Missing KIR ligand in the host-versus-graft (HvG) direction is associated with second cell infusion in children with NK+ severe combined immunodeficiency (SCID) receiving hematopoietic stem cell transplantation.

Abstract

Abstract Functional NK cells are thought to mediate graft rejection in allogeneic hematopoietic stem cell transplantation (HSCT) for SCID. We hypothesized that missing KIR ligand (MKL) in the HvG direction mediates NK alloreactivity and is associated with increased rates of 2nd cell infusion requirement in NK+ SCID patients treated with HSCT. Data collected by the Pediatric Immune Deficiency Treatment Consortium (PIDTC) from 1982 to 2012 were reviewed. A total of 174 NK+ SCID transplant recipients were identified. Of these, HLA-B typing was available for 172 recipient/donor pairs, and HLA-C typing was available for 131 pairs. MKL was identified if Bw4, C1, or C2 inhibitory ligands were present in the recipient but not the donor. MKL was identified for Bw4 in 18 of 172 donors; for C1 in 11 of 131 donors; and for C2 in 9 of 131 donors. Combined Bw4, C1, and C2 MKL analysis was feasible for 129 transplants; 38 of these donors were missing one or two ligands in the HvG direction. Missing Bw4 ligand alone was not associated with decreased EFS or increased need for 2nd cell infusion. The incidence of 2nd infusion at 2 years was significantly lower for pairs without missing HLA-B or HLA-C ligands (19.3%, 95% CI 11.8% – 28.2%) compared to those with MKL (28.9%, 95% CI 15.5% – 43.9%; Gray’s p=0.04). EFS was 63.2% in patients with MKL (95% CI 45.9% – 76.3%) and 75.2% in those without MKL (95% CI 64.7% – 82.9%; Gray’s p=0.05). Missing KIR ligand in the HvG direction is associated with 2nd cell infusion in HSCT for NK+ SCID and may represent a mechanism for NK alloreactivity in this setting. Multivariate analysis and biologic studies of NK reactivity in SCID patients are needed to better understand the role of recipient NK cells in HSCT.