Entwicklung eines lentiviralen Vektors zur gentherapeutischen Modifizierung von T und NK Zellen zur Kontrolle der Krankheitsaktivität in perforin-defizienten hämophagozytischen Lymphohistio-zytose (HLH) Patienten

• Antragsteller: Dr. Sujal Ghosh
• Fachliche Zuordnung: Rheumatologie ; Immunologie ; Kinder- und Jugendmedizin
• Förderung: Förderung von 2013 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 251204879

• Erstellungsjahr: 2018

Zusammenfassung der Projektergebnisse

Perforin deficiency is caused by mutations in the PRF1 gene and accounts for up to 58% of familial haemophagocytic lymphohistiocytosis (FHL) syndromes. A deficient cytolytic secretory pathway leads to hypercytokinaemia and hyperactivation of notably CD8 T cells with subsequent inflammation of various organs. The use of autologous gene corrected T cells has the potential to reduce disease activity, alleviate haemophagocytic lymphohistiocytosis (HLH) symptoms and bridge to desired haematopoietic stem cell transplantation (HSCT) or even confer long-term protection. We developed a gammaretroviral vector to transduce murine CD8 T cells and its subsets in the prf-/- mouse model. We saw efficient engraftment and functional reconstitution of cytotoxicity after intravenous administration of gene corrected prf-/- CD8 T cells into prf-/- mice. To verify further the functional correction of prf-/- CD8 T cells in vivo, we used a lymphocytic choriomeningitis virus (LCMV) epitope transfected murine lung carcinoma cell tumour model that has been evaluated in perforin deficient models. 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. Finally, we show the correction of cytotoxicity in human CD8 T cells of perforin deficient patients after transduction with a PRF1 encoding lentiviral vector. These pre-clinical data demonstrate the potential application of T cell gene therapy for perforin deficient HLH.

Projektbezogene Publikationen (Auswahl)

• T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations. J Allergy Clin Immunol. 2018 Jan 31
  Ghosh S, Carmo M, Calero-Garcia M, Ricciardelli I, Bustamante Ogando JC, Blundell MP, Schambach A, Ashton-Rickardt PG, Booth C, Ehl S, Lehmberg K, Thrasher AJ, Gaspar HB