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

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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

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Notes: The journal of allergy and clinical immunology. - 142, 3 (2018) , 904-913.e3, ISSN: 1097-6825

Classification: Medizin, Gesundheit

Event: Veröffentlichung

(where): Freiburg

(who): Universität

(when): 2019

Creator: Ghosh, Sujal
Carmo, Marlene
Calero-Garcia, Miguel
Ricciardelli, Ida
Bustamante Ogando, Juan Carlos
Blundell, Michael P.
Schambach, Axel
Ashton-Rickardt, Philip G.
Booth, Claire
Ehl, Stephan
Lehmberg, Kai
Thrasher, Adrian J.
Gaspar, Hubert Bobby

DOI: 10.1016/j.jaci.2017.11.050

URN: urn:nbn:de:bsz:25-freidok-1480374

Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 25.03.2025, 1:50 PM CET

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Associated

Ghosh, Sujal
Carmo, Marlene
Calero-Garcia, Miguel
Ricciardelli, Ida
Bustamante Ogando, Juan Carlos
Blundell, Michael P.
Schambach, Axel
Ashton-Rickardt, Philip G.
Booth, Claire
Ehl, Stephan
Lehmberg, Kai
Thrasher, Adrian J.
Gaspar, Hubert Bobby
Universität

Time of origin

2019

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

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Other Objects (12)

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