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

Authors :
Anusara Daenthanasanmak
Gustavo Salguero
Bala Sai Sundarasetty
Claudia Waskow
Kadriye Nehir Cosgun
Carlos A Guzman
Peggy Riese
Laura Gerasch
Andreas Schneider
Alexandra Ingendoh
Martin Messerle
Ildar Gabaev
Benno Woelk
Eliana Ruggiero
Manfred Schmidt
Christof von Kalle
Constanca Figueiredo
Britta Eiz-Vesper
Constantin von Kaisenberg
Arnold Ganser
Renata Stripecke
Source :
Molecular Therapy: Methods & Clinical Development, Vol 2, Iss , Pp - (2015)
Publication Year :
2015
Publisher :
Elsevier, 2015.

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 (âSmyleDCpp65â). 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.Rag1â/â.IL2γcâ/â 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.

Details

Language :
English
ISSN :
23290501
Volume :
2
Issue :
-
Database :
Directory of Open Access Journals
Journal :
Molecular Therapy: Methods & Clinical Development
Publication Type :
Academic Journal
Accession number :
edsdoj.97bc6c89db6841b6832e8de62e46edb1
Document Type :
article
Full Text :
https://doi.org/10.1038/mtm.2014.60