosh, Marlene, Carmo, Miguel, Calero-Garcia, Ida, Ricciardelli, Juan Carlos, Bustamante Ogando, Michael P, Blundell, Axel, Schambach, Philip G, Ashton-Rickardt, Claire, Booth, Stephan, Ehl, Kai, Lehmberg, Adrian J, Thrasher, H Bobby, Gaspar |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
WT Wild-type T cells CD8-Positive T-Lymphocytes Lymphocytic Choriomeningitis Lymphohistiocytosis Hemophagocytic Article TEM Effector memory T HSCT Hematopoietic stem cell transplantation Gene therapy FHL Familial hemophagocytic lymphohistiocytosis NK Natural killer TCM Central memory T Cell Line Tumor Animals Humans Lymphocytic choriomeningitis virus Mice Knockout Perforin perforin deficiency Genetic Therapy IRES Internal ribosomal entry site HLH Hemophagocytic lymphohistiocytosis PRF1 Perforin 1 LCMV Lymphocytic choriomeningitis virus Mice Inbred C57BL hemophagocytic lymphohistiocytosis Child Preschool GFP Green fluorescent protein PS Penicillin and streptomycin |
| Zdroj: | The Journal of Allergy and Clinical Immunology |
| ISSN: | 1097-6825 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect