Decreased Soluble Human Leukocyte Antigen E Levels in Patients After Allogeneic Hematopoietic Stem Cell Transplantation Are Associated With Severe Acute and Extended Chronic Graft-versus-Host Disease and Inferior Overall Survival

Abstract

HLA-E is a member of the non-classical HLA molecules and by interaction with activating or inhibitory receptors of NK and T cells, HLA-E can lead to immune activation or suppression context-dependently. Recently, the non-classical HLA molecules gain more attention in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). Most studies so far have focused on the two most frequent genotypes (HLA-E * 01:01 and HLA-E * 01:03) and investigated their potential association with clinical endpoints of HSCT, like graft-versus-host disease (GvHD), relapse, and overall survival (OS). However, these studies have produced inconsistent results regarding the role of HLA-E and the clinical endpoints after HSCT. We therefore here investigate the amount of soluble HLA-E (sHLA-E) in patients following HSCT and relate this to the clinical endpoints after HSCT. In univariate analysis, we observe a significant association of reduced levels of sHLA-E with severe acute GvHD, extended chronic GvHD and with inferior OS. Using receiver operating characteristic analyses specific thresholds obtained 1, 2, or 3 month(s) after HSCT were identified being indicative for severe acute GvHD, extended chronic GvHD, or inferior OS. In subgroup analyses, this effect can be confirmed in patients not treated with ATG, but is derogated in ATG-treated patients. Notably, we could not detect any association of the course of sHLA-E levels post-HSCT with the three most frequent HLA-E genotypes (HLA-E * 01:03/ * 01:03, HLA-E * 01:01/ * 01:01, HLA-E * 01:01/ * 01:03). However, with regard to 5-year-OS there was an association of HLA-E * 01:03 homozygosity with inferior OS. Taking ATG-treatment, recipient and donor HLA-E genotypes into consideration among other well-known risk factors, the sHLA-E status was found as an independent predictor for the development of extended cGvHD Kordelas et al. Soluble HLA-E and HSCT and inferior OS following HSCT irrespective of the sHLA-E thresholds. These findings shed some light on the possible impact of reduced sHLA-E levels after HSCT on GvHD and OS. Thus, sHLA-E appears to be a novel promising candidate for the prediction of clinical HSCT outcome with regards to extended cGvHD and OS.

Non‐KIR NK cell receptors: Role in transplantation of allogeneic haematopoietic stem cells

“… a In this study also a significant association of reduced plasma soluble HLA‐E levels with severe aGvHD, extended cGvHD, and with inferior OS was reported (Kordelas et al., 2020). …”

HLA‐E diversity unfolded: Identification and characterization of 170 novel HLA‐E alleles

“…Here, a HLA‐E*01:03 homozygous donor led to a decrease in disease‐free survival and an increase in transplantation‐related mortality in patients who received T cell replete transplants 7 . However, contradictions to other studies exist which might be caused by smaller sample sizes, different treatment regimens and other factors not yet known 7,8,10,13 . To our knowledge, the potential impact of alleles beside this dimorphism has never been studied.…”

Extended loci histocompatibility matching in HSCT—Going beyond classical HLA

“…Overall survival (OS) was mostly reported to improve from recipient or donor HLA‐E*01:03 homozygous genotype, but only in HLA‐E matched (89%–100%) transplant pairs (Danzer et al., 2009; Ludajic et al., 2009; Tamouza et al., 2006). Only one study found detrimental effects of HLA‐E*01:03 homozygous transplants on OS (Kordelas et al., 2019). However, this was also the only study to include HLA‐matched and mismatched transplant pairs.…”

“…However, this was also the only study to include HLA‐matched and mismatched transplant pairs. As for the effect of HLA‐E matching, one study reported decreased OS upon HLA‐E matching (Tsamadou et al., 2017), whereas other publications do not report any effect of HLA‐E matching on HSCT outcome (Furst et al., 2012; Kordelas et al., 2019; Tsamadou et al., 2019). In most studies, the analysis for disease‐free survival (DFS) revealed no HLA‐E‐related effect on this transplantation end point.…”

“…Kordelas et al. (2019) addressed these controversial results in a small single‐centre study with their hypothesis, that the measurable amount of soluble HLA‐E (sHLA‐E) post‐HSCT has a more substantial effect on immune modulation than HLA‐E genotype or matching, respectively. Whereas cell surface expression of HLA‐E*01:01 is lower when compared to HLA‐E*01:03, no such differences were found regarding sHLA‐E levels for HLA‐E*01:01 or HLA‐E*01:03 molecules, respectively, underlying their hypothesis.…”