Objectives:  Killer immunoglobulin‐like receptors (KIRs) regulate function of natural killer (NK) cells and a subset of T cells. In this study, we prospectively evaluated the impact of donor and recipient activating KIR genes on outcome of allogeneic hematopoietic stem cell transplantation (alloHSCT) for patients with hematological malignancies.

Methods:  One‐hundred consecutive recipients of myeloablative transplantation and their donors were tested for KIR genotype as well as for immune reconstitution, including activating KIR expression on NK cells and T cells.

Results:  In a multivariate analysis, mismatches of particular activating KIRs such that the patient was negative and the donor was positive (P⁻D⁺) resulted in increased risk of acute (KIR2DS1) and chronic (KIR2DS3) graft‐versus‐host disease (GVHD) as well as relapse (KIR2DS5). KIR2DS1 incompatibility in the same direction in the presence of HLA‐C‐group 2 ligand in recipient was associated with reduced overall (risk ratio, RR = 3.01; P = 0.01) and disease‐free survival (RR = 2.92, P = 0.03). Activating mismatches in P⁻D⁺ direction resulted in decreased CD4⁺ : CD8⁺ T‐cell ratio up to 1 yr after alloHSCT, as a consequence of decreased CD3⁺CD4⁺ number within the first 100 d and increased CD3⁺CD8⁺ number in later time‐points. Among six evaluated patients, expression of activating KIRs on NK cells and T cells was particularly prominent for those developing intestinal GVHD.

Conclusion:  Our findings indicate that the presence of particular activating KIRs in donor with their absence in recipient enhances GVHD, which is not accompanied by graft‐versus‐leukemia effect. Evaluation of activating KIR genotype may allow optimization of both donor selection and transplantation procedure in order to avoid GVHD.