Influence of the immunogenetic KIR and HLA systems on long-term renal transplant outcome

Manna, Gaetano La; Corsini, Serena; Iannelli, S.; Cappuccilli, Maria; Comai, Giorgia; Iorio, Mario; Todeschini, Paola; Carretta, Elisa; Scolari, Maria; Bontadini, Andrea; Stefoni, S

doi:10.12659/aot.889157

Cited by 13 publications

(8 citation statements)

References 26 publications

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“…In a murine kidney transplant model based on hybrid resistance, NK cells were shown to mediate long-term allograft injury in the absence of T and B cells [ 28 ]. In this context of missing-self recognition, an influence of certain KIR genes was proposed as KIR2DS3 without cognate HLA ligand was associated with better, with ligand with worse effects on kidney function [ 13 ]. In order to improve our understanding of the NK cell repertoire, function and the influence of immunosuppression in our patient cohort after KTx, we investigated receptor expression and response to in vitro stimulation of NK cells derived from KTx recipients compared to healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

“…The role of these NK cell subsets in kidney transplantation (KTx) has not been clarified yet, although recent studies revealed that a KIR-ligand mismatch between donor HLA class I molecules and recipient KIR repertoire has no impact on allograft outcome [ 12 ]. In a recent study, however, the presence of the KIR2DS3 gene in KTx recipients was associated with better graft function in the absence of the HLA class I ligand in the donor [ 13 ]. In addition, lower NK cell numbers with increased proportions of CD56 bright NK cells were identified in DSA-positive kidney transplanted patients [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

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NK Cells of Kidney Transplant Recipients Display an Activated Phenotype that Is Influenced by Immunosuppression and Pathological Staging

et al. 2015

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To explore phenotype and function of NK cells in kidney transplant recipients, we investigated the peripheral NK cell repertoire, capacity to respond to various stimuli and impact of immunosuppressive drugs on NK cell activity in kidney transplant recipients. CD56dim NK cells of kidney transplanted patients displayed an activated phenotype characterized by significantly decreased surface expression of CD16 (p=0.0003), CD226 (p<0.0001), CD161 (p=0.0139) and simultaneously increased expression of activation markers like HLA-DR (p=0.0011) and CD25 (p=0.0015). Upon in vitro stimulation via Ca++-dependent signals, down-modulation of CD16 was associated with induction of interferon (IFN)-γ expression. CD16 modulation and secretion of NFAT-dependent cytokines such as IFN-γ, TNF-α, IL-10 and IL-31 were significantly suppressed by treatment of isolated NK cells with calcineurin inhibitors but not with mTOR inhibitors. In kidney transplant recipients, IFN-γ production was retained in response to HLA class I-negative target cells and to non-specific stimuli, respectively. However, secretion of other cytokines like IL-13, IL-17, IL-22 and IL-31 was significantly reduced compared to healthy donors. In contrast to suppression of cytokine expression at the transcriptional level, cytotoxin release, i.e. perforin, granzyme A/B, was not affected by immunosuppression in vitro and in vivo in patients as well as in healthy donors. Thus, immunosuppressive treatment affects NK cell function at the level of NFAT-dependent gene expression whereby calcineurin inhibitors primarily impair cytokine secretion while mTOR inhibitors have only marginal effects. Taken together, NK cells may serve as indicators for immunosuppression and may facilitate a personalized adjustment of immunosuppressive medication in kidney transplant recipients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NK Cells of Kidney Transplant Recipients Display an Activated Phenotype that Is Influenced by Immunosuppression and Pathological Staging

et al. 2015

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“…Previous efforts [ 22 – 25 ] have tried to overcome the problems by matching with high accuracy those domains that directly interact with the antigen (exons 2 and 3 for HLA class I, and exon 2 for HLA class II), but this approach has proven to be insufficient alone [ 26 ]. Furthermore, while HLA typing and HLA gene validation are done routinely through molecular genotyping methods [ 27 – 29 ], the large and rapidly growing number of described HLA alleles are rendering them obsolete and unable to meet current clinical and research throughput demands [ 14 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Benchmarking the HLA typing performance of Polysolver and Optitype in 50 Danish parental trios

2018

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BackgroundThe adaptive immune response intrinsically depends on hypervariable human leukocyte antigen (HLA) genes. Concomitantly, correct HLA phenotyping is crucial for successful donor-patient matching in organ transplantation. The cost and technical limitations of current laboratory techniques, together with advances in next-generation sequencing (NGS) methodologies, have increased the need for precise computational typing methods.ResultsWe tested two widespread HLA typing methods using high quality full genome sequencing data from 150 individuals in 50 family trios from the Genome Denmark project. First, we computed descendant accuracies assessing the agreement in the inheritance of alleles from parents to offspring. Second, we compared the locus-specific homozygosity rates as well as the allele frequencies; and we compared those to the observed values in related populations. We provide guidelines for testing the accuracy of HLA typing methods by comparing family information, which is independent of the availability of curated alleles.ConclusionsAlthough current computational methods for HLA typing generally provide satisfactory results, our benchmark – using data with ultra-high sequencing depth – demonstrates the incompleteness of current reference databases, and highlights the importance of providing genomic databases addressing current sequencing standards, a problem yet to be resolved before benefiting fully from personalised medicine approaches HLA phenotyping is essential.

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“…KIR genotypes also affect transplantation outcomes. Donor/recipient KIR ligand mismatches reduce graft survival in hepatic and renal transplantation (Kuśnierczyk 2013; La Manna et al 2013; Legaz et al 2013; Van Bergen et al 2011). For instance, Cirocco et al (2007) and Kunert et al (2007) independently found that acute rejection was significantly decreased in transplants involving KIR2DL2+ recipients matched with HLA-C1+ donors compared to HLA-C1 - donors.…”

Section: Introductionmentioning

confidence: 99%

Improved full-length killer cell immunoglobulin-like receptor transcript discovery in Mauritian cynomolgus macaques

et al. 2017

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Killer cell Immunoglobulin-like Receptors (KIRs) modulate disease progression of pathogens including HIV, malaria, and hepatitis C. Cynomolgus and rhesus macaques are widely used as nonhuman primate models to study human pathogens and so considerable effort has been put into characterizing their KIR genetics. However, previous studies have relied on cDNA cloning and Sanger sequencing that lacks the throughput of current sequencing platforms. In this study, we present a high throughput, full-length allele discovery method utilizing PacBio circular consensus sequencing (CCS). We also describe a new approach to Macaque Exome Sequencing (MES) and the development of the Rhexome1.0, an adapted target capture reagent that includes macaque-specific capture probesets. By using sequence reads generated by whole genome sequencing (WGS) and MES to inform primer design, we were able to increase the sensitivity of KIR allele discovery. We demonstrate this increased sensitivity by defining nine novel alleles within a cohort of Mauritian cynomolgus macaques (MCM), a geographically isolated population with restricted KIR genetics that was thought to be completely characterized. Finally, we describe an approach to genotyping KIRs directly from sequence reads generated using WGS/MES reads. The findings presented here expand our understanding of KIR genetics in MCM by associating new genes with all eight KIR haplotypes and demonstrating the existence of at least one KIR3DS gene associated with every haplotype.

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Influence of the immunogenetic KIR and HLA systems on long-term renal transplant outcome

Abstract: The present study demonstrates an important role of the KIR immunogenetic system in the long-term immune response to kidney transplantation.

Cited by 13 publications

References 26 publications

NK Cells of Kidney Transplant Recipients Display an Activated Phenotype that Is Influenced by Immunosuppression and Pathological Staging

NK Cells of Kidney Transplant Recipients Display an Activated Phenotype that Is Influenced by Immunosuppression and Pathological Staging

Benchmarking the HLA typing performance of Polysolver and Optitype in 50 Danish parental trios

Improved full-length killer cell immunoglobulin-like receptor transcript discovery in Mauritian cynomolgus macaques

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