KIR and HLA-C Interactions Promote Differential Dendritic Cell Maturation and Is a Major Determinant of Graft Failure following Kidney Transplantation

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KIR and HLA-C Interactions Promote Differential Dendritic Cell Maturation and Is a Major Determinant of Graft Failure following Kidney Transplantation. / Hanvesakul, R; Kubal, Chandrashekhar; Moore, Jason; Neil, Desley; Cook, Mark; Ball, Simon; Briggs, D; Moss, Paul; Cockwell, Paul.

In: PLoS ONE, Vol. 6, No. 8, 01.08.2011, p. e23631.

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Hanvesakul, R ; Kubal, Chandrashekhar ; Moore, Jason ; Neil, Desley ; Cook, Mark ; Ball, Simon ; Briggs, D ; Moss, Paul ; Cockwell, Paul. / KIR and HLA-C Interactions Promote Differential Dendritic Cell Maturation and Is a Major Determinant of Graft Failure following Kidney Transplantation. In: PLoS ONE. 2011 ; Vol. 6, No. 8. pp. e23631.

Bibtex

@article{e2d74f70273f4859be68e19322719b26,
title = "KIR and HLA-C Interactions Promote Differential Dendritic Cell Maturation and Is a Major Determinant of Graft Failure following Kidney Transplantation",
abstract = "Background: HLA-C is an important ligand for killer immunoglobulin like receptors (KIR) that regulate natural killer (NK) cell function. Based on KIR specificity HLA-C molecules are allocated into two groups, HLA-C1 or HLA-C2; HLA-C2 is more inhibiting to NK cell function than HLA-C1. We studied the clinical importance of HLA-C genotypes on the long-term graft survival of 760 kidney transplants performed at our centre utilising a population based genetic study and cell culture model to define putative mechanisms. Methods and Findings: Genotyping was performed using conventional DNA PCR techniques and correlations made to clinical outcomes. We found that transplant recipients with HLA-C2 had significantly better long-term graft survival than transplant recipients with HLA-C1 (66% versus 44% at 10 years, log-rank p = 0.002, HR = 1.51, 95% CI = 1.16-1.97). In in-vitro NK and dendritic cell (DC) co-culture model we made several key observations that correlated with the population based genetic study. We observed that donor derived NK cells, on activation with IL-15, promoted differential HLA-C genotype dependent DC maturation. In NK-DC co-culture, the possession of HLA-C2 by DC was associated with anti-inflammatory cytokine production (IL-1RA/IL-6), diminished DC maturation (CD86, HLA-DR), and absent CCR7 expression. Conversely, possession of HLA-C1 by DC was associated with pro-inflammatory cytokine synthesis (TNF-alpha, IL-12p40/p70), enhanced DC maturation and up-regulation of CCR7 expression. By immunohistochemistry the presence of donor NK cells was confirmed in pre-transplant kidneys. Conclusions: We propose that after kidney transplantation IL-15 activated donor derived NK cells interact with recipient DC with less activation of indirect allo-reactivity in HLA-C2 positive recipients than HLA-C1 positive recipients; this has implications for long-term graft survival. Early events following kidney transplantation involving NK-DC interaction via KIR and HLA-C immune synapse may have a central role in long-term kidney transplant outcomes.",
author = "R Hanvesakul and Chandrashekhar Kubal and Jason Moore and Desley Neil and Mark Cook and Simon Ball and D Briggs and Paul Moss and Paul Cockwell",
year = "2011",
month = aug,
day = "1",
doi = "10.1371/journal.pone.0023631",
language = "English",
volume = "6",
pages = "e23631",
journal = "PLoSONE",
issn = "1932-6203",
publisher = "Public Library of Science (PLOS)",
number = "8",

}

RIS

TY - JOUR

T1 - KIR and HLA-C Interactions Promote Differential Dendritic Cell Maturation and Is a Major Determinant of Graft Failure following Kidney Transplantation

AU - Hanvesakul, R

AU - Kubal, Chandrashekhar

AU - Moore, Jason

AU - Neil, Desley

AU - Cook, Mark

AU - Ball, Simon

AU - Briggs, D

AU - Moss, Paul

AU - Cockwell, Paul

PY - 2011/8/1

Y1 - 2011/8/1

N2 - Background: HLA-C is an important ligand for killer immunoglobulin like receptors (KIR) that regulate natural killer (NK) cell function. Based on KIR specificity HLA-C molecules are allocated into two groups, HLA-C1 or HLA-C2; HLA-C2 is more inhibiting to NK cell function than HLA-C1. We studied the clinical importance of HLA-C genotypes on the long-term graft survival of 760 kidney transplants performed at our centre utilising a population based genetic study and cell culture model to define putative mechanisms. Methods and Findings: Genotyping was performed using conventional DNA PCR techniques and correlations made to clinical outcomes. We found that transplant recipients with HLA-C2 had significantly better long-term graft survival than transplant recipients with HLA-C1 (66% versus 44% at 10 years, log-rank p = 0.002, HR = 1.51, 95% CI = 1.16-1.97). In in-vitro NK and dendritic cell (DC) co-culture model we made several key observations that correlated with the population based genetic study. We observed that donor derived NK cells, on activation with IL-15, promoted differential HLA-C genotype dependent DC maturation. In NK-DC co-culture, the possession of HLA-C2 by DC was associated with anti-inflammatory cytokine production (IL-1RA/IL-6), diminished DC maturation (CD86, HLA-DR), and absent CCR7 expression. Conversely, possession of HLA-C1 by DC was associated with pro-inflammatory cytokine synthesis (TNF-alpha, IL-12p40/p70), enhanced DC maturation and up-regulation of CCR7 expression. By immunohistochemistry the presence of donor NK cells was confirmed in pre-transplant kidneys. Conclusions: We propose that after kidney transplantation IL-15 activated donor derived NK cells interact with recipient DC with less activation of indirect allo-reactivity in HLA-C2 positive recipients than HLA-C1 positive recipients; this has implications for long-term graft survival. Early events following kidney transplantation involving NK-DC interaction via KIR and HLA-C immune synapse may have a central role in long-term kidney transplant outcomes.

AB - Background: HLA-C is an important ligand for killer immunoglobulin like receptors (KIR) that regulate natural killer (NK) cell function. Based on KIR specificity HLA-C molecules are allocated into two groups, HLA-C1 or HLA-C2; HLA-C2 is more inhibiting to NK cell function than HLA-C1. We studied the clinical importance of HLA-C genotypes on the long-term graft survival of 760 kidney transplants performed at our centre utilising a population based genetic study and cell culture model to define putative mechanisms. Methods and Findings: Genotyping was performed using conventional DNA PCR techniques and correlations made to clinical outcomes. We found that transplant recipients with HLA-C2 had significantly better long-term graft survival than transplant recipients with HLA-C1 (66% versus 44% at 10 years, log-rank p = 0.002, HR = 1.51, 95% CI = 1.16-1.97). In in-vitro NK and dendritic cell (DC) co-culture model we made several key observations that correlated with the population based genetic study. We observed that donor derived NK cells, on activation with IL-15, promoted differential HLA-C genotype dependent DC maturation. In NK-DC co-culture, the possession of HLA-C2 by DC was associated with anti-inflammatory cytokine production (IL-1RA/IL-6), diminished DC maturation (CD86, HLA-DR), and absent CCR7 expression. Conversely, possession of HLA-C1 by DC was associated with pro-inflammatory cytokine synthesis (TNF-alpha, IL-12p40/p70), enhanced DC maturation and up-regulation of CCR7 expression. By immunohistochemistry the presence of donor NK cells was confirmed in pre-transplant kidneys. Conclusions: We propose that after kidney transplantation IL-15 activated donor derived NK cells interact with recipient DC with less activation of indirect allo-reactivity in HLA-C2 positive recipients than HLA-C1 positive recipients; this has implications for long-term graft survival. Early events following kidney transplantation involving NK-DC interaction via KIR and HLA-C immune synapse may have a central role in long-term kidney transplant outcomes.

U2 - 10.1371/journal.pone.0023631

DO - 10.1371/journal.pone.0023631

M3 - Article

C2 - 21912600

VL - 6

SP - e23631

JO - PLoSONE

JF - PLoSONE

SN - 1932-6203

IS - 8

ER -