Abstract
Slow T-cell reconstitution is a major clinical concern after transplantation of cord blood (CB)-derived hematopoietic stem cells. Adoptive transfer of in vitro-generated T-cell progenitors has emerged as a promising strategy for promoting de novo thymopoiesis and thus accelerating T-cell reconstitution. Here, we describe the development of a new culture system based on the immobilized Notch ligand Delta-like-4 (DL-4). Culture of human CD34+ CB cells in this new DL-4 system enabled the in vitro generation of large amounts of T-cell progenitor cells that (a) displayed the phenotypic and molecular signatures of early thymic progenitors and (b) had high T lymphopoietic potential. When transferred into NOD/SCID/γc−/− (NSG) mice, DL-4 primed T-cell progenitors migrated to the thymus and developed into functional, mature, polyclonal αβ T cells that subsequently left the thymus and accelerated T-cell reconstitution. T-cell reconstitution was even faster and more robust when ex vivo-manipulated and nonmanipulated CB samples were simultaneously injected into NSG mice (i.e., a situation reminiscent of the double CB transplant setting). This work provides further evidence of the ability of in vitro-generated human T-cell progenitors to accelerate T-cell reconstitution and also introduces a feeder-cell-free culture technique with the potential for rapid, safe transfer to a clinical setting.
Highlights
Unrelated cord blood transplantation (UCBT) has become an important therapeutic procedure for patients lacking human leukocyte antigen (HLA)-compatible donors [1]
Originally conceived for hematopoietic stem cell transplantation (HSCT) in children, the use of double cord blood (CB) units circumvents the limitation of low cell doses and makes double UCBT a valid option in adults
In Vitro Exposure of CB CD341 Cells to a DL-4 Fusion Protein Induces Phenotypic Changes that are Consistent with Early T-Cell Development
Summary
Unrelated cord blood transplantation (UCBT) has become an important therapeutic procedure for patients lacking human leukocyte antigen (HLA)-compatible donors [1]. Originally conceived for hematopoietic stem cell transplantation (HSCT) in children, the use of double cord blood (CB) units circumvents the limitation of low cell doses and makes double UCBT (dUCBT) a valid option in adults. Donor-derived T cells generated in the recipients thymus first appear 9 months after UCBT [1]. After HSCT, de novo T-cell generation from donor hematopoietic progenitors is disturbed at several successive steps. The generation of T-cell progenitors in the bone marrow (BM) and their delivery to the thymus have been shown to represent a limiting step in post-HSCT recovery [7]. Conditioning regimens, graft versus-host-disease, infectious disease, and inflammatory status damage the thymic stroma and thereby alter intrathymic T-cell differentiation [8]
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