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T-cell Gene Therapy for Perforin Deficiency Corrects Cytotoxicity Defects and Prevents Hemophagocytic Lymphohistiocytosis Manifestations
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
Hubert Bobby Gaspar
出版
Universität
, 2018
URL
http://books.google.com.hk/books?id=CT8K0AEACAAJ&hl=&source=gbs_api
註釋
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