Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation.
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.
Zakrzewski
Johannes L
JL
Department of Medicine, Zuckerman Research Center 1404, Mailbox 111, New York, New York 10021, USA.
Kochman
Adam A
AA
Lu
Sydney X
SX
Terwey
Theis H
TH
Kim
Theo D
TD
Hubbard
Vanessa M
VM
Muriglan
Stephanie J
SJ
Suh
David
D
Smith
Odette M
OM
Grubin
Jeremy
J
Patel
Neel
N
Chow
Andrew
A
Cabrera-Perez
Javier
J
Radhakrishnan
Radhika
R
Diab
Adi
A
Perales
Miguel-Angel
MA
Rizzuto
Gabrielle
G
Menet
Ewa
E
Pamer
Eric G
EG
Heller
Glen
G
Zúñiga-Pflücker
Juan Carlos
JC
Alpdogan
Onder
O
van den Brink
Marcel R M
MR
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*
D051523:Fibroblast Growth Factor 7