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

The aim of the present study was to determine the associations between the MICB genetic variability and the expression and the risk of development of post-transplant complications after allogeneic hematopoietic stem cell transplantation (HSCT). HSCT recipients and their donors were genotyped for two MICB polymorphisms (rs1065075, rs3828903). Moreover, the expression of a soluble form of MICB was determined in the recipients' serum samples after transplantation using the Luminex assay. Our results revealed a favorable role of the MICB rs1065075 G allele. Recipients with donors carrying this genetic variant were less prone to developing chronic graft-versus-host disease (cGvHD) when compared to recipients without any symptoms of this disease (41.41% vs. 65.38%, p = 0.046). Moreover, the MICB rs1065075 G allele was associated with a lower incidence of cytomegalovirus (CMV) reactivation, both as a donor (p = 0.015) and as a recipient allele (p = 0.039). The MICB rs1065075 G variant was also found to be associated with decreased serum soluble MICB (sMICB) levels, whereas serum sMICB levels were significantly higher in recipients diagnosed with CMV infection (p = 0.0386) and cGvHD (p = 0.0008) compared to recipients without those complications. A protective role of the G allele was also observed for the rs3828903 polymorphism, as it was more frequently detected among donors of recipients without cGvHD (89.90% vs. 69.23%; p = 0.013). MICB genetic variants, as well as serum levels of sMICB, may serve as prognostic factors for the risk of developing cGvHD and CMV infection after allogeneic HSCT.

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.

The impact of NKG2A and NKG2D receptors and HLA-E and MICA ligands polymorphisms on post-transplant complications after paediatric allogeneic HSCT: a single-centre experience.

Introduction: Natural Killer cells are the first subpopulation of lymphocytes that reconstitute after allogeneic haematopoietic stem cell transplantation (HSCT). Their activity is regulated by various receptor-ligand interactions, including stimulation of the activating NKG2D receptor by the MICA molecule, and inhibitory NKG2A receptor interacting with the HLA-E. In this study the research effort focused on the effect of selected NKG2A and NKG2D receptors and their ligands (HLA-E and MICA molecules) polymorphisms that may affect the pathomechanisms of post-transplant complications after HSCT in children. Methods: One hundred donor-recipient pairs from a single paediatric transplantation centre were investigated. Altogether six single nucleotide substitutions (NKG2A rs7301582; NKG2D rs1049174, rs1154831; HLA-E rs1264457; MICA rs1051792, rs1063635) were genotyped, and the influence of polymorphisms was analysed on acute and chronic graft-versus-host disease (GvHD), cytomegalovirus (CMV) infection incidence, disease relapse and survival. Results: The distribution of the evaluated polymorphisms did not differ between patients and their donors. The results showed a significant influence of HLA-E rs1264457 polymorphism in patients' HLA-E*01:01 allele, which was associated with increased risk of CMV infection (p = 0.050), especially in children positive for CMV IgG before transplantation (p = 0.001). Furthermore, the effect of HLA-E*01:01 allele on CMV infections was more evident in children above the age of 7 years (p = 0.031). Strong tendencies (0.05 < p < 0.10) towards association with the risk of acute GvHD were also observed for the NKG2A or MICA polymorphisms of the recipients. In addition, NKG2D rs1154831 AA and MICA rs1063635 GG might play a protective role as they were not present in any recipient who died after transplantation. Conclusion: In summary, there is emerging evidence that genotyping results of NKG2 receptors and their ligands, may have prognostic value for the outcome of paediatric allogeneic HSCT, but more extensive studies performed on larger groups of donors and transplant recipients are required to confirm these observations.

Activating NKG2C Receptor: Functional Characteristics and Current Strategies in Clinical Applications.

The interest in NK cells and their cytotoxic activity against tumour, infected or transformed cells continuously increases as they become a new efficient and off-the-shelf agents in immunotherapies. Their actions are balanced by a wide set of activating and inhibitory receptors, recognizing their complementary ligands on target cells. One of the most studied receptors is the activating CD94/NKG2C molecule, which is a member of the C-type lectin-like family. This review is intended to summarise latest research findings on the clinical relevance of NKG2C receptor and to examine its contribution to current and potential therapeutic strategies. It outlines functional characteristics and molecular features of CD94/NKG2C, its interactions with HLA-E molecule and presented antigens, pointing out a key role of this receptor in immunosurveillance, especially in the human cytomegalovirus infection. Additionally, the authors attempt to shed some light on receptor's unique interaction with its ligand which is shared with another receptor (CD94/NKG2A) with rather opposite properties.

NKG2D Natural Killer Cell Receptor-A Short Description and Potential Clinical Applications.

Natural Killer (NK) cells are natural cytotoxic, effector cells of the innate immune system. They can recognize transformed or infected cells. NK cells are armed with a set of activating and inhibitory receptors which are able to bind to their ligands on target cells. The right balance between expression and activation of those receptors is fundamental for the proper functionality of NK cells. One of the best known activating receptors is NKG2D, a member of the CD94/NKG2 family. Due to a specific NKG2D binding with its eight different ligands, which are overexpressed in transformed, infected and stressed cells, NK cells are able to recognize and attack their targets. The NKG2D receptor has an enormous significance in various, autoimmune diseases, viral and bacterial infections as well as for transplantation outcomes and complications. This review focuses on the NKG2D receptor, the mechanism of its action, clinical relevance of its gene polymorphisms and a potential application in various clinical settings.