42-OR

Abstract

Uncontrolled reactivation of Epstein-Barr virus (EBV) leading to post-transplant lymphoproliferative disorder (PTLD) is one of the major complications of T-cell depleted HCT associated with a high risk of mortality. Given the fact that NK cells are first in line of defense against viral infections, and are among the earliest to reconstitute after HCT, they are deemed important in the immunopathogenesis of EBV complications. Their exact role in this process, 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. 92 HCT donor-recipient pairs and 50 healthy individuals were KIR genotyped by Luminex-based rSSO method. The KIR repertoires were classified into AA and Bx genotypes as well as into centromeric and telomeric linkage groups. PBMNCs from healthy volunteers were stimulated with EBV lysate to enumerate EBV-induced NK cell response (degranulation and/or IFN γ production). Donor Centromeric KIR linkage group (2DS2-2DL2-2DS3-2DL5B) was strongly associated with the incidence of PTLD (p = 0.01, OR = 7.1). Further, the number of EBV induced IFNg producing and/or degranulating NK cells were significantly lower in individuals with than without centromeric KIR linkage group. NK cell responsiveness, a function of KIR gene repertoire has a profound effect on the development of PTLD. KIR genotype based identification of HCT recipients at high risk of developing PTLD will enable closer monitoring of EBV DNAemia and facilitate prompt therapy.