Selection of allogeneic hematopoietic cell transplant donors to optimize natural killer cell alloreactivity

Abstract

Natural killer (NK) cells are potent mediators of the graft versus leukemia phenomenon critical to the success of allogeneic hematopoietic cell transplantation. Central to calibrating NK effector function via their interaction with class I human leukocyte antigens are the numerous inhibitory killer Ig-like receptors (KIR). The KIR receptors are encoded by a family of polymorphic genes, whose expression is largely stochastic and uninfluenced by human leukocyte antigens genotype. These features provide the opportunity to select hematopoietic cell donors with favorable KIR genotypes that confer enhanced protection from relapse via NK-mediated graft versus leukemia. Over the last 2 decades, a large body of work has emerged examining the use of KIR genotyping to stratify potential donors based on anticipated NK alloreactivity. Overall, these results support KIR-based donor selection for patients undergoing allogeneic hematopoietic cell transplantation for a diagnosis of acute myelogenous leukemia. Despite this, the underlying factors that control NK cell responsiveness are not completely understood, and opportunities remain to refine donor selection using NK cell receptor genotyping. In this review, we will summarize the relevant findings with respect to KIR genotyping as a selection parameter for allogeneic hematopoietic cell donors and address practical considerations with respect to KIR-based selection of donors for patients with myeloid neoplasia.

Keywords: Acute myeloid leukemia; Allogeneic hematopoietic cell transplantation; HLA; KIR; Natural Killer Cells.

Figure 1:

Inhibitory and activating killer Ig-like receptors found to influence allo HCT outcomes and their cognate HLA ligands. KIR3DL1 receptors interact with HLA-B and HLA-A allotypes exhibiting the Bw4 epitope. KIR2DL1 interacts with HLA-C2 allotypes. KIR2DL2 and KIR2DL3 interact with HLA-C1 allotypes. KIR2DS1 interacts with HLA-C2 allotypes and KIR3DS1 interacts with HLA-F open conformers.[72]

Figure 2:

Donor KIR3DL1 and recipient HLA-Bw4 subtype combinations, their effects on NK function, and their associations with outcomes following allo HCT for AML.