Impaired Survival after Unrelated Hematopoietic Stem Cell Transplantation from KIR2DS1 and KIR2DS2 Positive Donors.

The function of NK cells is regulated by a balance between signals transmitted via actvating and inhibitory receptors, including killer-immunoglobulin-like receptors (KIRs). Activating KIRs (KIR2DS1 and KIR2DS2) are also present on subsets of T cells, which has recently been demonstrated to play a role in several autoimmune conditions. The goal of this analysis was to determine the relationship between donor activating KIRs genotype and outcome after unrelated donor hematopoietic stem cell transplantation (URD-HSCT).

Seventy five patients (age 30y; range 14–57) with hematological malignancies treated with URD-HSCT in a single centre between 2000 and 2006 were included in the analysis. Donors were selected using DNA-high resolution typing for both HLA class I and II alleles. KIR2DS1 and KIR2DS2 genes were examined in all donors. Additionally, in 16 cases a subpopulation of KIR2DS2/DL2/DL3-positive T cells in peripheral blood was monitored in donors as well as in recipients for 6 months after transplantation.

The conditioning regimen was myeloablative and based on chemotherapy alone (n=56) or TBI (n=19). Graft-vs-host disease (GVHD) prophylaxis was uniform and consisted of cyclosporin, methotrexate, and pre-transplant anti-thymocyte globulin. Twenty-five % of donors were positive for both KIR2DS1 and KIR2DS2 gene, 18% were positive for KIR2DS1 only, 25% - for KIR2DS2 only, and 32% were negative for both KIR2DS1 and KIR2DS2. In univariate and multivariate analysis, including other potential risk factors, the presence of both KIR2DS1 and KIR2DS2 genes of the donor was associated with decreased overall survival (0% vs. 80%, RR 3.2, p=0,01) and disease free survival (0% vs. 64%, RR 2.5, p=0,03), compared to the remaining subgroups. Furthermore, simultanous KIR2DS1 and KIR2DS2 positivity resulted in increased GVHD-related mortality (70% vs. 8%, p=0.01) in univariate analysis (incidence of both acute and chronic GVHD contributed to this effect). KIR2DS2/DL2/DL3-positive T cells were detected in 3/16 donors before URD-HSCT and in all recipients between day +28 and +180 after URD-HSCT. KIR-positive T cells were particularily frequent (32%–42% of all CD3 cells) in three patients who developed acute GVHD, and for whom the donors were KIR2DS2-positive.

We conclude that the simultaneous presence of both KIR2DS1 and KIR2DS2 in the donor is associated with decreased survival following URD-HSCT. The mortality may result from higher incidence of lethal GVHD. Preliminary observation suggests the role of KIR-bearing T lymphocytes in this effect.