Natural Killer Cells and Hematopoietic Cell Transplantation
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P226-227
2025-12-15
55
In greater than 95% of cases of patients undergoing hematopoietic cell transplantation (HCT) for leukemia, haploidentical individuals are available to act as donors of bone marrow or peripheral blood stem cells. Mismatches between donor KIR and recipient HLA create the potential for donor NK cell reactivity against leukemic cells as well as normal tissues within the recipient. Donor NK cells do not mediate significant graft-versus-host disease (GVHD) in the setting of HCT, likely due to the absence of significant activating signals being delivered by normal cells. In contrast, an effective NK cell-mediated graft-versus-leukemia (GVL) effect is possible when KIR on donor NK cells fail to encounter cognate HLA ligands on residual leukemic cells within the recipient. In 2002, Ruggeri et al. were the first to establish that the risk of relapse in acute myeloid leukemia (AML) following haploidentical HCT was markedly lowered when NK cell based alloreactivity was present based on KIR-HLA mismatch in the GVL direction and the existence of alloreactive NK cell clones with the ability to lyse recipient leukemic cells. These results were confirmed in a larger study of 112 AML patients where transplantation in the setting of complete remission with a NK cell alloreactive donor was associated with a significantly reduced relapse rate of 3% compared to 47%. Similar results were obtained for patients transplanted in relapse (6% vs. 34%). Variable results have been obtained in subsequent studies that reported the outcomes of KIR mismatched HCT that utilized various donor sources, such as umbilical cord blood, and sibling or unrelated donors. The precise mechanisms involved in the generation of an NK vs. leukemia effect are complex given the independent inheritance of KIR and HLA genes, and the large variety of KIR interactions that can occur post-transplant. Also, the strength of this effect can be influenced by the type of preparative chemotherapeutic regimen, graft dose, T-cell depletion strategy, and post-transplant conditioning regimens. Since a KIR mismatch requires the absence of a host KIR ligand that is present in the donor, NK alloreactivity is taking place in the setting of a major HLA-class I mismatch, and thus the extent of graft T-cell depletion becomes important. Indeed, the presence of T cells in the graft can adversely impact NK cell reconstitution. Given the diversity of KIR expression and the existence of multiple alleles with variable binding capacity and levels of expression, it is recommended that KIR genotyping for HCT be accompanied by phenotyping via cytometric methods or quantitative PCR with an evaluation of the ability of donor NK cells to kill allogeneic recipient targets, such as PHA lymphoblasts and/or leukemia cells. In adults, the beneficial effects of NK cell GVL activity are most prominent for AML rather than ALL; however the event-free survival post-HCT of pediatric ALL patients was significantly better for KIR B haplotype donors than for A haplotypes. The association of the KIR B haplotype with improved survival is also seen in the setting of unrelated donor HCT for AML and non-Hodgkin lymphoma. Activating KIR can also play a role in HCT outcomes, as evidenced by a significant reduction in infectious complications and non-relapse mortality when there was a GVL effect driven by the activating KIR2DS1 and KIR3DS1. Finally, in a study of over 600 patients receiving reduced intensity HCT, CMV reactivation was associated with improved disease-free survival and the expansion of a CMV-responsive population of NK cells with reduced expression of CD56 and elevated surface levels of CD57 and NKG2C.
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