Adoptive Transfer of T-cell Precursors Enhances T-cell Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation

Nat Med. 2006 Sep;12(9):1039-47. doi: 10.1038/nm1463. Epub 2006 Aug 27.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer*
  • Animals
  • Coculture Techniques
  • Fibroblast Growth Factor 7 / pharmacology
  • Graft vs Host Disease / immunology
  • Graft vs Tumor Effect / immunology
  • Hematopoietic Stem Cell Transplantation*
  • Listeriosis / immunology
  • Lymphocyte Depletion
  • Mice
  • Regeneration
  • Stem Cells / physiology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / physiology*

Substances

  • Fibroblast Growth Factor 7