title: Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation.
abstract: 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.
authors.affiliation: Department of Medicine, Zuckerman Research Center 1404, Mailbox 111, New York, New York 10021, USA.
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Zakrzewski
authors.forename: Adam A
authors.initials: AA
authors.lastname: Kochman
authors.forename: Sydney X
authors.initials: SX
authors.lastname: Lu
authors.forename: Theis H
authors.initials: TH
authors.lastname: Terwey
authors.forename: Theo D
authors.initials: TD
authors.lastname: Kim
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hubbard
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Muriglan
authors.forename: David
authors.initials: D
authors.lastname: Suh
authors.forename: Odette M
authors.initials: OM
authors.lastname: Smith
authors.forename: Jeremy
authors.initials: J
authors.lastname: Grubin
authors.forename: Neel
authors.initials: N
authors.lastname: Patel
authors.forename: Andrew
authors.initials: A
authors.lastname: Chow
authors.forename: Javier
authors.initials: J
authors.lastname: Cabrera-Perez
authors.forename: Radhika
authors.initials: R
authors.lastname: Radhakrishnan
authors.forename: Adi
authors.initials: A
authors.lastname: Diab
authors.forename: Miguel-Angel
authors.initials: MA
authors.lastname: Perales
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Rizzuto
authors.forename: Ewa
authors.initials: E
authors.lastname: Menet
authors.forename: Eric G
authors.initials: EG
authors.lastname: Pamer
authors.forename: Glen
authors.initials: G
authors.lastname: Heller
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Zúñiga-Pflücker
authors.forename: Onder
authors.initials: O
authors.lastname: Alpdogan
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018920:Coculture Techniques; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000276:immunology; D020350:Graft vs Tumor Effect / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D008088:Listeriosis / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D012038:Regeneration; D013234:Stem Cells / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000502:physiology*
chemical_list: D051523:Fibroblast Growth Factor 7