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Copy Number Variation in Donor KIR Genes and Motifs Titrates Natural Killer (NK) Cells' Functional Response to EBV Infections and Influences the Risk of Developing Post-Transplant Lymphoproliferative Disease (PTLD) after Allogeneic HCT
Friday, March 4, 2016: 1:45 PM
Salon D (JW Marriott)
Rehan M. Faridi, PhD, , , , , ,
Rationale: Uncontrolled reactivation of Epstein-Barr virus (EBV) leading to post-transplant lymphoproliferative disorder (PTLD) is one of the major complications after T-cell depleted allogeneic hematopoietic cell transplantation (HCT). Here, we set out to determine whether and how killer Ig-like receptor (KIR)-regulated NK cells influence the development of EBV-PTLD after HCT.

Methods: KIR gene repertoires of 356 HLA matched donor-recipient pairs of first alloHCT and 50 healthy donors were determined and characterized through Next Generation Sequencing of the KIR locus on the Illumina MiSeq platform. PBMNCs from KIR typed healthy volunteers were stimulated with EBV transformed target cells to enumerate NK cell response to EBV (degranulation) and/or IFNγ production) as a function of KIR gene content and motifs' distribution using a multicolor flow cytometry based assay. Effect of KIR gene profile on development of PTLD was analyzed using binomial competing risks regression statistics. Distribution of NK cell functional response across various KIR characterized groups was analyzed using Mann Whitney U statistics.

Results: Donor telomeric A motifs (tA01, KIR3DL1+veKIR2DS4+ve; KIR3DS1/2DS1+/ve), strongly protected against PTLD (p=0.0001, SHR=0.17) with at least one copy required for a significant protective effect. Copy number analysis of tA01 gene contents yielded similar associations. The number of EBV induced functional NK cell subsets were significantly higher in individuals with than without KIR genotypes containing tA01 motifs and was found to be increasing with an increasing number of tA01 copies. 

Conclusions: NK cell responsiveness, a function of KIR gene repertoire has a profound effect on the development of PTLD. Appropriately characterized KIR gene profile based identification of HCT recipients at high risk of developing PTLD will enable closer monitoring of EBV DNAemia and facilitate prompt therapy.