期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 41, 期 12, 页码 3596-3603出版社
WILEY-BLACKWELL
DOI: 10.1002/eji.201141561
关键词
Committed T-lymphoid progenitors; Human peripheral blood stem cells; OP9/N-DLL1; T-cell re-constitution; Three-dimensional matrix
类别
资金
- Jurgen-Manchot Foundation
- Wilhelm-Sander-Foundation [2003.023.1]
- Tour of Hope Foundation
T-cell re-constitution after allogeneic stem cell transplantation (alloSCT) is often dampened by the slow differentiation of human peripheral blood CD34(+) (huCD34(+)) hematopoietic stem cells (HSCs) into mature T cells. This process may be accelerated by the co-transfer of in vitro-pre-differentiated committed T/NK-lymphoid progenitors (CTLPs). Here, we analysed the developmental potential of huCD34(+) HSCs compared with CTLPs from a third-party donor in a murine NOD-scid IL2R gamma(null) model of humanised chimeric haematopoiesis. CTLPs (CD34(+) lin(-)CD45RA(+)CD7(+)) could be generated in vitro within 10 days upon co-culture of huCD34(+) or cord blood CD34(+) (CB-CD34) HSCs on murine OP9/N-DLL-1 stroma cells but not in a novel 3-D cell-culture matrix with DLL-1(low) human stroma cells. In both in vitro systems, huCD34(+) and CB-CD34(+) HSCs did not give rise to mature T cells. Upon transfer into 6-wk-old immune-deficient mice, CTLPs alone did not engraft. However, transplantation of CTLPs together with huCD34(+) HSCs resulted in rapid T-cell engraftment in spleen, bone marrow and thymus at day 28. Strikingly, at this early time point mature T cells originated exclusively from CTLPs, whereas descendants of huCD34(+) HSCs still expressed a T-cell-precursor phenotype (CD7(+) CD5(+)CD1a(+/-)). This strategy to enhance early T-cell re-constitution with ex vivo-pre-differentiated T-lymphoid progenitors could bridge the gap until full T-cell recovery in severely immunocompromised patients after allogeneic stem cell transplantation.
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