Effect of Donor KIR2DL1 Allelic Polymorphism on the Outcome of Pediatric Allogeneic Hematopoietic Stem-Cell Transplantation

Abstract

A B S T R A C T PurposeKiller-cell immunoglobulin-like receptors (KIRs) that regulate natural-killer cells are highly polymorphic. Some KIR2DL1 alleles encode receptors that have stronger signaling function than others. We tested the hypothesis that the clinical outcomes of allogeneic hematopoietic stem-cell transplantation (HSCT) could be affected by donor KIR2DL1 polymorphism. Patients and MethodsAll 313 pediatric patients received allogeneic HSCT at a single institution. Donor KIR2DL1 functional allele typing was retrospectively performed using single nucleotide polymorphism assay. ResultsPatients who received a donor graft containing the functionally stronger KIR2DL1 allele with arginine at amino acid position 245 (KIR2DL1-R 245 ) had better survival (P ϭ .0004) and lower cumulative incidence of disease progression (P ϭ .001) than those patients who received a donor graft that contained only the functionally weaker KIR2DL1 allele with cysteine at the same position (KIR2DL1-C 245 ). The effect of KIR2DL1 allelic polymorphism was similar in patients with acute myeloid leukemia or acute lymphoblastic leukemia among all allele groups (P Ն .71). Patients who received a KIR2DL1-R 245 -positive graft with HLA-C receptor-ligand mismatch had the best survival (P ϭ .00003) and lowest risk of leukemia progression (P ϭ .0005) compared with those who received a KIR2DL1-C 245 homozygous graft. ConclusionDonor KIR2DL1 allelic polymorphism affects recipient outcomes after allogeneic HSCT. These findings have substantial implications for prognostication and donor selection.

γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes

“…[1][2][3][4] The therapeutic effect of haplo-HSCT is largely dependent on the graft-versus-leukemia effect exerted by natural killer (NK) cells, which contribute to eradicate leukemia cells surviving the preparative regimen. [5][6][7][8] Unfortunately, in the haplo-HSCT setting performed through the infusion of positively selected CD34…”

KIR ligand C2 is associated with increased susceptibility to childhood ALL and confers an elevated risk for late relapse

“…Analysis of allele-specific expression in NK cells of healthy controls by flow cytometry revealed a significantly decreased expression of KIR2DL1*004, an allele that was previously shown to have impaired signaltransduction capacity (supplemental Table 3). 16 However, PCR-SSP subtyping for the most common alleles (covering .98% of KIR2DL1 allotypes in whites) 15 including KIR2DL1*004 did not reveal significant differences (Table 1 and supplemental Table 2). Similarly, no significant changes in frequency and CNV were found for the C2-specific stimulatory KIR2DS1 (Table 1 and supplemental Table 2).…”

Infusions of Allogeneic Natural Killer Cells as Cancer Therapy

“…Notably, this assay requires less than 0.1 mg of DNA and can be performed within 1 day. Using this assay, investigations showed that patients who received a donor graft containing the stronger KIR allele had fewer relapses, better survival, and less transplant-related mortality (29). These effects were observed regardless of primary disease [acute myelogenous leukemia (AML) vs.…”