Epstein‐Barr virus infections are strongly dependent on activating and inhibitory KIR‐HLA pairs after T‐cell replate unrelated hematopoietic stem cell transplantation, the principles, and method of pairing analysis

Abstract

Viral infections are the main cause of increased morbidity and mortality among recipients in allogeneic hematopoietic stem cell transplantation (HSCT). Natural killer (NK) cells fight virally infected cells provided directional activation of cytotoxicity. In this study, we analyzed the role of receptor‐ligand pairs that include inhibitory or activating killer cell immunoglobulin‐like receptors (KIRs) with their HLA class I ligands in the course of viral infections. The paper also presents an algorithm that allows performing automated inhibitory (i) KIR:HLA pairing and rechecking in the clinical setting. The obtained results indicate a significant adverse roles of reduced number of iKIR:HLA pairs (40% vs 9%; odds ratio [OR] = 6.67; P = .0057; 95% confidence interval [CI] 1.74‐25.62) and the presence of activating KIR:HLA pairs (15% vs 5%, OR = 3.58, P = .028, 95% CI 1.19‐10.73) in EBV infections post HSCT.

Decreased iKIR-HLA C Pair Confers Worse Clinical Outcomes for Patients With Myeloid Disease Receiving Antithymocyte Globulin-Based Haploidentical Hematopoietic Stem Cell Transplantation

“…Since the HLA environment may be altered after transplantation (from donor to recipient), the variations in iKIR-HLA pairs could be divided into three groups (decreased group: cognate iKIR-HLA pairs present in donor but absent in recipient; unchanged group: cognate iKIR-HLA pairs present both in donor and recipient; increased group: cognate iKIR-HLA pairs present in recipient but absent in donor). Consistent results from their studies showed that decreased iKIR-HLA pairs post transplantation correlated with a higher risk of relapse and inferior overall survival (OS), indicating that poor NK cell education resulted in weaker graft versus leukemia (GVL) effects ( 20 – 22 ). To further investigate the effects of these KIR interactions on transplant outcomes, we designed a retrospective study to evaluate a cohort of 246 patients, and evaluated our clinical outcomes using the iKIR-HLA model, the receptor-ligand model and KIR gene content.…”

“…Previously, Nowak et al. proposed the iKIR-HLA model that could be used to predict transplant outcomes ( 20 – 22 ). Among the multiple interactions between the iKIRs and HLA ligands, we identified that only decreased iKIR-HLA C pair post transplantation was a negative indicator for relapse and survival, especially in patients with myeloid disease.…”

Killer Cell Immunoglobulin-Like Receptor Haplotype B Modulates Susceptibility to EBV-Associated Classic Hodgkin Lymphoma

“…Thus, NK cells in KIR haplotype B subgroup carriers are more easily activated upon viral infection due to presence of multiple activating KIR genes that for example can recognize virally induced cellular stress by interacting with open conformers of HLA-F (21). Previous studies showed a role of NK cells in controlling primary EBV infection (25,26), and demonstrated a more effective response against EBV infected cells in KIR haplotype B carriers (Figure 1). A few studies have investigated associations of KIR genes with cHL but little attention has been paid to KIR associations in EBV stratified cHL subgroups (27)(28)(29).…”

“…Each NK cell can express different subsets of the KIR genes resulting in a highly heterogeneous mix of NK cells within each individual (20). Multiple KIR haplotype B-specific activating genes are known to play a protective role in diseases caused by viral infection by the human immunodeficiency virus (HIV), Human Cytomegalovirus (HCMV), hepatitis C virus (HCV) or EBV (21)(22)(23)(24)(25)(26). Thus, NK cells in KIR haplotype B subgroup carriers are more easily activated upon viral infection due to presence of multiple activating KIR genes that for example can recognize virally induced cellular stress by interacting with open conformers of HLA-F (21).…”

Influence of KIR and NK Cell Reconstitution in the Outcomes of Hematopoietic Stem Cell Transplantation

“…Recently, the Nowak team proposed that inhibitory KIR (iKIR)-HLA pairs could predict the post-HSCT NK cell education status, i.e., donors presenting cognate HLA for donor iKIR and recipients lacking it predict a downward education level; in contrast, recipients presenting cognate HLA for donor iKIR and donors lacking it predict an upward education level. Those authors found that the decrease in iKIR-HLA pairs posttransplantation is associated with a higher relapse and poorer survival (160)(161)(162), indicating that reconstituted NK cells acquire better functions after interaction with more cognate HLA class I ligands in recipients. Zhao et al also observed that, when the donors and recipients expressed three major HLA ligands (HLA-C1, C2, Bw4), patients with AML and myelodysplastic syndrome (MDS) experienced the lowest relapse rate, and NK cells expressing three inhibitory receptors exhibited the greatest cytotoxicity and cytokine responsiveness against K562 targets (163).…”