KIR/HLA-I Mismatching Predicts Risk of Relapse in Pediatric Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for a variety of hematologic malignancies. Recent studies have indicated the presence of donor-derived alloreactive NK cells as an additional factor influencing transplantation outcome, NK cells being regulated by signals delivered from multiple activating and inhibitory receptors. In the allogeneic HSCT setting, several studies considered donor-recipient HLA-I mismatch as the basis for NK alloreactivity. The implication of the KIR ligand incompatibility model is that donor's NK cells exhibit the relevant inhibitory KIR for the self HLA-I ligands. It is known, however, that the KIR genes and the HLA genes segregate independently of each other in normal mendelian fashion. This allows the possibility that individuals lack HLA ligands for their KIR receptors and indicates that NK cells alloreactivity can occur also in HLA-matched or HLA-identical transplants. Recent investigations suggest that relapse and KIR-driven alloreactivity in the transplantation setting might be better predicted if the donor KIR genotype is considered in addition to the HLA genotype of the recipient. The aim of this study was to investigate at genetic level the prognostic impact of recipient HLA-I lacking for donor KIR on allotransplanted patients outcome. We analyzed donors KIR genotype and HLA genotype of 60 pediatric patients who received related (n.15) or unrelated (n.45) transplantation. When patients were grouped on the basis of the KIR gene type involved in the KIR/HLA-I mismatch, we did not observe any relapse in the group of patients characterized by mismatches involving only inhibitory KIR. On the contrary, all relapses were observed in patients showing at least one activating gene involved in the mismatch (p<0.05). Although the biological mechanism accounting for this putative genetic rule is still to be clarified, we suggest that a careful survey of KIR/HLA-I mismatching should be taken into account in the selection of donor in related and unrelated HSCT.