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2006: Zakrzewski Johannes L; Kochman Adam A; Lu Sydney X; Terwey Theis H; Kim Theo D; Hubbard Vanessa M; Muriglan Stephanie J; Suh David; Smith Odette M; Grubin Jeremy; Patel Neel; Chow Andrew; Cabrera-Perez Javier; Radhakrishnan Radhika; Diab Adi; Perales Miguel-Angel; Rizzuto Gabrielle; Menet Ewa; Pamer Eric G; Heller Glen; Zúñiga-Pflücker Juan Carlos; Alpdogan Onder; van den Brink Marcel R M
Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation.
Nature medicine 2006;12(9):1039-47.
Immunoincompetence after allogeneic hematopoietic stem cell transplantation (HSCT) affects in particular the T-cell lineage and is associated with an increased risk for infections, graft failure and malignant relapse. To generate large numbers of T-cell precursors for adoptive therapy, we cultured mouse hematopoietic stem cells (HSCs) in vitro on OP9 mouse stromal cells expressing the Notch-1 ligand Delta-like-1 (OP9-DL1). We infused these cells, together with T-cell-depleted mouse bone marrow or purified HSCs, into lethally irradiated allogeneic recipients and determined their effect on T-cell reconstitution after transplantation. Recipients of OP9-DL1-derived T-cell precursors showed increased thymic cellularity and substantially improved donor T-cell chimerism (versus recipients of bone marrow or HSCs only). OP9-DL1-derived T-cell precursors gave rise to host-tolerant CD4+ and CD8+ populations with normal T-cell antigen receptor repertoires, cytokine secretion and proliferative responses to antigen. Administration of OP9-DL1-derived T-cell precursors increased resistance to infection with Listeria monocytogenes and mediated significant graft-versus-tumor (GVT) activity but not graft-versus-host disease (GVHD). We conclude that the adoptive transfer of OP9-DL1-derived T-cell precursors markedly enhances T-cell reconstitution after transplantation, resulting in GVT activity without GVHD.

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