The Impact of NOD2/CARD15 and KIR Polymorphisms on the Incidence of Infectious Complications in allo-HSCT Recipients.
Authors: Holowiecka-Goral Aleksandra , Giebel Sebastian , Nowak Izabela , Czerw Tomasz , Wojnar Jerzy , Krawczyk-Kulis Malgorzata , Pietruszka Elzbieta , Markiewicz Miroslaw , Kusnierczyk Piotr , Wylezol Iwona , Prof Jerzy Holowiecki 
Published: October 2019

Abstract
BACKGROUND: Infections remain the major obstacle for successful allogeneic stem cell transplantation (alloHSCT). As specific immune response is profoundly suppressed during the first months after transplantation, the components of innate immunity are expected to play important role in anti-infectious responses. The goal of this prospective study was to evaluate the impact of NOD2/CARD15 gene single nucleotide polymorphisms (SNPs) as well as killer immunoglobulin-like receptors (KIRs), on the frequency of infectious complications after alloHSCT. NOD2/CARD15 protein is broadly expressed on epithelial cells, APCs and both B and T lymphocytes. KIRs regulate function of NK cells and a subset of T cells. Both were documented to take part in innate immunity.
PATIENTS: One-hundred-two consecutive patients with hematological malignancies, aged 32 (18-58)y, treated with alloHSCT from HLA-matched related (n=34) or matched unrelated donor (MUD) (n=68) were included. The conditioning regimen was myeloablative, GVHD prophylaxis consisted of CsA, Mtx, and, in case of MUD-HSCT, pre-transplant ATG.
METHODS: Donors and recipients were tested for SNP8,12,13 of the NOD2/CARD15 gene as well as 11 KIR genes. Study end-points included the incidence of G(+) and G(–) bacterial, fungal and clinically relevant viral infections. Infections were recognized based on clinical symptoms, microbial cultures and in case of CMV and EBV- PCR screening. Pneumonia was confirmed by radiograms. We analyzed separately infections occurring in the early, cytopenic phase and those occurring after engraftment.
RESULTS: Presence of KIR2DS3 gene in the donor protected against bacterial pharyngitis (46% vs. 66%, p=0.05), whereas KIR2DS1 in the donor was associated with decreased incidence of pneumonia (12% vs. 32%, p=0.02). Presence of KIR2DS1 in the donor correlated with lower rate of EBV infection (0% vs. 10,2%, p=0.04). SNP8 of the NOD2/CARD15 gene in the recipient tended to increase the risk of severe bacterial pharyngitis (100% vs. 57%, p=0.08) and neutropenic pneumonia (40% vs 7%; p=0.06). As in our previous report there was a lower incidence of urinary tracts infection in NOD2/CARD15 SNPs carriers (32% vs. 59%; p=0.04). As well, NOD2/CARD15 SNPs carriers tended to be protected against HSV infections (0% vs. 9,6%, p=0.08).
CONCLUSIONS: NOD2/CARD15 and KIR gene polymorphisms both influence the incidence of infections after alloHSCT. In particular, the effect of donor activating KIRs is generally protective while recipients with NOD2/CARD15 SNPs seems to more susceptible to respiratory tract infections. The genomic analysis may be useful for prediction of infectious complications. Pathogen-specific antibiotic and antiviral prophylaxis based on individual risk assessment may contribute to reduction of infection-related alloHSCT failures.