Donor activating KIR3DS1 is associated with decreased acute GVHD in unrelated allogeneic hematopoietic stem cell transplantation.

The natural killer cell receptor KIR3DS1 is associated with improved outcome in malignancies, infections, and autoimmune diseases, but data for the impact of KIR3DS1 in HSCT are inconsistent. Using genomic DNA from the National Marrow Donor Program, we performed donor KIR genotyping for 1087 patients who received an unrelated hematopoietic stem cell transplantation. A total of 33% of donors were KIR3DS1(+). Compared with KIR3DS1(-) donors, donor KIR3DS1 was associated with lower-grade II-IV acute graft-versus-host disease (GVHD; odds ratio = 0.71; 95% confidence interval, 0.55-0.92; P = .009), but not with relapse (hazard ratio = 0.97; 95% confidence interval, 0.73-1.29; P = .82). Furthermore, grade II-IV acute GVHD, overall mortality, and transplantation-related mortality all decreased as the number of copies of donor KIR3DS1 increased (P = .007, P = .03, and P = .02, respectively), with the lowest failure rate occurring among patients homozygous for donor KIR3DS1. Selection of donors with KIR3DS1 may decrease acute GVHD without compromising relapse-free survival, separating the graft-versus-tumor effect from unwanted GVHD.

Breaking tolerance to self, circulating natural killer cells expressing inhibitory KIR for non-self HLA exhibit effector function after T cell-depleted allogeneic hematopoietic cell transplantation.

Alloreactive natural killer (NK) cells are an important influence on hematopoietic stem cell transplantation (HSCT) outcome. In HLA-mismatched HSCT, alloreactivity occurs when licensed donor NK cells expressing inhibitory killer Ig-like receptors (KIR) for donor MHC class I ligands recognize the lack of the class I ligands in the mismatched recipient ("missing self"). Studies in HLA-matched HSCT, however, have also demonstrated improved outcome in patients lacking class I ligands for donor inhibitory KIR ("missing ligand"), indicating that classically nonlicensed donor NK cells expressing KIR for non-self MHC class I ligands may exhibit functional competence in HSCT. We examined NK function in 16 recipients of T cell-depleted allografts from HLA-identical or KIR-ligand matched donors after myeloablative therapy. After HSCT, nonlicensed NK cells expressing inhibitory KIR for non-self class I exhibit robust intracellular IFN-gamma and cytotoxic response to target cells lacking cognate ligand, gradually becoming tolerized to self by day 100. These findings could not be correlated with cytokine environment or phenotypic markers of NK development, nor could they be attributed to non-KIR receptors such as CD94/NKG2A. These findings confirm that NK alloreactivity can occur in HLA-matched HSCT, where tolerance to self is either acquired by the stem cell-derived NK cell after exiting the bone marrow or where tolerance to self can be temporarily overcome.