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
Department of Medicine, Zuckerman Research Center 1404, Mailbox 111, New York, New York 10021, USA.
Nat Med. 2006 Sep;12(9):1039-47. doi: 10.1038/nm1463. Epub 2006 Aug 27.
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.
异基因造血干细胞移植（HSCT）后的免疫无能尤其影响T细胞谱系，并与感染、移植物失败和恶性复发风险增加相关。为了产生大量用于过继性治疗的T细胞前体，我们在体外将小鼠造血干细胞（HSC）培养于表达Notch-1配体Delta样-1的OP9小鼠基质细胞（OP9-DL1）上。我们将这些细胞与去除T细胞的小鼠骨髓或纯化的HSC一起注入接受致死性照射的异基因受体，并确定它们对移植后T细胞重建的影响。接受OP9-DL1来源的T细胞前体的受体胸腺细胞增多，供体T细胞嵌合率显著提高（与仅接受骨髓或HSC的受体相比）。OP9-DL1来源的T细胞前体产生具有正常T细胞抗原受体库、细胞因子分泌和对抗原增殖反应的宿主耐受CD4+和CD8+群体。给予OP9-DL1来源的T细胞前体可增强对单核细胞增生李斯特菌感染的抵抗力，并介导显著的移植物抗肿瘤（GVT）活性，但不引起移植物抗宿主病（GVHD）。我们得出结论，过继性转移OP9-DL1来源的T细胞前体可显著增强移植后的T细胞重建，产生GVT活性而无GVHD。
