Search Results (22)

Maternal–fetal tolerance mechanisms are crucial during human pregnancy to prevent the immune rejection of the embryo. A well-known mechanism blocking NK-cell cytotoxicity is the interaction of their inhibitory killer-cell immunoglobulin-like receptors (iKIR) with HLA-C molecules on the target cells. In this study, we aimed to investigate the expression of iKIRs (KIR2DL1 and KIR2DL2/3) on the matched decidual and peripheral γδT cells and the localization of HLA-C ligands throughout human pregnancy. The degranulation of γδT cells of pregnant and non-pregnant women in the presence of trophoblast cells was evaluated as well. Our results showed a higher proportion of iKIR-positive γδT cells at the maternal–fetal interface early in human pregnancy compared to the paired blood of pregnant women and full-term pregnancy decidua. In accordance, HLA-C was intensively expressed by the intermediate cytotrophoblasts and decidua-invading extravillous trophoblasts (EVTs) in early but not late pregnancy. Decidual γδT cells during early pregnancy showed higher spontaneous degranulation compared to their blood pairs, but neither decidual nor peripheral γδ T cells increased their degranulation in the presence of Sw71 EVT-like cells. The latter were unable to suppress the higher cytotoxicity of γδT cells, suggesting a complex regulatory landscape beyond NK-like activity inhibition. Full article

Background: Immunotherapy is gaining great relevance in both non-muscle-invasive bladder cancer (NMIBC), with the use of bacille Calmette–Guerin (BCG), and in muscle-invasive BC (MIBC) with anti-checkpoint therapies blocking PD-1/PD-L1, CTLA-4/CD80-CD86, and, more recently, NKG2A/HLA-E interactions. Biomarkers are necessary to optimize the use of these therapies. Methods: We evaluated killer-cell immunoglobulin-like receptors (KIRs) and HLA-I genotyping and the expression of NK cell receptors in circulating T and NK lymphocytes at diagnosis in 325 consecutive BC patients (151 treated with BCG and 174 treated with other therapies), as well as in 648 patients with other cancers and 973 healthy donors as controls. The proliferation and production of cytokines and cytotoxicity were evaluated in peripheral blood mononuclear cells, stimulated in vitro with anti-CD3/CD28 or BCG, from selected patients based on HLA-B −21M/T dimorphism (NKG2A ligands). Results: The HLA-B −21M/T genotype showed opposing results in BC patients treated with BCG or other therapies. The MM genotype, compared to MT and TT, was associated with a longer 75th-percentile overall survival (not reached vs. 68.0 ± 13.7 and 52.0 ± 8.3 months, p = 0.034) in BCG, but a shorter (8.0 ± 2.4 vs. 21.0 ± 3.4 and 19.0 ± 4.9 months, p = 0.131) survival in other treatments. The HLA-B −21M/T genotype was an independent predictive parameter of the progression-free survival (HR = 2.08, p = 0.01) and the OS (HR = 2.059, p = 0.039) of BC patients treated with BCG, together with age and tumor histopathologic characteristics. The MM genotype was associated with higher counts of circulating CD56^bright, fewer KIR2DL1/L2⁺ NK cells, and lower NKG2A expression, but not with differential in vitro NK cell functionality. Conclusions: The HLA-B −21M/T is independently associated with BC patient outcomes and can help to optimize the use of new immunotherapies in these patients. Full article

HLA-B27 and HLA-B57 are associated with autoimmunity and long-term viral control and protection against HIV and HCV infection; however, their role in cancer immunity remains unknown. HLA class I molecules interact with innate checkpoint receptors of the LILRA, LILRB and KIR families present in diverse sets of immune cells. Here, we demonstrate that an open format (peptide free conformation) and expression- and stability-optimized HLA-B57-B2m-IgG4_Fc fusion protein (IOS-1002) binds to human leukocyte immunoglobulin-like receptor B1 and B2 (LILRB1 and LILRB2) and to killer immunoglobulin-like receptor 3DL1 (KIR3DL1). In addition, we show that the IgG4 Fc backbone is required for engagement to Fcγ receptors and potent activation of macrophage phagocytosis. IOS-1002 blocks the immunosuppressive ITIM and SHP1/2 phosphatase signaling cascade, reduces the expression of immunosuppressive M2-like polarization markers of macrophages and differentiation of monocytes to myeloid-derived suppressor cells, enhances tumor cell phagocytosis in vitro and potentiates activation of T and NK cells. Lastly, IOS-1002 demonstrates efficacy in an ex vivo patient-derived tumor sample tumoroid model. IOS-1002 is a first-in-class multi-target and multi-functional human-derived HLA molecule that activates anti-tumor immunity and is currently under clinical evaluation. Full article

The infusion autograft absolute number of inhibitory killer immunoglobulin-like receptor (KIR) 2DL2 and activating natural killer (NK)p30 cells are predictors of clinical outcomes in lymphoma patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). To assess if the long-term recovery of these NK cell subsets still holds clinical relevance, we set up to investigate their prognostic ability at day 100 post-APBHSCT. This was a retrospective single-institution study including 107 patients from our prior phase III trial who had a clinical assessment at day 100 post-APBHSCT. The median follow-up from day 100 was 168.19 months (interquartile range: 156.85–181.28 months). Patients with day 100 inhibitory KIR2DL2 < 0.08 cells/µL and activating NKp30 ≥ 0.19 cells/µL experienced superior overall survival (OS) and progression-free survival (PFS). A multivariate analysis revealed both the day 100 inhibitory KIR2DL2 [OS: HR = 1.449, 95%CI, 1.231–1.895, p < 0.013; and PFS: HR = 2.069, 95%CI, 1.134–3.775, p < 0.021] and activating NKp30 [OS: HR = 4.985, 95%CI, 2.614–9.506, p < 0.0001; and PFS: HR = 4.661, 95%CI, 2.598–8.393, p < 0.0001] were independent predictors for OS and PFS. Inhibitory KIR2DL2 and activating NKp30 NK cells at day 100 are prognostic immune biomarkers in lymphoma patients treated with APBHSCT. Full article

This study examines the interplay between human leukocyte antigen (HLA) compatibility and killer-cell immunoglobulin-like receptor (KIR) genotypes in influencing kidney transplantation outcomes. Understanding these interactions is crucial for improving graft survival and minimizing rejection risks. We evaluated 84 kidney transplant recipients, dividing them into two groups based on post-transplant outcomes: there were 68 with stable graft function (SGF) and 16 who experienced chronic rejection (CR). Patients were selected based on specific inclusion criteria. HLA mismatches (Class I: HLA-A, -B; Class II: HLA-DR) and KIR genotypes were determined using standard genotyping techniques. Statistical analyses, including logistic regression, were performed to correlate these factors with transplant outcomes. Significant age differences were observed, with younger patients more likely to experience graft rejection, while no significant gender-based differences were noted. A significant correlation was found between Class II mismatches and increased rejection rates, highlighting the importance of HLA-DR compatibility. Further analysis revealed that certain inhibitory KIRs, such as KIR3DL1, were associated with favorable outcomes, suggesting a protective role against graft rejection. These findings were corroborated by evaluating serum creatinine levels over multiple years, serving as a biomarker for renal function post transplant. This study underscores the critical need for meticulous HLA matching and the consideration of KIR genotypes in pre-transplant evaluations to enhance graft survival and minimize rejection risks. Integrating these genetic factors into routine clinical assessments could significantly improve personalized transplant medicine strategies, ultimately enhancing patient outcomes. Further research is needed to explore the underlying mechanisms and validate these findings in larger, diverse populations. Full article

Background: Middle East respiratory syndrome (MERS) is a lower respiratory tract disease caused by a beta coronavirus (CoV) called MERS-CoV, characterized by a high mortality rate. We aimed to evaluate the association between genetic variation in killer cell immunoglobulin-like receptors (KIRs) and the risk of MERS in South Koreans. Methods: KIR genes were genotyped by multiplex polymerase chain reaction with sequence-specific primers (PCR-SSP). A case-control study was performed to identify the odds ratios (OR) of KIR genes for MERS and the association of KIR genes and their ligands, human leukocyte antigens (HLA) genes. Results: KIR2DS4D and KIR3DP1F showed higher frequencies in the group of all patients infected with MERS-CoV than in the control group (p = 0.023, OR = 2.4; p = 0.039, OR = 2.7). KIR2DL1, KIR2DP1, and KIR3DP1D were significantly associated with moderate/mild (Mo/Mi) cases. KIR2DL2, KIR2DS1, and KIR3DP1F were affected in severe cases. When we investigated the association between KIR genes and their ligands in MERS patient and control groups, KIR3DL1+/Bw4(80I)+, KIR3DL1+/Bw6+, KIR3DL1+/Bw6−, KIR2DS1+/C2+, and KIR3DS+/Bw4(80I)+ were associated with MERS. KIR3DL1+/Bw6− was found in Mo/Mi cases. KIR2DS1+/C2+ and KIR2DS2+/C1+ were found in severe cases. Conclusion: Further investigations are needed to prove the various immune responses of MERS-CoV-infected cells according to variations in the KIR gene and ligand gene. A treatment strategy based on current research on the KIR gene and MERS-CoV will suggest potential treatment targets. Full article

Background: The second-most frequent diagnosis among patients receiving liver transplants (LTs) is alcoholic liver disease. The multifactorial pathophysiology of alcoholic liver disease depends on the innate immune system and the inflammatory cascade. According to recent studies on these receptors, killer-cell immunoglobulin-like receptors (KIRs) may be involved in sepsis, liver rejection, and virus relapse. We aimed to investigate the impact of preclinical issues like ascites and encephalopathy and KIR genetic traits on death from sepsis, multiorgan failure (MF), and graft failure (GF) in AC patients undergoing LTs. Methods: We retrospectively reviewed 164 consecutive and deceased Caucasian AC patients who underwent LTs. Pre-transplant complications, cause of death, and patient survival were analyzed. Genomic DNA was taken from peripheral blood, and PCR-SSO was used for genotyping KIR. Results: Compared to GF patients, there was a statistically significant increase in the frequency of KIR2DL2+ (75.8% vs. 51.2%; p = 0.047). Another increase in frequency was also observed in KIR2DS2+ in sepsis compared to the GF group (51.2% vs. 43.7%; p = 0.018). In patients who passed away from MF, a decrease in KIR2DL5+ was observed in AC patients with and without encephalopathy (p = 0.018). The frequency of KIR3DL1+ in the AC patients significantly increased the mortality from sepsis (p = 0.045), which was confirmed by multivariate logistic regression. The frequency of KIR3DL1+ in the AC patients significantly increased the mortality from sepsis (p = 0.012) and was confirmed by multivariate logistic regression. KIR2DS1+ and KIR2DS4+ showed increased mortality due to GF compared to patients without these genes (p = 0.011 and 0.012, respectively). However, this fact was confirmed only for KIR2DS1+ by multivariate logistic Cox regression. Conclusions: The presence of the KIR2DL2/S2+, KIR2DL5+, and KIR3DL1+ genes increases the frequency of death from multiple organ failure or graft failure. Our findings highlight the AC patient’s vulnerability to a LT during hospitalization. Following the transplant and outside of it, we adopt essential preventive measures to create a routine healthcare screening to enhance and modify treatments to increase survival. Full article

Natural killer (NK) cells play a role in defence against viral infections by killing infected cells or by producing cytokines and interacting with adaptive immune cells. Killer immunoglobulin-like receptors (KIRs) regulate the activation of NK cells through their interaction with human leucocyte antigens (HLA). Ninety-six Sicilian patients positive to Human Immunodeficiency Virus-1 (HIV) and ninety-two Sicilian patients positive to SARS-CoV-2 were genotyped for KIRs and their HLA ligands. We also included fifty-six Sicilian patients with chronic hepatitis B (CHB) already recruited in our previous study. The aim of this study was to compare the distribution of KIR–HLA genes/groups of these three different infected populations with healthy Sicilian donors from the literature. We showed that the inhibitory KIR3DL1 gene and the KIR3DL1/HLA-B Bw4 pairing were more prevalent in individual CHB. At the same time, the frequency of HLA-C2 was increased in CHB compared to other groups. In contrast, the HLA-C1 ligand seems to have no contribution to CHB progression whereas it was significantly higher in COVID-19 and HIV-positive than healthy controls. These results suggest that specific KIR–HLA combinations can predict the outcome/susceptibility of these viral infections and allows to plan successful customized therapeutic strategies. Full article

A number of studies have suggested that human herpesvirus 6A (HHV-6A) may play a role in multiple sclerosis (MS). Three possible hypotheses have been investigated: (1) U24 from HHV-6A (U24-6A) mimics myelin basic protein (MBP) through analogous phosphorylation and interaction with Fyn-SH3; (2) U24-6A affects endocytic recycling by binding human neural precursor cell (NPC) expressed developmentally down-regulated protein 4-like WW3* domain (hNedd4L-WW3*); and (3) MS patients who express Killer Cell Immunoglobulin Like Receptor 2DL2 (KIR2DL2) on natural killer (NK) cells are more susceptible to HHV-6 infection. In this contribution, we examined the validity of these propositions by investigating the interactions of U24 from HHV-6B (U24-6B), a variant less commonly linked to MS, with Fyn-SH3 and hNedd4L-WW3* using heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) titrations and isothermal titration calorimetry (ITC). In addition, the importance of phosphorylation and the specific role of U24 in NK cell activation in MS patients were examined. Overall, the findings allowed us to shed light into the models linking HHV-6 to MS and the involvement of U24. Full article

Chronic liver rejection (CR) represents a complex clinical situation because many patients do not respond to increased immunosuppression. Killer cell immunoglobulin-like receptors/Class I Human Leukocyte Antigens (KIR/HLA-I) interactions allow for predicting Natural Killer (NK) cell alloreactivity and influence the acute rejection of liver allograft. However, its meaning in CR liver graft remains controversial. KIR and HLA genotypes were studied in 513 liver transplants using sequence-specific oligonucleotides (PCR-SSO) methods. KIRs, human leucocyte antigen C (HLA-C) genotypes, KIR gene mismatches, and the KIR/HLA-ligand were analyzed and compared in overall transplants with CR (n = 35) and no-chronic rejection (NCR = 478). Activating KIR (aKIR) genes in recipients (rKIR2DS2⁺ and rKIR2DS3⁺) increased CR compared with NCR groups (p = 0.013 and p = 0.038). The inhibitory KIR (iKIR) genes in recipients rKIR2DL2⁺ significantly increased the CR rate compared with their absence (9.1% vs. 3.7%, p = 0.020). KIR2DL3 significantly increases CR (13.1% vs. 5.2%; p = 0.008). There was no influence on NCR. CR was observed in HLA-I mismatches (MM). The absence of donor (d) HLA-C2 ligand (dC2⁻) ligand increases CR concerning their presence (13.1% vs. 5.6%; p = 0.018). A significant increase of CR was observed in rKIR2DL3⁺/dC1⁻ (p = 0.015), rKIR2DS4/dC1⁻ (p = 0.014) and rKIR2DL3⁺/rKIR2DS4⁺/dC1⁻ (p = 0.006). Long-term patient survival was significantly lower in rKIR2DS1⁺rKIR2DS4⁺/dC1⁻ at 5–10 years post-transplant. This study shows the influence of rKIR/dHLA-C combinations and aKIR gene-gene mismatches in increasing CR and KIR2DS1⁺/C1-ligands and the influence of KIR2DS4⁺/C1-ligands in long-term graft survival. Full article

Abdominal aortic aneurysm (AAA) is an immune-mediated disease with a genetic component. The multifactorial pathophysiology is not clear and there is still no pharmacotherapy to slow the growth of aneurysms. The signal integration of cell-surface KIRs (killer cell immunoglobulin-like receptors) with HLA (ligands, human leukocyte class I antigen molecules) modulates the activity of natural killer immune cells. The genetic diversity of the KIR/HLA system is associated with the risk of immune disorders. This study was a multivariate analysis of the association between genetic variants of KIRs, HLA ligands, clinical data and AAA formation. Genotyping was performed by single polymerase chain reaction with sequence-specific primers using commercial assays. Patients with HLA-A-Bw4 have a larger aneurysm by an average of 4 mm (p = 0.008). We observed a relationship between aneurysm diameter and BMI in patients with AAA and co-existing CAD; its shape was determined by the presence of HLA-A-Bw4. There was also a nearly 10% difference in KIR3DL1 allele frequency between the study and control groups. High expression of the cell surface receptor KIR3DL1 may protect, to some extent, against AAA. The presence of HLA-A-Bw4 may affect the rate of aneurysm growth and represents a potential regional pathogenetic risk of autoimmune injury to the aneurysmal aorta. Full article

Natural killer cells are partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined the risk of hepatocellular carcinoma (HCC) in relation to KIR–HLA pairs in patients with compensated hepatitis C virus (HCV)-associated cirrhosis. A total of 211 Japanese compensated HCV cirrhotic cases were retrospectively enrolled. After KIR, HLA-A, HLA-Bw, and HLA-C typing, associations between HLA, KIR, and KIR–HLA combinations and HCC development were evaluated using the Cox proportional hazards model with the stepwise method. During a median follow-up period of 6.6 years, 69.7% of patients exhibited HCC. The proportions of HLA-Bw4 and the KIR3DL1 + HLA-Bw4 pair were significantly higher in patients with HCC than in those without (78.9% vs. 64.1%; odds ratio (OR)—2.10, 95% confidence interval (CI)—1.10–4.01; p = 0.023 and 76.2% vs. 60.9%, odds ratio—2.05, p = 0.024, respectively). Multivariate analysis revealed the factors of male gender (hazard ratio (HR)—1.56, 95% CI—1.12–2.17; p = 0.009), α-fetoprotein > 5.6 ng/mL (HR—1.56, 95% CI—1.10–2.10; p = 0.011), and KIR3DL1 + HLA-Bw4 (HR—1.69, 95% CI—1.15–2.48; p = 0.007) as independent risk factors for developing HCC. Furthermore, the cumulative incidence of HCC was significantly higher in patients with KIR3DL1 + HLA-Bw4 than in those without (log-rank test; p = 0.013). The above findings suggest KIR3DL1 + HLA-Bw4, in addition to HLA-Bw4, as a novel KIR–HLA pair possibly associated with HCC development in HCV cirrhosis. HCV-associated cirrhotic patients with the risk factors of male gender, α-fetoprotein > 5.6 ng/mL, and KIR3DL1 + HLA-Bw4 may require careful surveillance for HCC onset. Full article

Cytomegalovirus (CMV) causes clinical issues primarily in immune-suppressed conditions. CMV-associated anterior uveitis (CMV-AU) is a notable new disease entity manifesting recurrent ocular inflammation in immunocompetent individuals. As patient demographics indicated contributions from genetic background and immunosenescence as possible underlying pathological mechanisms, we analyzed the immunogenetics of the cohort in conjunction with cell phenotypes to identify molecular signatures of CMV-AU. Among the immune cell types, natural killer (NK) cells are main responders against CMV. Therefore, we first characterized variants of polymorphic genes that encode differences in CMV-related human NK cell responses (Killer cell Immunoglobulin-like Receptors (KIR) and HLA class I) in 122 CMV-AU patients. The cases were then stratified according to their genetic features and NK cells were analyzed for human CMV-related markers (CD57, KLRG1, NKG2C) by flow cytometry. KIR3DL1 and HLA class I combinations encoding strong receptor–ligand interactions were present at substantially higher frequencies in CMV-AU. In these cases, NK cell profiling revealed expansion of the subset co-expressing CD57 and KLRG1, and together with KIR3DL1 and the CMV-recognizing NKG2C receptor. The findings imply that a mechanism of CMV-AU pathogenesis likely involves CMV-responding NK cells co-expressing CD57/KLRG1/NKG2C that develop on a genetic background of KIR3DL1/HLA-B allotypes encoding strong receptor–ligand interactions. Full article

We have recently shown a broad disparity of Natural Killer (NK) cell responses against leukemia highlighting good and bad responders resting on the Killer cell Immunoglobulin-like Receptors (KIR) and HLA genetics. In this study, we deeply studied KIR2D allele expression, HLA-C recognition and functional effect on NK cells in 108 blood donors in combining high-resolution KIR allele typing and multicolor flow cytometry. The KIR2DL1*003 allotype is associated with centromeric (cen) AA motif and confers the highest NK cell frequency, expression level and strength of KIR/HLA-C interactions compared to the KIR2DL1*002 and KIR2DL1*004 allotypes respectively associated with cenAB and BB motifs. KIR2DL2*001 and *003 allotypes negatively affect the frequency of KIR2DL1⁺ and KIR2DL3⁺ NK cells. Altogether, our data suggest that cenAA individuals display more efficient KIR2DL alleles (L1*003 and L3*001) to mount a consistent frequency of KIR2DL⁺ NK cells and to confer an effective NK cell responsiveness. The transposition of our in vitro observations in the T-replete haplo-identical HSCT context led us to observe that cenAA HSC grafts limit significantly the incidence of relapse in patients with myeloid diseases after T-replete haplo-identical HSCT. As NK cells are crucial in HSCT reconstitution, one could expect that the consideration of KIR2DL1/2/3 allelic polymorphism could help to refine scores used for HSC donor selection. Full article

Human leukocyte antigen G (HLA-G) mediates maternal-fetal immune tolerance. It is also considered an immune checkpoint in cancer since it may mediate immune evasion and thus promote tumor growth. HLA-G is, therefore, a potential target for immunotherapy. However, existing monoclonal antibodies directed against HLA-G lack sufficient specificity and are not suitable for immune checkpoint inhibition in a clinical setting. For this reason, it is essential that alternative approaches are explored to block the interaction between HLA-G and its receptors. In this review, we discuss the structure and peptide presentation of HLA-G, and its interaction with the receptors Ig-like transcript (ILT) 2, ILT4, and Killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4). Based on our findings, we propose three alternative strategies to block the interaction between HLA-G and its receptors in cancer immunotherapy: (1) prevention of HLA-G dimerization, (2) targeting the peptide-binding groove of HLA-G, and (3) targeting the HLA-G receptors. These strategies should be an important focus of future studies that aim to develop immune checkpoint inhibitors to block the interaction between HLA-G and its receptors for the treatment of cancer. Full article