Killer Cell Immunoglobulin-like Receptors Genotypes Research Articles

Killer Cell Immunoglobulin-like Receptor Variants Are Associated with Protection from Symptoms Associated with More Severe Course in Parkinson Disease.

Immune dysfunction plays a role in the development of Parkinson disease (PD). NK cells regulate immune functions and are modulated by killer cell immunoglobulin-like receptors (KIR). KIR are expressed on the surface of NK cells and interact with HLA class I ligands on the surface of all nucleated cells. We investigated KIR-allelic polymorphism to interrogate the role of NK cells in PD. We sequenced KIR genes from 1314 PD patients and 1978 controls using next-generation methods and identified KIR genotypes using custom bioinformatics. We examined associations of KIR with PD susceptibility and disease features, including age at disease onset and clinical symptoms. We identified two KIR3DL1 alleles encoding highly expressed inhibitory receptors associated with protection from PD clinical features in the presence of their cognate ligand: KIR3DL1*015/HLA-Bw4 from rigidity (p c = 0.02, odds ratio [OR] = 0.39, 95% confidence interval [CI] 0.23-0.69) and KIR3DL1*002/HLA-Bw4i from gait difficulties (p c = 0.05, OR = 0.62, 95% CI 0.44-0.88), as well as composite symptoms associated with more severe disease. We also developed a KIR3DL1/HLA interaction strength metric and found that weak KIR3DL1/HLA interactions were associated with rigidity (pc = 0.05, OR = 9.73, 95% CI 2.13-172.5). Highly expressed KIR3DL1 variants protect against more debilitating symptoms of PD, strongly implying a role of NK cells in PD progression and manifestation.

Decreased HLA-C1 alleles in couples of KIR2DL2 positive women with recurrent pregnancy loss

Specific killer cell immunoglobulin-like receptor (KIR) in women with recurrent pregnancy loss (RPL) and HLA ligands in couples invoke a susceptibility to RPL. However, the relationship between KIR2DL2 and its cognate ligand HLA-C1 has not been explored. In this prospective cohort study, 160 Caucasian women with RPL and 99 partners were included. KIR/HLA-C typing, NK assay, Th1/Th2 intracellular cytokine ratios, 25-(OH)-vitamin D level, and the presence of autoantibodies were analyzed. KIR2DL2 positive women (P = 0.023) and their partners (P = 0.017) had lower allele frequencies of HLA-C1 than those of KIR2DL2 negative women. KIR2DL2 positive women had significantly lower genotype frequency of HLA-C1C1 as compared to the North American Caucasian population controls (P < 0.05). In the partners of KIR2DL2 positive women, there was a substantially higher frequency of HLA-C2C2 than controls (P = 0.016). Besides, KIR2DL2 negative women had a higher prevalence of anti-ssDNA antibody as compared with that of KIR2DL2 positive women (P = 0.043). There were no differences in the distribution of HLA-C genotypes based on KIR2DL2, regardless of pregnancy outcome in women with RPL and their partners while on immunomodulation treatment. In conclusion, decreased ligands for inhibitory KIRs (inhKIR) could lead to insufficient inhibition of maternal uterine NK cells toward the trophoblast, thereby contributing to the pathogenesis of RPL. Specific KIR and HLA-C genotyping may predict the reproductive outcome of women with RPL.

Parental human leukocyte antigen-C allotypes are predictive of live birth rate and risk of poor placentation in assisted reproductive treatment

To study the pregnancy, miscarriages, and live birth rates (LBRs) according to maternal killer cell immunoglobulin-like receptor (KIR) genes expressed by uterine natural killer cells and paternal or oocyte donor human leukocyte antigen-C (HLA-C) genes expressed by trophoblast cells in patients with recurrent reproductive failure. Prospective observational cohort study. Private infertility center. Participants included 204 women with recurrent miscarriage or recurrent implantation failure. The KIR and HLA-C genotypes of all women and HLA-C of their partners, gamete donors, miscarriage tissue, and babies were analyzed. All clinical variables (pregnancy, miscarriage, and LBRs) were analyzed and categorized based on KIR, oocyte origin, and single embryo transfer (SET)/double embryo transfer (DET). A higher miscarriage rate was observed after DETs in KIR AA mothers (47.8% egg donation and 37.5% invitro fertilization [IVF]) compared with KIR AB (10.5% egg donation and 12.5% IVF) or KIR BB (6.7% egg donation and 0% IVF). A significantly decreased LBR was observed after DETs with oocyte donation in KIR AA patients (4.3%) compared with KIR AB (26.3%) or BB (46.7%). The LBR decreased significantly as the fetal HLA-C2 load increased in KIR AA women. Elective SET improves the reproductive outcomes compared with DET. An increased embryo HLA-C2 load has a negative impact on the LBR in KIR AA patients. The selection of HLA-C1 over HLA-C2 donors could have a positive impact on the LBR in KIR AA patients. NCT04052438.

Polymorphism in killer cell immunoglobulin-like receptors and human leukocyte antigen-c and predisposition to preeclampsia in Ethiopian pregnant women population

IntroductionPreeclampsia (PE) is a human specific pregnancy-related syndrome of unknown etiology that affects 2–8 % of pregnancies. Polymorphism in maternal Killer Cell Immunoglobulin-like Receptors (KIRs) and the ligand fetal Human Leukocyte Antigen-C (HLA-C) may predispose pregnant mothers for PE due to defective trophoblast invasion into the maternal decidua. Our study aimed to investigate the association between maternal KIR and fetal HLA-C polymorphism and PE in Ethiopian pregnant women. MethodsWe included a total of 288 (157 controls and 131 PE cases) in a case-controls study at Adama Regional Referral Hospital, Ethiopia. The KIR and HLA-C genotyping was done using traditional polymerase chain reaction on genomic DNA extracted form maternal venous and cord blood followed by 2% agarose gel electrophoresis. ResultsThe statistical associations between variables were evaluated using Pearson’s Chi-square test. P < 0.05, with 95 % confidence interval was considered statistically significant. A significant association was observed between the KIR2DS1 and PE, with a higher frequency (60.5 %) of the gene in the control group. Similarly, a significant association was observed between KIR AA genotype and PE, with a higher frequency (38.2 %) of this genotype in the PE group. Ethiopians share the same risk genotype for PE as seen in previous African and European studies, namely homozygosity of a maternal KIR AA genotype. However, Ethiopians differ from other East African populations by sharing the same protective KIR2DS1 gene as Europeans.

Maternal killer-cell immunoglobulin-like receptors and paternal human leukocyte antigen ligands in recurrent pregnancy loss cases in Turkey.

Objective The survival of a semi-allogeneic fetus depends on several immunological mechanisms, and it has been suggested that recurrent pregnancy loss (RPL) could develop as a result of one or more immunological abnormalities.Methods Compatibility between partners for human leukocyte antigen (HLA) genotypes and the relationships between maternal killer-cell immunoglobulin-like receptor (KIR) and paternal HLA-Bw4/Bw6 and HLA-C1/C2 supra-groups were investigated in 25 couples with RPL in comparison to healthy couples with children. HLA and KIR genotyping was performed using polymerase chain reaction with sequence-specific primers and/or sequence-specific oligonucleotides.Results HLA class I incompatibility between partners, especially in HLA-B alleles, was more common in the RPL group (p= 0.01). HLA-C2 homozygosity was more frequent in the male partners of RPL couples than in other groups (p= 0.03). The KIR2DL5 gene frequency was significantly higher in both the female and male partners of RPL couples, whereas the KIR2DS3 gene frequency in male partners of RPL couples was significantly reduced (p= 0.03). The presence of KIR2DL3 in women with RPL was correlated with the presence of HLA-C2 alleles in their spouses (p= 0.03).Conclusion Our data from a Turkish population suggest that male HLA-C2 homozygosity may play an important role in RPL. Additionally, an incidental match between male HLA-C2 and female HLA-C1 ligand KIR receptors might perturb the balance between activatory and inhibitory KIR-ligand interactions during pregnancy in couples affected by RPL. The roles of orphan KIR2DL5 and orphan KIR2DS3 in RPL remain obscure.

KIR3DL1 and HLA-Bw4 Interaction Showed a Favorable Role in Patients with Myelodysplastic Syndromes in Chinese Southern Han.

Background The association studies of killer cell immunoglobulin-like receptors (KIRs) with the occurrence of myelodysplastic syndromes (MDS) are limited worldwide; this study investigated the genetic risk/protective factors of MDS in KIR and human leucocyte antigen (HLA) systems to gain a better understanding of the role played by KIR and their cognate HLA ligands in MDS pathogenesis. Methods We genotyped a total number of 77 patients with MDS from Chinese Southern Han and 745 healthy controls for the KIR loci and HLA class I. The carrier frequencies of KIR genes, KIR genotypes, class I HLA ligands, and KIR-HLA combinations were calculated by direct counting. The effect of individual KIR genes and HLA ligands on MDS risk was evaluated by logistic regression analyses using SAS 9.2 software. Results We found that neither the KIR genes nor the KIR genotypes were associated with the occurrence of MDS. However, we observed that the frequencies for the strong inhibitory ligand HLA-Bw4 as well as KIR3DL1-HLA-Bw4 combination were significantly higher in healthy controls than those in the MDS patient group, respectively (73.42% vs. 62.34%, P = 0.038; 70.87% vs. 59.74%, P = 0.043). Conclusion Our results showed that HLA-Bw4 ligand and KIR3DL1-HLA-Bw4 combination could confer a protective effect against MDS in Chinese Southern Han.

External validation of models for KIR2DS1/KIR3DL1-informed selection of hematopoietic cell donors fails

AbstractSeveral studies suggest that harnessing natural killer (NK) cell reactivity mediated through killer cell immunoglobulin-like receptors (KIRs) could reduce the risk of relapse after allogeneic hematopoietic cell transplantation. Based on one promising model, information on KIR2DS1 and KIR3DL1 and their cognate ligands can be used to classify donors as KIR-advantageous or KIR-disadvantageous. This study was aimed at externally validating this model in unrelated donor hematopoietic cell transplantation. The impact of the predictor on overall survival (OS) and relapse incidence was tested in a Cox regression model adjusted for patient age, a modified disease risk index, Karnofsky performance status, donor age, HLA match, sex match, cytomegalovirus match, conditioning intensity, type of T-cell depletion, and graft type. Data from 2222 patients with acute myeloid leukemia or myelodysplastic syndrome were analyzed. KIR genes were typed by using high-resolution amplicon-based next-generation sequencing. In univariable analyses and subgroup analyses, OS and the cumulative incidence of relapse of patients with a KIR-advantageous donor were comparable to patients with a KIR-disadvantageous donor. The adjusted hazard ratio from the multivariable Cox regression model was 0.99 (Wald test, P = .93) for OS and 1.04 (Wald test, P = .78) for relapse incidence. We also tested the impact of activating donor KIR2DS1 and inhibition by KIR3DL1 separately but found no significant impact on OS and the risk of relapse. Thus, our study shows that the proposed model does not universally predict NK-mediated disease control. Deeper knowledge of NK-mediated alloreactivity is necessary to predict its contribution to graft-versus-leukemia reactions and to eventually use KIR genotype information for donor selection.

The Roles of Uterine Natural Killer (NK) Cells and KIR/HLA-C Combination in the Development of Preeclampsia: A Systematic Review.

Preeclampsia (PE) is termed as a systemic disease that involves multiple organs; however, the exact etiology is still quite unclear. It is believed that the poor remodeling of uterine spiral arteries triggers PE, thereby causing failed placentation and producing inflammatory factors. The decline of blood flow results in lowering the nutrients and oxygen received by the fetus and augmenting the placental pressure in PE. Decidual immune cells, especially uterine natural killer (uNK) cells, are involved in the process of placentation. Decidual NK (dNK) cells significantly contribute to the vascular remodeling through the secretion of cytokines and angiogenic mediators in normal placental development. The abnormal activation of NK cells in both the peripheral blood and the decidua was counted among the causes leading to PE. The correlation existing between maternal killer cell immunoglobulin-like receptor (KIR) and HLA-C in trophoblast cells constitutes a robust evidence for the genetic etiology of PE. The combinations of the two kinds of gene systems, together with the KIR genotype in the mother and the HLA-C group in her fetus, are likely to exactly decide the pregnancy outcome. The women, who have the inappropriate match of KIR/HLA-C, are likely to be prone to the augmented risk of PE. However, the combinations of KIR/HLA-C in PE undergo ethnic changes. The extensive prospective research works in Europe, Asia, and Africa are required for providing more findings in PE patients.

Impact of donor KIRs and recipient KIR/HLA class I combinations on GVHD in patients with acute leukemia after HLA-matched sibling HSCT

In addition to T cells, NK cells can also participate in the outcome of hematopoietic stem cell transplantation (HSCT) mainly through the interaction between donor killer cell immunoglobulin-like receptors (KIRs) and recipient human leukocyte antigen (HLA) class I molecules. There is a risk of GVHD other than leukemia relapse after allogeneic HSCT that activation of donor NK cells in the absence of appropriate inhibitory ligands will be one of the reasons. To investigate the impact of donor KIRs and recipient KIR/HLA class I combinations on GVHD and leukemia relapse in patients with acute leukemia after HSCT, 100 patients with acute leukemia who received HSCT from their HLA-matched siblings were included in this study. Genotypes of 16 KIR genes and two 2DS4 variants (full length and deleted alleles), along with HLA-A/B genotypes, were determined by PCR-SSP. HLA-C genotyping was done with the SSO-Luminex method. Chimerism analysis was done using 16 short tandem repeats (STRs) to detect early leukemia relapse. Acute (a)GVHD occurred in 38 patients, and 16 of them died during the study. None of the recipients showed any sign of leukemia relapse after HSCT. Full donor chimerism was observed in all tested patients during the first year after HSCT. Our results also indicated an increased risk of aGVHD in AA recipients with the C2/Cx, Bw4+ (or A-Bw4+) or HLA-A3−/A11− genotypes who received HSCT from Bx donors. Our results showed that donor selection based on donor-recipient KIR genotypes and recipient HLA class I status can improve the outcome of HSCT.

Killer cell immunoglobulin-like receptors (KIR) and human leukocyte antigen-C (HLA-C) allorecognition patterns in women with endometriosis

Endometriosis shares similarities with several autoimmune diseases. The human leukocyte antigen (HLA)-C genotype is associated with several human autoimmune diseases. HLA-C is a ligand of killer cell immunoglobulin receptors (KIRs) and is an essential regulator of natural killer cell activity, which is associated with endometriosis progression. Polymorphisms in HLA-C and KIR affect the activity of NK cells and susceptibility to several diseases. Therefore, we attempted to investigate an association between HLA-C genotype and KIR polymorphism and the occurrence of endometriosis. We tested the association of certain KIR and HLA-C combinations and the development of endometriosis by characterizing both KIR and HLA-C genes in 147 women with endometriosis and 117 controls. The HLA-C genotypes and KIR polymorphisms were analyzed via DNA-based method for higher-resolution genotyping. We found that the occurrence of HLA-C*03:03*01 was increased in endometriosis than in control groups. Analysis of various KIR haplotypes revealed differences between the endometriosis and control cohorts. The number of KIR centromeric A/A haplotypes was increased in the endometriosis group than controls. Moreover, the endometriosis cohort was characterized by reduced number of KIR2DS2-positive individuals in the Han Chinese population. Our current findings suggest that the KIR and HLA-C genotypes are associated with the pathogenesis of endometriosis.

Killer Cell Immunoglobulin-Like Receptor Genotypes and Haplotypes Contribute to Susceptibility to Hepatitis B Virus and Hepatitis C Virus Infection in Cameroon.

Over 325 million people worldwide are living with hepatitis B and C viral infections and are at greater risk of developing hepatocellular carcinoma. The interactions between killer cell immunoglobulin-like receptors (KIRs) and their cognate ligands, human leukocyte antigens, modulate both infection processes and disease progression. We report here (1) genotype and haplotype variations in KIR genes in Cameroon and (2) their impact on susceptibility to hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. In 98 unrelated individuals (33 HCV+, 31 HBV+, and 34 uninfected healthy controls), we determined the presence of 15 KIR genes by polymerase chain reaction-sequence-specific primer techniques. One pseudogene and all 14 KIR genes were present. We identified 36 KIR genotypes, 5 of which have not been previously reported in public databases. Two inhibitory (KIR2DL1 and KIR2DL3) and three activating (KIR2DS4, KIR2DS2, and KIR2DS3) genes were present in all HCV-infected individuals. Similarly, KIR3DL1, KIR2DL1, and KIR2DS4 were present at 100% in the HBV+ group. Compared with uninfected healthy controls, the frequencies of KIR2DL2 and KIR3DS1 were significantly lower in the HBV+ group (p = 0.003 and p < 0.001, respectively). Conversely, KIR3DS1 was significantly overrepresented in the HCV+ group compared with controls (97.0% vs. 64.7%, respectively, p < 0.001). These results may imply that KIR3DS1 carriers were less likely to be HBV infected, but may be predisposed to HCV infection compared with uninfected controls, indicating their important role in transmission of these viruses. However, phenotypic, functional, and genomic studies to elucidate the role of these KIR genotypes and haplotypes in infection with HBV and HCV are important.

A Targeted Genetic Association Study of the Rare Type of Osteomyelitis

Chronic nonbacterial osteomyelitis is a rare bone disorder that can be found in the jaw. It is often associated with systemic conditions, including autoimmune deficiencies. However, little is known about how the genetic and immunologic background of patients influences the disease. Here, we focus on human leukocyte antigen (HLA), killer cell immunoglobulin-like receptors (KIRs), and their specific combinations that have been difficult to analyze owing to their high diversity. We employed a recently developed technology of simultaneous typing of HLA alleles and KIR haplotype and investigated alleles of the 35 HLA loci and KIR haplotypes composed of centromeric and telomeric motifs in 18 cases and 18 controls for discovery and 472 independent controls for validation. We identified an amino acid substitution of threonine at position 94 of HLA-C in combination with the telomeric KIR genotype of haplotype tA01/tB01 that had significantly higher frequency (>20%) in the case population than in both control populations. Multiple logistic regression analysis based on a dominant model with adjustments for age and sex revealed and validated its statistical significance and high predictive accuracy (C-statistic ≥0.85). Structure-based analysis revealed that the combination of the amino acid change in HLA-C and the telomeric genotype tA01/tB01 could be associated with lower stability of HLA-C. This is the first case-control study of a rare disease that employed the latest sequencing technology enabling simultaneous typing and investigated amino acid polymorphisms at HLA loci in combination with KIR haplotype.

Association of Killer Cell Immunoglobulin-like Receptor Genotypes and Haplotypes in Dry Eye Disease Patients Treated with Restasis and Systane

ABSTRACT Purpose: whether the Killer immunoglobulin-like receptor (KIR) genotypes and haplotypes are associated with the improvement in dry eye disease (DED) patients treated with Restasis and Systane (RS) remain unclear. Methods: Polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to analyze KIR genes in a Chinese Han population of 198 severe DED patients treated with RS. Results: The higher frequencies of KIR genotype M, AF, AJ and haplotype 2 and 8 (P = .001, P = .03, P = .004, P = .000 and P = .023, respectively) and the lower frequencies of genotype AG and haplotype 1 (P = .000 and P = .000, respectively) were observed in complete responders (CR) than those in null or partial responders (NPR) of DED patients treated by RS. Conclusions: The patients with KIR genotype M, AF and AJ might be of advantage to therapy with RS, which are useful for improving novel personalized precise therapy strategy in DED patients.

Donor KIR2DS1-Mediated Decreased Relapse and Improved Survival Depending on Remission Status at HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide

HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) using post-transplantation cyclophosphamide (PT/Cy-haplo) is becoming the standard of care for patients without an HLA-matched related or unrelated donor. PT/Cy-haplo can give more patients the opportunity to undergo allo-HCT, because most patients have multiple available HLA-haploidentical related donor candidates. The optimal donor selection algorithm in the PT/Cy-haplo setting has not yet been established, however. To contribute to the establishment of a donor selection formula based on disease status and killer-cell immunoglobulin-like receptor (KIR) genotype, we retrospectively analyzed 91 patients who underwent PT/Cy-haplo at our institution. In both patients and donors, HLA allele genotyping was performed for HLA-A, -B, -C, and -DRB1, and 16 KIR genes were genotyped. Patients in complete remission (CR) who underwent PT/Cy-haplo from a KIR2DS1-positive donor had a significantly lower cumulative incidence of relapse (CIR) than those who underwent PT/Cy-haplo from a KIR2DS1-negative donor (1-year CIR: 0% versus 32.6%, P=.037; 2-year CIR: 9.2% versus 42%, P=.037). Moreover, PT/Cy-haplo from a KIR2DS1-positive donor was significantly associated with improved overall survival (OS) (1-year OS: 91.7% versus 58.7%, P=.010; 2-year OS: 83% versus 34%, P=.010). In contrast, in non-CR individuals, PT/Cy-haplo from KIR2DS1-positive donors did not significantly improve CIR or OS (1-year CIR: 56.5% versus 64.7%, P=.973; 2-year CIR: not reached versus 64.7%, Pnot evaluable; 1-year OS: 25.4% versus 20.6%, P=.418; 2-year OS: 5.1% versus 20.6%, P=.418). In addition, lower infused CD34+ cell dose, female-to-male transplantation, and acute myelogenous leukemia were significantly associated with increased risk of relapse and mortality. This study demonstrates that graft-versus-leukemia/tumor effects were exerted through donor KIR2DS1 at PT/Cy-haplo when patients have low tumor burdens. It would be worth examining the inclusion of donor KIR genotyping and disease status assessment in establishing optimal donor selection criteria for PT/Cy-haplo.

Combined association of recipient killer cell immunoglobulin‐like haplotype AA and donor HLA‐C*07 gene with BK virus associated nephropathy in kidney transplant patients

Kidney transplant recipient killer cell immunoglobulin-like receptors (KIR) genotype and HLA-C status of their donors have been separately associated with BK virus-associated nephropathy (BKVAN) and BK virus infection. Our aim was to determine whether different combinations of recipients KIR genes and donor HLA-C ligands influence the risk of BKVAN. Retrospective case-control study included 23 recipients with BKVAN and 46 recipients with persistently negative BK virus. Donor HLA-C*07 positivity was associated with lower odds for BKVAN, recipients bearing KIR haplotype AA or lacking any activating KIR genes were more frequent in BKVAN while recipient/donor combination HLA-C*07 negative/KIR AA positive was significantly associated with BKVAN. Our study complements and confirms results from several previously published studies, suggesting potential clinical usefulness.

Distribution of human killer cell immunoglobulin-like receptors and ligands among blood donors of Catalonia.

Killer cell immunoglobulin-like receptors (KIR) belong to a diverse family of receptors present in NK cells and certain subsets of T cells. They bind to HLA class I molecules and, such as these, are highly polymorphic. This study is the first to determine KIR gene content diversity and perform high-resolution genotyping of corresponding HLA class I ligands in 445 unrelated blood donors resident in Catalonia (northeast Spanish region) and registered in the Blood and Tissue Bank of Barcelona between 2017 and 2018. The study was performed using a new next-generation sequencing method developed and validated by our group, with an important hands-on-time reduction and very cost-effectiveness. Thirty-eight KIR genotypes were observed. Haplotype combination frequencies were 24.49% for AA, 75.51% for BX. The most frequent genotype, found in 109 individuals (24.49%), was genotype ID 1. Seventeen genotypes occurred only once. Thirty individuals carried all KIR genes (genotype ID 6). We detected 46 HLA-A, 63 HLA-A-B, and 40 HLA-A-C alleles. A majority of individuals were heterozygous for C1/C2 (42.24%), 38.43% were homozygous for C1, and 19.33% were homozygous for C2. The most common KIR-HLA ligand pair was KIR3DL1-Bw4+, present in 75.73% of cases. No differences were found in KIR gene frequencies between the Catalan cohort and other Iberian Peninsula populations. Our findings will be useful for guiding further research evaluating the functional significance of KIR-ligand associations in specific diseases.

Impact of Donor KIR and HLA Genotypes on Clinical Outcomes According to Pre-Transplant Remission Status after HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide

Impact of Donor KIR and HLA Genotypes on Clinical Outcomes According to Pre-Transplant Remission Status after HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide

Impact of KIR/HLA Incompatibilities after Posttransplant Cyclophosphamide Based T Cell-Replete Haploidentical Hematopoietic Stem Cell Transplantation

Introduction: Posttransplantation cyclophosphamide (PTCy) based T cell-replete haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) is a valid option for patients with indication for allogeneic HSCT without a human leucocyte antigen (HLA) matched donor. However, selection criteria to determine the optimal among several available haplo donors are still a matter of debate. Especially, the impact of killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA) incompatibilities (inc) in the setting of PTCy T cell-replete haplo HSCT is unclear. PTCy has been reported to eliminate most mature donor NK cells infused with the graft, including single KIR+ NK cells, thereby blunting NK cell alloreactivity in this setting (Russo et al., Blood 2018). Willem et al. (J Immunol 2019) reported (i) a significant loss of KIR2DL2/3+ NK cells at day +30 in patients with inhibitory KIR/HLA incompatibility (inc.) suggesting that PTCy might target responsive KIR NK cells and (ii) a correlation of genetic KIR2DL/HLA inc. with less relapse, but more graft-versus-host-disease (GvHD). Similarly, NK alloreactivity defined as KIR receptor-ligand mismatch or group B KIR haplotype with the presence of KIR2DS2 has been correlated with improved survival (Salomon et al., BBMT 2018). Aims of our study were to evaluate the impact of (i) HLA/KIR inc, (ii) donor KIR genotype and (iii) HLA-DP mismatch status on survival and incidence of relapse, acute and chronic GvHD in our homogeneously treated, independent patient cohort. Patients and methods: We retrospectively analyzed the outcome of 51 consecutively transplanted patients (AML/MDS (n=28/5), ALL (n=9), HD (n=2), NHL (n=5), CML (n=1), PMF (n=1)) receiving a PTCy based T cell-replete haplo HSCT between 01/2011-12/2018. All patients received a myeloablative conditioning regimen (fludarabine/total body irradiation (FTBI) or thiotepa/busulfan/fludarabine (TBF)) with unmanipulated bone marrow (98%) as the preferred graft (median CD34+ cells: 3.02 x 106/kg (range, 1.50-6.90) and median CD3+ T cells: 3.54 x 107/kg (range 1.52-43.74)). GvHD prophylaxis with ciclosporin A started on day 0, mycophenolate-mofetil on day +1, PTCy was applied on day +3 and +5. Results: Patient, donor and transplant characteristics as detailed in table 1 were well balanced between the inh. KIR/HLA inc. group (n=29) vs. no inh. KIR/HLA inc. group (n=22) with the exception of the median donor age (41.7 (range, 23.4-73.7) vs. 33.6 years (range, 19.0-56.2), resp. All patients engrafted. At day +28 (range, 20-29; n=26) CD3+ cells were 88.5/nL (range, 3-665), CD3+CD4+ cells 22.5/nL (range, 0-277.0), CD3+CD8+ cells 117.0/nL (range, 7-478), CD19+ cells 1.0/nL (range, 0-12), CD56bright cells 74.4/nL (range11.1-93.4), CD56dim cells 25.5/nL (range, 6.4-88.9) measured by flow cytometry and without differences between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. Cytomegalovirus (CMV) reactivation occurred in 73.3% of patients at risk and median time of occurrence was 32 days (range, 12-97) without difference between groups. Median follow-up for surviving patients was 26.1 months (range, 2.8-92.8) and we found no significant differences in 2-year overall survival (OS; 65.3±10.3 vs. 89.6±7.0, p=0.311), 2-year relapse-free survival (RFS; 66.0±9.4 vs 77.8±10.2, p=0.235), GvHD- and relapse-free survival (GRFS; 48.4±9.8 vs 60.5±12.0, p=0.182) as well as cumulative incidence (CI) of relapse (23.3% vs 16.2%, p= 0.283), acute GvHD grade 2-4 (27.6% vs 31.8, p=0.563), moderate-severe chronic GvHD (22.2% vs. 9.9%, p=0.227) and NRM (16.3% vs 5.3%, p=0.283) between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. This was also the case for donor KIR genotype AA vs AB (n=46; 2-y OS: 74.9±13.0% vs. 73.0±9.9%, p=0.844; 2-y RFS: 60.0±14.8% vs 74.5±8.4%, p=0.645) and HLA-DP-identical/permissive mismatch (MM) vs non permissive MM (n=45; 2-y OS: 70.7±10.0% vs 72.7±13.4%, p=0.945; 2-y RFS: 73.2±8.2% vs 63.6.0±14.5%, p=0.798) Conclusion: Our outcome data support the hypothesis of PTCy eliminating mature donor NK cells infused with the graft and thereby reducing the impact of alloreactivity in this setting. However, our patient number is quite small and the findings need to be validated in larger cohorts and preferably prospective studies. Disclosures Lindner: Celegene, Sanofi, Neovii: Honoraria, Research Funding. Berg:Riemser Pharma GmbH: Consultancy, Honoraria; Incyte, Abbvie, Astellas, Alexion and Celgene: Other: travel support. Bug:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Neovii: Other: travel grant; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Hexal: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Sanofi: Other: travel grants. Schwaeble:Uniqure BV: Research Funding. Ullrich:CellGenix: Honoraria, Research Funding; Novartis: Research Funding.

Population-specific criterion to distinguish killer cell immunoglobulin-like receptor genotypes and haplotypes in a large Eastern Han population.

With the goal of improving the population-specific criteria to distinguish KIR genotypes and haplotypes in the region, we examined the KIR gene and haplotype data of Eastern Han based on a large population and analyzed the component genes of centromeric (Cen) and telomeric (Tel) KIR haplotype segments, which may differ in the protection they provide in hematopoietic stem cell transplantation. Samples from 598 families and 2845 unrelated individuals of Eastern Han origin were collected between 2010 and 2017. Genotyping of 17 KIR genes was performed by PCR-SSP and SSO methods. The results showed we obtained the KIR gene distribution of the Eastern Han population. The KIR gene frequencies (GF) in the present study are similar to those observed in other studies on Han but different from other populations. We observed a total of 56 different genotypes, including 1 AA and 55 group B genotypes. The high-frequency KIR genotype profiles found in the present population were consistent with other studies on Han populations but different from those conducted on other populations. In the family panel, a total of 28 KIR haplotypes were identified in the segregation study. The majority of Eastern Han carried group A KIR gene motifs. Comparison of the frequencies of Cen and Tel KIR gene motifs shows that they differ from other populations. The study on the distribution of KIR genes in the population may aid in the development of a complementary population-specific criterion to distinguish between KIR haplotypes and offer a research direction for further gene functional studies.

Association of KIR genes and their HLA ligands diversity with colorectal cancer in Lur population of Iran

ObjectivesThis study was aimed to evaluate the disease association of each killer-cell immunoglobulin-like receptor (KIR) genes and their known human leukocyte antigen (HLA) ligands (HLA-C and -Bw4) as well as KIR haplotypes and KIR-HLA interactions in Lur population of west of Iran. MethodsIn this case-control study, 50 cases with colorectal cancer and 100 healthy controls were taken. The genomic DNA was extracted and polymerase chain reaction with sequence specific primers (PCR-SSP) was used to genotyping the samples. Statistical analysis was done using 2 by 2 tables. In order to compare the results with other previous studies, funnel plot and cluster analysis were used. ResultsAmong the single gene analyses, only the association of KIR2DS5 was statistically significant (Pearson chi-square P = .0206; Yate's corrected chi-square P = .0323; OR = 2.25 [1.12–4.49 95% CI]). No significant association was observed for neither KIR nor HLA genotypes. Among the KIR-HLA interactions, no significant association was observed as well. ConclusionThe results of this paper supported the results of previous studies as well as the rationale existing behind the tumor biology. The ligand of KIR2DS5 should be discovered and evaluated in future.