Significance of HLA-E and its two NKG2 receptors in development of complications after allogeneic transplantation of hematopoietic stem cells.

Transplantation of hematopoietic stem cells (HSCT) is a procedure commonly used in treatment of various haematological disorders which is associated with significantly improved survival rates. However, one of its drawbacks is the possibility of development of post-transplant complications, including acute and chronic graft-versus-host disease (GvHD) or CMV infection. Various studies suggested that NK cells and their receptors may affect the transplant outcome. In the present study, patients and donors were found to significantly differ in the distribution of the NKG2A rs7301582 genetic variants - recipients carried the C allele more often than their donors (0.975 vs 0.865, p<0.0001). Increased soluble HLA-E (sHLA-E) levels detected in recipients' serum 30 days after transplantation seemed to play a prognostic and protective role. It was observed that recipients with higher sHLA-E levels were less prone to chronic GvHD (11.65 vs 6.33 pg/mL, p=0.033) or more severe acute GvHD grades II-IV (11.07 vs 8.04 pg/mL, p=0.081). Our results also showed an unfavourable role of HLA-E donor-recipient genetic incompatibility in CMV infection development after transplantation (OR=5.92, p=0.014). Frequencies of NK cells (both CD56dim and CD56bright) expressing NKG2C were elevated in recipients who developed CMV, especially 30 and 90 days post-transplantation (p<0.03). Percentages of NKG2C+ NK cells lacking NKG2A expression were also increased in these patients. Moreover, recipients carrying a NKG2C deletion characterized with decreased frequency of NKG2C+ NK cells (p<0.05). Our study confirms the importance of NK cells in the development of post-transplant complications and highlights the effect of HLA-E and NKG2C genetic variants, sHLA-E serum concentration, as well as NKG2C surface expression on transplant outcome.

Siemaszko J ，Łacina P ，Szymczak D ，Szeremet A ，Majcherek M ，Czyż A ，Sobczyk-Kruszelnicka M ，Fidyk W ，Solarska I ，Nasiłowska-Adamska B ，Skowrońska P ，Bieniaszewska M ，Tomaszewska A ，Basak GW ，Giebel S ，Wróbel T ，Bogunia-Kubik K ... -  《Frontiers in Immunology》

Regulation of Adaptive NK Cells and CD8 T Cells by HLA-C Correlates with Allogeneic Hematopoietic Cell Transplantation and with Cytomegalovirus Reactivation.

Mass cytometry was used to investigate the effect of CMV reactivation on lymphocyte reconstitution in hematopoietic cell transplant patients. For eight transplant recipients (four CMV negative and four CMV positive), we studied PBMCs obtained 6 mo after unrelated donor hematopoietic cell transplantation (HCT). Forty cell-surface markers, distinguishing all major leukocyte populations in PBMC, were analyzed with mass cytometry. This group included 34 NK cell markers. Compared with healthy controls, transplant recipients had higher HLA-C expression on CD56(-)CD16(+) NK cells, B cells, CD33(bright) myeloid cells, and CD4CD8 T cells. The increase in HLA-C expression was greater for CMV-positive HCT recipients than for CMV negative recipients. Present in CMV-positive HCT recipients, but not in CMV-negative HCT recipients or controls, is a population of killer cell Ig-like receptor (KIR)-expressing CD8 T cells not previously described. These CD8 T cells coexpress CD56, CD57, and NKG2C. The HCT recipients also have a population of CD57(+)NKG2A(+) NK cells that preferentially express KIR2DL1. An inverse correlation was observed between the frequencies of CD57(+)NKG2C(+) NK cells and CD57(+)NKG2A(+) NK cells. Although CD57(+)NKG2A(+) NK cells are less abundant in CMV-positive recipients, their phenotype is of a more activated cell than the CD57(+)NKG2A(+) NK cells of controls and CMV-negative HCT recipients. These data demonstrate that HCT and CMV reactivation are associated with an increased expression of HLA-C. This could influence NK cell education during lymphocyte reconstitution. The increased inhibitory KIR expression by proliferating CMV-specific CD8 T cells suggests regulatory interactions between HLA-C and KIR might promote Graft-versus-Leukemia effects following transplantation.

Horowitz A ，Guethlein LA ，Nemat-Gorgani N ，Norman PJ ，Cooley S ，Miller JS ，Parham P ... -  《-》

Characterization of IFNγ-producing natural killer cells induced by cytomegalovirus reactivation after haploidentical hematopoietic stem cell transplantation.

Jin F ，Lin H ，Gao S ，Wang H ，Yan H ，Guo J ，Hu Z ，Jin C ，Wang Y ，Wang Z ，Zhao Y ，Liu Y ，Zheng X ，Tan Y ，Li W ，Dai Y ，Yang Y ... -  《Oncotarget》

MICB Genetic Variants and Its Protein Soluble Level Are Associated with the Risk of Chronic GvHD and CMV Infection after Allogeneic HSCT.

Siemaszko J ，Dratwa M ，Szeremet A ，Majcherek M ，Czyż A ，Sobczyk-Kruszelnicka M ，Fidyk W ，Solarska I ，Nasiłowska-Adamska B ，Skowrońska P ，Bieniaszewska M ，Tomaszewska A ，Basak GW ，Giebel S ，Wróbel T ，Bogunia-Kubik K ... -  《-》

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.

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 sub-group 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 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.

Kordelas L ，Schwich E ，Lindemann M ，Heinemann FM ，Buttkereit U ，Horn PA ，Beelen DW ，Rebmann V ... -  《Frontiers in Immunology》