The presence of IFNG 3/3 genotype in the recipient associates with increased risk for Epstein–Barr virus reactivation after allogeneic haematopoietic stem cell transplantation

Abstract

Summary Recent studies have shown that interferon‐γ gene (IFNG) polymorphism constitutes a risk factor for acute and chronic graft‐versus‐host disease (GvHD) after allogeneic haematopoietic stem cell transplantation (HSCT). Patients with IFNG 3/3 have been found to be more prone to GvHD. This rather puzzling result, as 3/3 genotype is associated with a decreased IFN‐γ production, was investigated in the present study in the context of Epstein–Barr virus (EBV) reactivation. Microsatellite polymorphism (CA)n within the first intron of IFNG gene was assessed in 83 HSCT recipients and related to EBV load. Quantification of EBV copies was performed by a real‐time polymerase chain reaction in peripheral blood cells taken from the patients 2–3 months after HSCT. It was found, that patients having IFNG 3/3 genotype presented with a high number of EBV copies (over 10/105 blood cells) when compared with the recipients with other IFNG genotypes (10/14 vs. 17/69, P < 0·001). This association was independent of recipient's age, underlying disease, conditioning regimen, type of donor, source of stem cells or pretransplant donor and recipient EBV serological status. Thus IFNG 3/3 genotype, known to be associated with a decreased IFN‐γ production, appeared as a factor significantly contributing to the risk of EBV reactivation after allogeneic HSCT.

Natural killer–cell receptor polymorphisms and posttransplantation non-Hodgkin lymphoma

“…In contrast to published data, 10,11 no significantly increased risk for posttransplantation lymphoma development was apparent in heterozygous or homozygous carriers of the low IFN-producing A allele (HR 1.04, 95% CI 0.59-1.81-2.07, P ϭ .90 for heterozygous AT carriers; and HR 0.81, 95% CI 0.44-1.47, P ϭ .48 for homozygous AA carriers). No significant association of the IFN-␥ polymorphism on survival after lymphoma diagnosis was observed (5-year survival: 44%, 44%, and 49% for AA, AT, and TT allele carriers, respectively; P ϭ .83).…”

“…Furthermore, previous studies suggesting an impact of allelic polymorphisms in cytokine genes and HLA on the development of posttransplantation lymphoma could not be confirmed in our study. [10][11][12][13] We made, however, the intriguing observation that polymorphisms in receptors expressed by NK cells were significantly associated with survival after the diagnosis of lymphoma. Homozygous carriers of the high-affinity 158V allele of the FCGR3A (VV patients) showed a significantly improved 5-year survival rate compared with VF and FF patients (Figure 2A-B).…”

“…9 Cytokines are important mediators of both innate and adaptive immunity. Polymorphisms in genes encoding interferon-␥ (IFN-␥), 10,11 transforming growth factor-␤ (TGF-␤), 12,13 and interleukin-10 (IL-10) 12 have been suggested to play a role in the development of posttransplantation lymphoma.…”

Association of transforming growth factor- 1 gene polymorphism in the development of Epstein-Barr virus-related hematologic diseases

“…Interestingly, high EBV copy numbers in the blood, suggesting EBV reactivation in recipients of allogeneic hematopoietic stem cell transplantation, were found to be prevalent among patients with a certain IFN-γ genotype. 33 Although previous reports also showed that serum levels of EBV copy numbers may differentiate the clinical features of IM and HLH, 34,35 in our study, we were unable to demonstrate a difference in IFN-γ polymorphisms among patients with IM, HLH and CAEBV. Apart from cytokine gene polymorphisms, Zaitsu et al 36 previously identified a higher prevalence of the QPY haplotype of granzyme B in patients with EBV-HLH than in either patients with IM or healthy controls.…”

The presence of functional CCR5 and EBV reactivation after allogeneic haematopoietic stem cell transplantation

“…The evaluation of the EBV-specific DNA copies was performed using TaqMan chemistry with detection on Opticon 2 (MJ Research, Waltham, MA, USA) as described previously. 11 Considering that virus-infected cells constitute approximately 1 in 10 4 -10 5 memory B lymphocytes, 12 we assumed the detection threshold for viral reactivation of our method as 10 EBV-DNA copies/10 5 peripheral blood cells.…”