Journal
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
Volume 7, Issue 10, Pages 532-542Publisher
CARDEN JENNINGS PUBL CO LTD
DOI: 10.1016/S1083-8791(01)70014-6
Keywords
hematopoietic cell transplantation; expanded CD8(+) NK-T cells; lymphoma; graft-versus-tumor effect; GVHD; hematopoietic stem cell; mice
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Funding
- NATIONAL CANCER INSTITUTE [P01CA049605] Funding Source: NIH RePORTER
- NCI NIH HHS [CA49605, CA8006-01] Funding Source: Medline
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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-gamma, 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-beating 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.
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