Human NK receptors: From the molecules to the therapy of high risk leukemias

Natural killer cells are important players of the innate immunity. In humans, they express HLA-class I-specific inhibitory receptors including the allotypic-specific KIR and various activating receptors. In most instances, in an autologous setting NK cells do not kill self cells. In contrast, in an allogeneic setting as the haploidentical hematopoietic stem cell transplantation to cure high risk leukemias, donor-derived NK cells may express inhibitory KIR that are not engaged by the HLA-class I alleles (KIR ligands) expressed by recipient cells. Such “alloreactive” NK cells may be responsible for the eradication of leukemia blasts escaping the preparative regimen, residual host dendritic cells and T lymphocytes, thus preventing leukemia relapse, GvHD and graft rejection, respectively. These NK-mediated effects result in a sharp improvement of the estimated 5 years survival.

► In haplo-HSCT, donor derived alloreactive NK cells are present when a “KIR/KIR-ligand mismatch” in GvH direction exists.
► Some anti-KIR mAb can discriminate between certain inhibitory and activating KIR.
► The size of the alloreactive NK subset can be estimated by immunofluorescence analysis with a combination of anti-KIR mAbs.
► The activating KIR2DS1 receptor recognizes C2 epitope and plays a substantial role in mediating alloreactivity.
► Alloreactive NK cells with anti-leukemia activity are conserved after transplantation and persist over time.