ERAP, KIR, and HLA-C Profile in Recurrent Implantation Failure

The mother’s uterine immune system is dominated by uterine natural killer (NK) cells during the first trimester of pregnancy. These cells express killer cell immunoglobulin-like receptors (KIRs) of inhibitory or activating function. Invading extravillous trophoblast cells express HLA-C molecules, and both maternal and paternal HLA-C allotypes are presented to KIRs. Endoplasmic reticulum aminopeptidase 1 (ERAP1) and 2 (ERAP2) shape the HLA class I immunopeptidome. The ERAPs remove N-terminal residues from antigenic precursor peptides and generate optimal-length peptides to fit into the HLA class I groove. The inability to form the correct HLA class I complexes with the appropriate peptides may result in a lack of immune response by NK cells. The aim of this study was to investigate the role of ERAP1 and ERAP2 polymorphisms in the context of KIR and HLA-C genes in recurrent implantation failure (RIF). In addition, for the first time, we showed the results of ERAP1 and ERAP2 secretion into the peripheral blood of patients and fertile women. We tested a total of 881 women. Four hundred ninety-six females were patients who, together with their partners, participated in in vitro fertilization (IVF). A group of 385 fertile women constituted the control group. Women positive for KIR genes in the Tel AA region and HLA-C2C2 were more prevalent in the RIF group than in fertile women (p/pcorr. = 0.004/0.012, OR = 2.321). Of the ERAP polymorphisms studied, two of them (rs26653 and rs26618) appear to affect RIF susceptibility in HLA-C2-positive patients. Moreover, fertile women who gave birth in the past secreted significantly more ERAP1 than IVF women and control pregnant women (p < 0.0001 and p = 0.0005, respectively). In the case of ERAP2, the opposite result was observed; i.e., fertile women secreted far less ERAP2 than IVF patients (p = 0.0098). Patients who became pregnant after in vitro fertilization embryo transfer (IVF-ET) released far less ERAP2 than patients who miscarried (p = 0.0032). Receiver operating characteristic (ROC) analyses indicate a value of about 2.9 ng/ml of ERAP2 as a point of differentiation between patients who miscarried and those who gave birth to a healthy child. Our study indicates that both ERAP1 and ERAP2 may be involved in processes related to reproduction.

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HLA Influence on NK Cell Expansion

Blood ◽

10.1182/blood.v112.11.4924.4924 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4924-4924

Author(s):

Jennifer Schellekens ◽

Anna Stserbakova ◽

Madis Tõns ◽

Hele Everaus ◽

Marcel GJ Tilanus ◽

...

Keyword(s):

Nk Cells ◽

Cell Lines ◽

Cell Expansion ◽

Nk Cell ◽

Killer Cell ◽

Hla Class I ◽

Class I ◽

Haematopoietic Stem Cell ◽

Specific Priming

Abstract Natural Killer (NK) cells are effector cells in the innate immune system. The anti-leukaemic capacities of NK cells in haematopoietic stem cell transplantation make these cells a potential treatment modality to improve clinical outcome. Immunotherapy with NK cells requires transfusion of large quantities, which obviates the need for an in vitro culture system for NK cells. The killer cell immunoglobulin-like receptors (KIR) on NK cells recognise defined groups of HLA class I alleles. To elucidate the influence of these interactions on proliferation, the peripheral blood mononuclear cells (PBMCs) of 29 patients and donors were cultured in CellGro SCGM with IL-2 and OKT3 antibody to expand the NK cell fraction. The killer cell immunoglobulin-like receptor (KIR) and HLA repertoire were determined by sequence specific priming and sequence based typing respectively. The percentage of NK cell expansion from the total PBMC fraction varied between 5.4% and 71.6%. A significantly better NK cell expansion was observed for individuals homozygous for HLA-C epitope group 2 (p<0.05). For evaluation of cytolytic competence of the cultured NK cells, specific killing of an HLA class I expression deficient LCL 721.221 cell line and three 721.221 cell lines transfected with different HLA-C alleles was determined. A significantly better NK cell-induced specific cytotoxicity was observed towards the untransfected 721.221 cells compared to the HLA-C transfected 721.221 cells. No significant differences were observed between killing of the three HLA-C transfected 721.221 cell lines. We have shown that cytolytic capacities of the cultured NK cells are maintained and in vitro expansion of NK cells is dependant on the presence of HLA-C alleles.

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Human natural killer cell receptors for HLA-class I molecules. Evidence that the Kp43 (CD94) molecule functions as receptor for HLA-B alleles.

Journal of Experimental Medicine ◽

10.1084/jem.180.2.545 ◽

1994 ◽

Vol 180 (2) ◽

pp. 545-555 ◽

Cited By ~ 146

Author(s):

A Moretta ◽

M Vitale ◽

S Sivori ◽

C Bottino ◽

L Morelli ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Killer Cell ◽

Hla Class I ◽

Cytolytic Activity ◽

Class I ◽

Target Cells ◽

Human Natural Killer Cell ◽

Ligand Interaction ◽

Hla Class I Molecules

GL183 or EB6 (p58) molecules have been shown to function as receptors for different HLA-C alleles and to deliver an inhibitory signal to natural killer (NK) cells, thus preventing lysis of target cells. In this study, we analyzed a subset of NK cells characterized by a p58-negative surface phenotype. We show that p58-negative clones, although specific for class I molecules do not recognize HLA-C alleles. In addition, by the use of appropriate target cells transfected with different HLA-class I alleles we identified HLA-B7 as the protective element recognized by a fraction of p58-negative clones. In an attempt to identify the receptor molecules expressed by HLA-B7-specific clones, monoclonal antibodies (mAbs) were selected after mice immunization with such clones. Two of these mAbs, termed XA-88 and XA-185, and their F(ab')2 fragments, were found to reconstitute lysis of B7+ target cells by B7-specific NK clones. Both mAbs were shown to be directed against the recently clustered Kp43 molecule (CD94). Thus, mAb-mediated masking of Kp43 molecules interferes with recognition of HLA-B7 and results in target cell lysis. Moreover, in a redirected killing assay, the cross-linking of Kp43 molecules mediated by the XA185 mAb strongly inhibited the cytolytic activity of HLA-B7-specific NK clones, thus mimicking the functional effect of B7 molecules. Taken together, these data strongly suggest that Kp43 molecules function as receptors for HLA-B7 and that this receptor/ligand interaction results in inhibition of the NK-mediated cytolytic activity. Indirect immunofluorescence and FACS analysis of a large number of random NK clones showed that Kp43 molecules (a) were brightly expressed on a subset of p58-negative clones, corresponding to those specific for HLA-B7; (b) displayed a medium/low fluorescence in the p58-negative clones that are not B7-specific as well as in most p58+ NK clones; and (c) were brightly expressed as in the p58+ clone ET34 (GL183-/EB6+, Cw4-specific). Functional analysis revealed that Kp43 functioned as an inhibitory receptor only in NK clones displaying bright fluorescence. These studies also indicate that some NK clones (e.g., the ET34) can coexpress two distinct receptors (p58 and Kp43) for different class I alleles (Cw4 and B7). Finally, we show that Kp43 molecules function as receptors only for some HLA-B alleles and that still undefined receptor(s) must exist for other HLA-B alleles including B27.

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The Activating KIR Genes 2DS1 and 2DS2 Regulate NK Alloreactivity In Vitro.

Blood ◽

10.1182/blood.v108.11.927.927 ◽

2006 ◽

Vol 108 (11) ◽

pp. 927-927

Author(s):

Joseph H. Chewning ◽

Charlotte N. Gudme ◽

Bo Dupont

Keyword(s):

Stem Cell ◽

Nk Cells ◽

Hematopoietic Stem Cell ◽

Hla Class I ◽

Class I ◽

Target Cells ◽

Ligand Specificity ◽

Hematopoietic Stem ◽

Allogeneic Hsct

Abstract The role of Natural Killer (NK) cells in host protection against viral infection and malignant transformation has been well described. NK cells may also lead to a reduction in post-transplant relapse and improved survival in hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML). It has been hypothesized that the genotype for the inhibiting killer immunoglobulin-like receptor (KIR) of the hematopoietic stem cell donor in combination with the HLA class I genotype of the recipient could control NK alloreactivity leading to a reduction in post-transplant complications. The KIR gene family encodes however both activating and inhibiting receptors. Here we test the hypothesis that activating KIRs with ligand specificity for HLA class I may contribute to alloreactivity, and potentially could be a genetic factor of significance in allogeneic HSCT. We tested this hypothesis in studies of two pairs of inhibiting and activating KIRs with highly homologous codon sequences in the extracellular domain, namely KIR2DL2/3-KIR2DS2 and KIR2DL1-KIR2DS1. Both the inhibitory 2DL1 and activating 2DS1 have ligand specificity for HLA-Cw group 2, and 2DL2 and 2DL3, have ligand specificity for HLA-Cw group 1, while the activating 2DS2 does not bind in vitro to C1 group. Using an EBV-transformed B-lymphoblastoid cell line (EBV-BLCL) target cell panel homozygous for HLA Class I alleles, we found that NK cells from donors with KIR haplotypes lacking KIR2DS1 or 2DS2 were not cytotoxic to allogeneic EBV-BLCL, independent of the target HLA class I genotype. Polyclonal NK cells obtained from KIR2DS1 positive and C1 group positive donors mediated NK cytotoxicity against C2 positive targets. In contrast, NK cells from KIR2DS1 positive, C2 group homozygous donors displayed minimal cytotoxicity against the C2 group targets (p<0.01). NK clones generated from 2DS1 positive, C2-group negative individuals were cytotoxic to C2-group target cells, while such NK clones could not be obtained from individuals positive for 2DS1 and cognate ligands. Similar findings were made for the relationship between 2DS2, 2DL2/3 and cognate ligand C1 group. Both polyclonal IL-2 propagated NK cells and NK clones from individuals positive for 2DS2 and homozygous for C2 group displayed specific cytotoxicity against C1 positive target cells. The cytotoxicity of 2DS2 positive, C1 group positive NK cells against the C1 positive BLCLs was minimal (p<0.01). These studies demonstrate that 2DS1 and 2DS2 are activating receptors that can induce an alloantigen response. We also present a model for combinations of KIR and HLA genotypes in which the allogeneic function of KIR2DS1 and 2DS2 is consistently seen in donor NK cells. Activating KIR may therefore play a role in allogeneic HSCT, and could contribute to the balance between activating and inhibiting signals for NK cells in HLA-Cw incompatible donor-recipient combinations. Activating KIR interactions with cognate ligand could potentially also play a role in the innate immune response. In the normal host, the increased affinity of the inhibiting KIR isoforms for HLA class I may prevent auto-reactivity, while the activating isoforms may only function in an HLA restricted pattern in context of specific pathogens or transformed cells. It is possible that the low affinity activating KIR may require additional co-stimulating signals that are up-regulated during cellular stress.

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Increased expression of HMGB1 in the implantation phase endometrium is related to recurrent implantation failure

10.21203/rs.3.rs-695265/v1 ◽

2021 ◽

Author(s):

Mi Han ◽

Yi Cao ◽

Wenjie Zhou ◽

Mingjuan Zhou ◽

Xiaowei Zhou ◽

...

Keyword(s):

Epithelial Cells ◽

Underlying Mechanism ◽

Endometrial Receptivity ◽

In Vitro Assays ◽

Control Group ◽

Implantation Failure ◽

Recurrent Implantation Failure ◽

Tubal Infertility ◽

Endometrial Stromal Cells

Abstract Impaired endometrial receptivity is the main cause of recurrent implantation failure (RIF), however, its underlying mechanism is unclear. In this study, we found that HMGB1 expression was significantly decreased in the implantation phase endometrium in the control group (patients with tubal infertility who successfully achieved conception after the first embryo transfer) (P = 0.006). However, the expression levels of HMGB1 mRNA and protein were significantly upregulated during the implantation phase in endometrial tissues obtained from patients with RIF compared to those in the control group (P = 0.001), consistent with the results of genome-wide expression profiling. Moreover, in vitro assays showed that increased expression of HMGB1 in human endometrial epithelial cells cause marked deficiency in supporting blastocysts and human embryonic JAR cell adhesion, mimicking the process of embryo adhesion. However, overexpression of HMGB1 had no effect on cell proliferation and in-vitro decidualization in a human endometrial stromal cell line (T-HESCs) and in primary human endometrial stromal cells (HESCs). These findings indicate that increased HMGB1 levels suppressed the adhesion capability of epithelial cells, contributing to impaired endometrial receptivity in patients with recurrent implantation failure. This characteristic can be used as a target for detecting and treating recurrent implantation failure in clinical practice.

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Relevance of Polymorphic KIR and HLA Class I Genes in NK-Cell-Based Immunotherapies for Adult Leukemic Patients

Cancers ◽

10.3390/cancers13153767 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3767

Author(s):

Léa Dubreuil ◽

Patrice Chevallier ◽

Christelle Retière ◽

Katia Gagne

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Current Knowledge ◽

Killer Cell ◽

Hla Class I ◽

Class I ◽

Cell Repertoire ◽

Hematopoietic Stem ◽

Structural Formation ◽

The Impact

Since the mid-1990s, the biology and functions of natural killer (NK) cells have been deeply investigated in healthy individuals and in people with diseases. These effector cells play a particularly crucial role after allogeneic hematopoietic stem-cell transplantation (HSCT) through their graft-versus-leukemia (GvL) effect, which is mainly mediated through polymorphic killer-cell immunoglobulin-like receptors (KIRs) and their cognates, HLA class I ligands. In this review, we present how KIRs and HLA class I ligands modulate the structural formation and the functional education of NK cells. In particular, we decipher the current knowledge about the extent of KIR and HLA class I gene polymorphisms, as well as their expression, interaction, and functional impact on the KIR+ NK cell repertoire in a physiological context and in a leukemic context. In addition, we present the impact of NK cell alloreactivity on the outcomes of HSCT in adult patients with acute leukemia, as well as a description of genetic models of KIRs and NK cell reconstitution, with a focus on emergent T-cell-repleted haplo-identical HSCT using cyclosphosphamide post-grafting (haplo-PTCy). Then, we document how the immunogenetics of KIR/HLA and the immunobiology of NK cells could improve the relapse incidence after haplo-PTCy. Ultimately, we review the emerging NK-cell-based immunotherapies for leukemic patients in addition to HSCT.

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A Human Histocompatibility Leukocyte Antigen (HLA)-G–specific Receptor Expressed on All Natural Killer Cells

Journal of Experimental Medicine ◽

10.1084/jem.189.7.1093 ◽

1999 ◽

Vol 189 (7) ◽

pp. 1093-1100 ◽

Cited By ~ 506

Author(s):

Sumati Rajagopalan ◽

Eric O. Long

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Killer Cell ◽

Hla Class I ◽

Class I ◽

Target Cells ◽

Trophoblast Cells ◽

Leukocyte Antigen ◽

Hla Class I Molecules ◽

Decidual Cells

Human natural killer (NK) cells express several killer cell immunoglobulin (Ig)-like receptors (KIRs) that inhibit their cytotoxicity upon recognition of human histocompatibility leukocyte antigen (HLA) class I molecules on target cells. Additional members of the KIR family, including some that deliver activation signals, have unknown ligand specificity and function. One such KIR, denoted KIR2DL4, is structurally divergent from other KIRs in the configuration of its two extracellular Ig domains and of its transmembrane and cytoplasmic domains. Here we show that recombinant soluble KIR2DL4 binds to cells expressing HLA-G but not to cells expressing other HLA class I molecules. Unlike other HLA class I–specific KIRs, which are clonally distributed on NK cells, KIR2DL4 is expressed at the surface of all NK cells. Furthermore, functional transfer of KIR2DL4 into the cell line NK-92 resulted in inhibition of lysis of target cells that express HLA-G, but not target cells that express other class I molecules including HLA-E. Therefore, given that HLA-G expression is restricted to fetal trophoblast cells, KIR2DL4 may provide important signals to maternal NK decidual cells that interact with trophoblast cells at the maternal–fetal interface during pregnancy.

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Neonatal NK-cell repertoires are functionally, but not structurally, biased toward recognition of self HLA class I

Blood ◽

10.1182/blood-2011-02-334441 ◽

2011 ◽

Vol 117 (19) ◽

pp. 5152-5156 ◽

Cited By ~ 30

Author(s):

Kathrin Schönberg ◽

Johannes C. Fischer ◽

Gesine Kögler ◽

Markus Uhrberg

Keyword(s):

Nk Cells ◽

Cytokine Production ◽

Nk Cell ◽

Killer Cell ◽

Human Leukocyte ◽

Hla Class I ◽

Class I ◽

Structural Adaptation ◽

Leukocyte Antigen ◽

Kir Receptors

Abstract Human natural killer (NK)–cell repertoires are biased toward more frequent expression of inhibitory killer cell Ig-like receptor (KIR) receptors for self-human leukocyte antigen (HLA) class I. Moreover, only those NK cells that express cognate receptors for self are fully functional in terms of cytotoxicity and cytokine production. It is so far unknown whether functional education and structural adaptation to HLA class I are implemented during NK-cell development and whether both processes are mechanistically connected. Here we show that NK-cell repertoires in cord blood are not yet shaped toward increased clonal frequencies of KIR for self-HLA class I as determined for the 3 major KIR ligands C1, C2, and Bw4. Nonetheless, neonatal NK cells expressing cognate KIR exhibited enhanced effector function on the level of degranulation and cytokine production. The study suggests that functional education of cognate KIR by self-HLA class I precedes structural adaptation of KIR repertoires and that both processes are not directly linked to each other.

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The Expression of miR-31 and its Target Gene FOXP3 in Recurrent Implantation Failure Patients

International Journal of Women s Health and Reproduction Sciences ◽

10.15296/ijwhr.2020.62 ◽

2020 ◽

Vol 8 (4) ◽

pp. 389-395

Author(s):

Azita Azarpoor ◽

Abdolreza Ardeshirylajimi ◽

Samira Mohammadi Yeganeh ◽

Elham Pour matrood ◽

Zeinab Dehghan ◽

...

Keyword(s):

Gene Expression ◽

Target Gene ◽

Control Group ◽

Implantation Failure ◽

Recurrent Implantation Failure ◽

Tissue Samples ◽

Significant Difference ◽

Immunological Disorder ◽

Recurrent Abortions ◽

Fertile Women

Objectives: Endometrial receptivity is a complex event that occurs during the midluteal phase of the menstrual cycle known as the "window of implantation". During this period, the endometrium develops characteristics that allow the adhesion and invasion of the embryo to the uterine epithelium. Accordingly, the expressions of miR-31 and its target gene were evaluated to study the effect of miR-31 on FOPX3 gene expression in recurrent implantation failure (RIF) patients and normal fertile women. More precisely, the aim of this study was to understand the expression of miR-31 as one of the important regulators of the FOXP3 gene in the endometrium of RIF patients versus receptive endometria from fertile patients. Materials and Methods: This case-control study was conducted on 20 endometrial tissue samples of normal fertile women and RIF patients in order to evaluate miR-31 and its target gene expression. Results: According to the results of this study, a significant difference existed between RIF patients and normal fertile women (control group). The expression of the FOXP3 gene was more significant in the control group. miR-31 was also significantly expressed, which was due to the endometrial immunological disorder leading to the decreased expression of its target gene (FOXP3). Conclusions: In general, implant abnormalities and recurrent abortions were observed in RIF patients due to the decreased expression of the FOXP3 gene resulting from the inhibitory effects of miR-31.

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Vaginal microbiota alterations in women with recurrent implantation failure and the associated metabolome

10.21203/rs.2.17203/v1 ◽

2019 ◽

Author(s):

Min Fu ◽

Xiaowei Zhang ◽

Weiping Qian ◽

Yiheng Liang ◽

Shouren Lin ◽

...

Keyword(s):

In Vitro Fertilization ◽

Vaginal Microbiota ◽

Control Group ◽

P Value ◽

Implantation Failure ◽

Recurrent Implantation Failure ◽

Vitro Fertilization ◽

Α Diversity ◽

Rdna Sequencing

Abstract In vitro fertilization-embryo transfer (IVF-ET) is now widely applied in treating infertility. As the number of IVF cycles continues to increase, recurrent implantation failure (RIF) has become a big challenge. The cause of RIF is very complex and remains largely unrevealed, especially for those without any pathological features. It has been proved that vaginal microbiota is associated with many female reproductive diseases, such as pregnancy-related diseases, sexually transmitted diseases, tubal factor infertility, and first trimester miscarriage after in vitro fertilization (IVF) and so on. Hence, vaginal microbiota and its metabolome may also relate to RIF. In this study, we characterized the vaginal microbiota and metabolome of patients with unexplained RIF, while patients who achieved clinical pregnancy in the first IVF cycle were used as controls. Results Based on 16S rDNA sequencing of the vaginal microbiota, the RIF group presented higher microbial α-diversity than the control group (0.80±0.50 vs 0.50±0.39, P-value=0.016) and harbored more non-Lactobacillus microorganisms, including 25 significantly increased genera of both aerobic and anaerobic bacteria. The metabolomic profile showed that the relative abundances of 37 metabolites among 2,507 metabolites were significantly different between the two groups. Among them, 2',3-cyclic UMP and phosphoinositide were the top two metabolites significantly upregulated in the RIF group, while glycerophospholipids and benzopyran were important metabolites that were significantly downregulated. Lysobisphosphatidic acid (LPA) and prostaglandin (PG) metabolized from glycerophospholipids are key factors affecting implantation and decidualization. Benzopyran, as a selective estrogen receptor modulator (SERM), may affect the outcome of pregnancy. All of the metabolome outcomes may result in or from the differential microbiota composition in the RIF patients. Conclusions In conclusion, significant differences were presented in the vaginal microbiota and metabolome between RIF patients and women who became pregnant in the first IVF cycle, which are related to embryo implantation. This study not only deeply investigates the relationship between RIF and the vaginal microbial community and its metabolites but also provides a profound understanding of the pathogenesis of RIF.

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Carfilzomib Enhances Natural Killer Cell-Mediated Lysis of Myeloma Linked with Decreasing Expression of HLA Class I

Blood ◽

10.1182/blood.v126.23.1854.1854 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1854-1854

Author(s):

Jumei Shi ◽

Guang Yang ◽

Yuanyuan Kong ◽

Minjie Gao ◽

Yi Tao ◽

...

Keyword(s):

Multiple Myeloma ◽

Nk Cells ◽

Natural Killer ◽

Hematological Malignancies ◽

Nk Cell ◽

Killer Cell ◽

Hla Class I ◽

Class I ◽

Dependent Manner ◽

Down Regulation

Abstract Multiple myeloma (MM) is a malignant disorder characterized by uncontrolled monoclonal plasma cell proliferation. It accounts for 10% of all hematological malignancies and causes 15-20% of deaths from hematological malignancies. Although new therapies were introduced and overall survival of MM was improved in the last 10 years, MM still remains an incurable disease due to drug resistance. Natural killer (NK) cell-based treatments are promising therapies for multiple myeloma (MM). Carfilzomib (CFZ), a second-generation proteasome inhibitor, is used to treat patients with MM who are refractory or intolerant to both bortezomib and lenalidomide (or thalidomide). In this study, we determined that CFZ treatment enhanced the sensitivity of MM cells to NK cell-mediated lysis. Here, we report that CFZ decreased the expression of human leukocyte antigen (HLA) class I on MM cell lines and primary MM cells, the mean reduction was 47.7 ± 9.4% and 42.8 ± 12.4%, respectively. The down-regulation caused by CFZ occurred in a dose- and time- dependent manner. We compared the cell surface levels of HLA class I on MM cells in the presence or absence of CFZ after acid treatment. CFZ also down-regulated the expression of newly formed HLA class I on MM cells. CD107a expression levels were used to measure NK-cell degranulation. When NK cells were incubated with MM cells with CFZ treatment, the percentage of NK cells expressing CD107a on the surface greatly increased (mean ± SD: 33.6 ± 2.1%, for treated cells vs 16.7 ± 2.3%, for control cells, P < 0.05). We also showed that CFZ augmented NK-cell cytotoxity by a perforin/granzyme-mediated mechanism, because such enhancement was abolished when CMA, but not anti-TRAIL or anti-Fas-L antibodies, was added. Treatment of MM with CFZ significantly sensitized patients' MM cells to NK cell-mediated lysis (mean ± SD: 43.1 ± 6.4%, for treated cells vs 16.1 ± 4.0%, for control cells at effector/target (E/T) ratio of 10:1, n = 9, P < 0.01). Furthermore, the exogenous HLA-C binding peptides, used in the CFZ treated group rescued the down-regulation of HLA-C and reduced NK cell-mediated lysis to a similar level as in the untreated group. Blocking NKG2D, NCRs and TRAIL did not have a significant impact on NK cell lysis of myeloma cells. These implied the enhancement of NK cell-mediated lysis was mainly linked with the decreased expression of HLA class I. Our findings show a novel activity of CFZ as an immunomodulating agent and suggest a possible approach to therapeutically augment NK cell function in MM patients. Disclosures No relevant conflicts of interest to declare.

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