TY - JOUR
T1 - Tumor necrosis factor promotes human T-cell development in nonobese diabetic/severe combined immunodeficient mice
AU - Samira, Sarit
AU - Ferrand, Christophe
AU - Peled, Amnon
AU - Nagler, Arnon
AU - Tovbin, Yosef
AU - Ben-Hur, Herzl
AU - Taylor, Naomi
AU - Globerson, Amiela
AU - Lapidot, Tsvee
PY - 2004
Y1 - 2004
N2 - A major problem after clinical hematopoietic stem cell transplantations is poor T-cell reconstitution. Studying the mechanisms underlying this concern is hampered, because experimental transplantation of human stem and progenitor cells into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice usually results in low T-lymphocyte reconstitution. Because tumor necrosis factor α (TNFα) has been proposed to play a role in T-lineage commitment and differentiation in vitro, we investigated its potential to augment human T-cell development in vivo. Administration of TNF to irradiated NOD/SCID mice before transplantation of human mononuclear cells from either cord blood or adult G-CSF-mobilized peripheral blood (MPBL) led 2-3 weeks after transplantation to the emergence of human immature CD4+CD8 + double-positive T-cells in the bone marrow (BM), spleen, and thymus, and in this organ, the human cells also express CD1a marker. One to 2 weeks later, single-positive CD4+ and CD8+ cells expressing heterogenous T-cell receptor αβ were detected in all three organs. These cells were also capable of migrating through the blood circulation. Interestingly, human T-cell development in these mice was associated with a significant reduction in immature lymphoid human CD19 + B cells and natural killer progenitors in the murine BM. The human T cells were mostly derived from the transplanted immature CD34+ cells. This study demonstrates the potential of TNF to rapidly augment human T lymphopoiesis in vivo and also provides clinically relevant evidence for this process with adult MPBL progenitors.
AB - A major problem after clinical hematopoietic stem cell transplantations is poor T-cell reconstitution. Studying the mechanisms underlying this concern is hampered, because experimental transplantation of human stem and progenitor cells into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice usually results in low T-lymphocyte reconstitution. Because tumor necrosis factor α (TNFα) has been proposed to play a role in T-lineage commitment and differentiation in vitro, we investigated its potential to augment human T-cell development in vivo. Administration of TNF to irradiated NOD/SCID mice before transplantation of human mononuclear cells from either cord blood or adult G-CSF-mobilized peripheral blood (MPBL) led 2-3 weeks after transplantation to the emergence of human immature CD4+CD8 + double-positive T-cells in the bone marrow (BM), spleen, and thymus, and in this organ, the human cells also express CD1a marker. One to 2 weeks later, single-positive CD4+ and CD8+ cells expressing heterogenous T-cell receptor αβ were detected in all three organs. These cells were also capable of migrating through the blood circulation. Interestingly, human T-cell development in these mice was associated with a significant reduction in immature lymphoid human CD19 + B cells and natural killer progenitors in the murine BM. The human T cells were mostly derived from the transplanted immature CD34+ cells. This study demonstrates the potential of TNF to rapidly augment human T lymphopoiesis in vivo and also provides clinically relevant evidence for this process with adult MPBL progenitors.
KW - Cord blood
KW - Mobilized peripheral blood cells Hematopoietic stem cells
KW - T lymphopoiesis
KW - TNF
KW - Transplantation
UR - http://www.scopus.com/inward/record.url?scp=8644290208&partnerID=8YFLogxK
U2 - 10.1634/stemcells.22-6-1085
DO - 10.1634/stemcells.22-6-1085
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C2 - 15536198
AN - SCOPUS:8644290208
SN - 1066-5099
VL - 22
SP - 1085
EP - 1100
JO - Stem Cells
JF - Stem Cells
IS - 6
ER -