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GRAFT VERSUS LEUKEMIA EFFECTS OF NATURAL KILLER CELLS IN HLA MISMATCHED HEMATOPOIETIC TRANSPLANTATION.
Victoria Turner PhD , Wing Leung MD,PhD , Rekha Iyengar PhD , Annie Barbarin-Dorner , Martha Holladay , James Houston , Paul Conn MT, CHS , Thasia Leimig MD and Rupert Handgretinger MD, PhD . Memphis TN, St. Jude Children
s Research Hospital, 38105, Department of Hematology-Oncology and Memphis TN, St. Jude Childrens Research Hospital, 38105, Department of Pathology .
Hematopoietic stem cell transplantation for high risk leukemias using HLA-non-identical donors is associated with increased risk of graft rejection and graft-versus-host disease compared with the use of matched sibling donors. Despite these disadvantages, transplantation using an HLA-nonidentical donor provides an opportunity for study of donor natural killer (NK) cell antileukemia effects. The characteristics of donor NK cells, recipient leukemia cells and the cytokine environment that predict the antileukemia effects of allogeneic NK cells were studied both clinically and in the laboratory.
Twenty-two pediatric patients with high-risk hematologic malignancies who received a stem cell transplant from a one haplotype matched family member were included in this study. Monitoring of the number of killer cell immunoglobulin-like receptors (KIRs), the repertoire of KIRs and the cytotoxicity of the NK cells towards K562 cells was performed on blood samples obtained from the donor before G-CSF mobilization and from the patient at intervals after transplantation.
We found that the risk of relapse in this patient group was best predicted by the presence of KIRs on the donor's NK cells and the absence of corresponding KIR ligands in the recipient's HLA repertoire (a receptor-ligand model). In laboratory studies human NK cell cytotoxicity toward human leukemia cells with 11q23 chromosomal rearrangement increased with the number of receptor ligand mismatched pairs or with prestimulation with IL-12 and IL-18. These findings provide new insights into the determinants of antileukemia effects of allogeneic NK cells and therapeutic strategies.