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Mol Ther Methods Clin Dev. 2015 Jan 7;1:14060. doi: 10.1038/mtm.2014.60. eCollection 2015.

Engineered dendritic cells from cord blood and adult blood accelerate effector T cell immune reconstitution against HCMV.

Author information

1
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School , Hannover, Germany.
2
Regeneration in Hematopoiesis, DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden , Dresden, Germany.
3
Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infections Research , Braunschweig, Germany.
4
Institute of Virology, Hannover Medical School , Hannover, Germany.
5
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center , Heidelberg, Germany.
6
Department of Transfusion Medicine, Hannover Medical School , Hannover, Germany.
7
Department of Obstetrics and Gynecology, Hannover Medical School , Hannover, Germany.

Abstract

Human cytomegalovirus (HCMV) harmfully impacts survival after peripheral blood hematopoietic stem cell transplantation (PB-HSCT). Delayed immune reconstitution after cord blood (CB)-HSCT leads to even higher HCMV-related morbidity and mortality. Towards a feasible dendritic cell therapy to accelerate de novo immunity against HCMV, we validated a tricistronic integrase-defective lentiviral vector (coexpressing GM-CSF, IFN-α, and HCMV pp65 antigen) capable to directly induce self-differentiation of PB and CB monocytes into dendritic cells processing pp65 ("SmyleDCpp65"). In vitro, SmyleDCpp65 resisted HCMV infection, activated CD4(+) and CD8(+) T cells and expanded functional pp65-specific memory cytotoxic T lymphocytes (CTLs). CD34(+) cells obtained from PB and CB were transplanted into irradiated NOD.Rag1(-/-).IL2γc(-/-) mice. Donor-derived SmyleDCpp65 administration after PB-HSCT stimulated peripheral immune effects: lymph node remodeling, expansion of polyclonal effector memory CD8(+) T cells in blood, spleen and bone marrow, and pp65-reactive CTL and IgG responses. SmyleDCpp65 administration after CB-HSCT significantly stimulated thymopoiesis. Expanded frequencies of CD4(+)/CD8(+) T cell precursors containing increased levels of T-cell receptor excision circles in thymus correlated with peripheral expansion of effector memory CTL responses against pp65. The comparative in vivo modeling for PB and CB-HSCT provided dynamic and spatial information regarding human T and B cell reconstitution. In vivo potency supports future clinical development of SmyleDCpp65.

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