Publikationsdatum:
2013-11-15
Beschreibung:
The interactions of variable killer-cell immunoglobulin-like receptors (KIR) with polymorphic HLA class I ligands form an extraordinary immunogenetic system that influences NK cell biology, human susceptibility to disease, and the outcome of hematopoietic cell transplantation (HCT). The independent segregation of KIR and HLA genes, on chromosomes 19 and 6, respectively, increases the functional diversity of the system. Previously we found that patients undergoing unrelated donor (URD) HCT for acute myelogenous leukemia (AML) had superior leukemia-free survival (LFS) and less relapse with KIR B/x genotype donors than with KIR A/A donors. At higher resolution we identified the significant protective effect of donors with “Better” (≥2 B-motifs) and “Best” (≥2 B-motifs with Cen-B/B) KIR gene content compared to “Neutral” (0 or 1 B-motif) donors, supporting a donor selection strategy that is being tested in an ongoing prospective multicenter trial. The heterogeneity of transplant cohorts (preparative regimens, graft source, T cell depletion, HLA match status) has complicated the evaluation of the mechanisms underlying the beneficial effects mediated by NK cells. We analyzed 2404 URD transplants for AML and found a strong interaction between the protection associated with KIR B donors and the conditioning intensity (myeloablative [MA] vs. reduced intensity [RI]) for relapse (p=0.0002) and LFS (p=0.043). “Better” and “Best” donors were associated with significantly enhanced LFS and relapse protection in MA transplants, but appears to have an opposite effect in RI transplants. Therefore, to further explore the mechanisms of NK cell mediated protection, we focused our evaluation on a cohort of 1007 MA, T cell replete URD transplants for AML. We evaluated the interaction of donor KIR with recipient and donor HLA C1, C2 and Bw4. Superior LFS (RR 0.78 [0.66-0.92], p=0.0024) and relapse protection (RR 0.50 [0.38-0.67], p
Print ISSN:
0006-4971
Digitale ISSN:
1528-0020
Thema:
Biologie
,
Medizin