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Tumor Necrosis Factor Promotes Human T-Cell Development in Nonobese Diabetic/Severe Combined Immunodeficient Mice

^a Immunology Department, Weizmann Institute of Science, Rehovot, Israel;
^b Etablissement Francais du Sang Bourgogne/Franche-Comte, Besancon, France;
^c Gene Therapy Institute, Hadassah University Hospital, Jerusalem, Israel;
^d Hematology and Bone Marrow Transplantation Department, Chaim Sheba Medical Center, Tel-Hashomer, Israel;
^e Department of Obstetrics and Gynecology, Assaf-Harofeh Medical Center, Zerifin, Israel;
^f Institut de Genetique Moleculaire de Montpellier, Montpellier, France

Key Words. TNF • Transplantation • T lymphopoiesis • Cord blood • Mobilized peripheral blood cells • Hematopoietic stem cells

Correspondence: Tsvee Lapidot, Ph.D.,Weizmann Institute of Science, Department of Immunology, PO Box 26, Rehovot, 76100, Israel. Telephone: 972-8-9342481; Fax: 972-8-9344141; e-mail; Tsvee.Lapidot{at}weizmann.ac.il

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 (TNF) 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 ß 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.

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