Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation

TY - JOUR

T1 - Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation

AU - Zakrzewski, Johannes L.

AU - Kochman, Adam A.

AU - Lu, Sydney X.

AU - Terwey, Theis H.

AU - Kim, Theo D.

AU - Hubbard, Vanessa M.

AU - Muriglan, Stephanie J.

AU - Suh, David

AU - Smith, Odette M.

AU - Grubin, Jeremy

AU - Patel, Neel

AU - Chow, Andrew

AU - Cabrera-Perez, Javier

AU - Radhakrishnan, Radhika

AU - Diab, Adi

AU - Perales, Miguel Angel

AU - Rizzuto, Gabrielle

AU - Menet, Ewa

AU - Pamer, Eric G.

AU - Heller, Glen

AU - Zúñiga-Pflücker, Juan Carlos

AU - Alpdogan, Önder

AU - Van Den Brink, Marcel R.M.

PY - 2006/9

Y1 - 2006/9

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/33748459567

U2 - 10.1038/nm1463

DO - 10.1038/nm1463

M3 - Article

C2 - 16936725

SN - 1078-8956

VL - 12

SP - 1039

EP - 1047

JO - Nature medicine

JF - Nature medicine

IS - 9

ER -