Engineering hematopoietic grafts: purified allogeneic hematopoietic stem cells plus expanded CD8+ NK-T cells in the treatment of lymphoma.
A major benefit of allogeneic hematopoietic cell transplantation (HCT) in the treatment of malignancies is the graft-versus-tumor (GVT) effect conferred by lymphocytes contained within the graft. However, lymphocytes can also induce the potentially lethal complication of graft-versus-host disease (GVHD). We have previously reported a method of generating large numbers of ex vivo activated and expanded T cells with antitumor activity after culture with interferon-y, cross-linking antibodies to CD3, and interleukin-2. Murine splenocytes expanded under these conditions are a heterogeneous population of which approximately 20% to 60% of cells express natural killer (NK)-cell markers (NK1.1 and DX5) and display major histocompatibility complex (MHC)-unrestricted antitumor activity. Here we demonstrate the in vivo antitumor activity of this population of expanded CD8+ NK-T cells when transplanted across MHC barriers into tumor-bearing hosts. In cotransfer studies with purified allogeneic hematopoietic stem cells, expanded CD8+ NK-T cells confer GVT activity with minimal to no GVHD. In vitro studies show that, although expanded NK-T cells lyse normal allogeneic bone marrow cells, they preferentially mediate cytolysis against tumor targets. These cells persist in the peripheral circulation of host animals for at least 3 weeks posttransfer. GVT activity is dependent on perforin, but not on Fas-ligand. We conclude that expanded CD8+ NK-T cells may serve as a valuable adjuvant population for allogeneic HCT because they mediate GVT effects with minimal GVHD.
Verneris
M R
MR
Department of Medicine, Stanford University School of Medicine, California 94305, USA.
Ito
M
M
Baker
J
J
Arshi
A
A
Negrin
R S
RS
Shizuru
J A
JA
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D053222:Fas Ligand Protein; D020350:Graft vs Tumor Effect / Q000276:immunology*; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D008223:Lymphoma / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D033581:Stem Cell Transplantation / Q000379:methods*; D014184:Transplantation, Homologous / Q000276:immunology
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin