Killer Immunoglobulin-like Receptor (KIR) Genotypes Influences NK Cells' Response to Epstein - Barr Virus and the Risk of Developing Post-Transplant Lymphoproliferative Disease (PTLD) after Allogeneic HCT

BACKGROUND: A compromised immune system of Hematopoietic Cell Transplantation (HCT) recipients early after transplantation renders them vulnerable to a heightened risk of reactivation of otherwise latent viral infections. Uncontrolled reactivation of Epstein-Barr virus (EBV) is one of such events that can culminate into post-transplant lymphoproliferative disorder (PTLD), a complication associated with high risk of mortality. Recovering within weeks after transplantation and being first in the line of defense against viral infections, natural killer (NK) cells are deemed important in the immune surveillance against the reactivation and complications of EBV. Their role however remains elusive. The complexity of NK cell response is a function of a series of activating and inhibitory cell surface receptors known as Killer Immunoglobulin-like Receptors (KIR), which sense perturbations in HLA expression after viral transformation of the target cell. Here, we set out to determine whether and how KIR gene repertoire of HCT donors and/or recipients influences the development of PTLD after allo-HCT.

STUDY DESIGN:

KIR gene repertoires of 356 HLA-matched donor-recipient pairs of first allo-HCT and 50 healthy individuals were determined by Luminex based rSSO method. The KIR genotypes were classified into AA and B/x genotypes. Presence or absence of one or more haplotype-B defining KIR genes further identified genotypes for centromeric (Cen) and telomeric (Tel) parts of the KIR locus. PBMNCs from 50 KIR-genotyped healthy volunteers were stimulated with EBV-transformed cells to enumerate EBV-induced NK cell response (degranulation and/or IFNγ production) as a function of KIR gene distribution using a multicolor flow cytometry-based assay. Effect of KIR gene repertoires on development of PTLD was analyzed using binomial competing risks regression statistics.

RESULTS:

Donor telomeric A motifs (Tel-A, KIR3DL1^+veKIR2DS4^+ve; KIR3DS1/2DS1^+/-ve), strongly protected against PTLD (p=0.0002, SHR=0.21; Figure 1A). The protection of donor Tel-A motifs against PTLD shows a dose dependent effect as cumulative incidence of PTLD in HCT recipients receiving graft from donors carrying two Tel-A motifs, one Tel-A motif and no Tel-A motif was 6%, 11% and 19% respectively. Further, the numbers of EBV induced functional NK cell subsets were significantly higher in individuals with than without KIR genotypes containing Tel-A motifs (Figure 1B).

CONCLUSIONS:

NK cell responsiveness, a function of KIR gene repertoire has a profound effect on the development of PTLD. KIR genotype based identification of HCT donor-recipient pairs at high risk of developing PTLD will enable closer monitoring of EBV DNAemia and facilitate prompt therapy.

 [A]

[B]

Figure 1: Influence of KIR Telomeric-A (Tel-A) motifs on [A] the development of PTLD after allogeneic HCT; and [B] NK cell response against EBV transformed cells