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Engineered dendritic cells from cord blood and adult blood accelerate effector T cell immune reconstitution against HCMV.
Daenthanasanmak, Anusara Salguero, Gustavo Sundarasetty, Bala Sai Waskow, Claudia Cosgun, Kadriye Nehir Guzman, Carlos A Gerasch, Laura Schneider, Andreas Ingendoh, Alexandra
Daenthanasanmak, Anusara
Salguero, Gustavo
Sundarasetty, Bala Sai
Waskow, Claudia
Cosgun, Kadriye Nehir
Guzman, Carlos A
Gerasch, Laura
Schneider, Andreas
Ingendoh, Alexandra
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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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Engineered dendritic cells from cord blood and adult blood accelerate effector T cell immune reconstitution against HCMV. 2015, 1:14060 Mol Ther Methods Clin Dev
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en
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2329-0501
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openAccess