Article

Impact of chemokine receptor CX3CR1 in human renal allograft rejection.

Department of Internal Medicine II-Nephrology, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
Transplant Immunology (impact factor: 1.46). 08/2010; 23(4):204-8. DOI:10.1016/j.trim.2010.06.006 pp.204-8
Source: PubMed

ABSTRACT Chemokine receptors play pivotal roles for leukocyte recruitment in acute and chronic inflammatory processes. This study was performed to analyze the expression, distribution and cellular localization of CX3CR1 in human renal transplant biopsies and to assess its role as potential diagnostic and prognostic marker. CX3CR1 was prospectively analyzed in 174 renal graft biopsies from patients with normal morphology (n=76), antibody-mediated acute rejection (n=6), acute tubulointerstitial rejection (n=27), acute vascular rejection (n=31), and with acute tubulus necrosis (n=34). Double immunofluorescence was additionally performed for CX3CR1 and CD4, CD8, CD20, CD68, and CD209/DC-SIGN. The number of CX3CR1 positive interstitial cells was significantly higher in the biopsies with acute tubulointerstitial and acute vascular rejection as compared to normal renal allograft biopsies. CX3CR1 positive cells were mainly CD68 positive monocytes/macrophages and CD209/DC-SIGN positive dendritic cells. The percentage of the CX3CR1 positive staining area was a predictor for steroid responsiveness and for worse clinical outcome 3 and 12 months after transplantation. CX3CR1 positive macrophages and/or dendritic cells are significantly elevated in acute renal allograft rejection. As CX3CR1 was associated with outcome parameters, it has to be further evaluated as a prognostic marker in human renal transplantation.

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    Article: Fractalkine expression induces endothelial progenitor cell lysis by natural killer cells.
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    ABSTRACT: Circulating CD34(+) cells, a population that includes endothelial progenitors, participate in the maintenance of endothelial integrity. Better understanding of the mechanisms that regulate their survival is crucial to improve their regenerative activity in cardiovascular and renal diseases. Chemokine-receptor cross talk is critical in regulating cell homeostasis. We hypothesized that cell surface expression of the chemokine fractalkine (FKN) could target progenitor cell injury by Natural Killer (NK) cells, thereby limiting their availability for vascular repair. We show that CD34(+)-derived Endothelial Colony Forming Cells (ECFC) can express FKN in response to TNF-α and IFN-γ inflammatory cytokines and that FKN expression by ECFC stimulates NK cell adhesion, NK cell-mediated ECFC lysis and microparticles release in vitro. The specific involvement of membrane FKN in these processes was demonstrated using FKN-transfected ECFC and anti-FKN blocking antibody. FKN expression was also evidenced on circulating CD34(+) progenitor cells and was detected at higher frequency in kidney transplant recipients, when compared to healthy controls. The proportion of CD34(+) cells expressing FKN was identified as an independent variable inversely correlated to CD34(+) progenitor cell count. We further showed that treatment of CD34(+) circulating cells isolated from adult blood donors with transplant serum or TNF-α/IFN-γ can induce FKN expression. Our data highlights a novel mechanism by which FKN expression on CD34(+) progenitor cells may target their NK cell mediated killing and participate to their immune depletion in transplant recipients. Considering the numerous diseased contexts shown to promote FKN expression, our data identify FKN as a hallmark of altered progenitor cell homeostasis with potential implications in better evaluation of vascular repair in patients.
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Keywords

174 renal graft biopsies
 
acute renal allograft rejection
 
acute tubulointerstitial
 
acute tubulointerstitial rejection
 
acute tubulus necrosis
 
acute vascular rejection
 
antibody-mediated acute rejection
 
CD209/DC-SIGN positive dendritic cells
 
cellular localization
 
chronic inflammatory processes
 
CX3CR1 positive cells
 
CX3CR1 positive interstitial cells
 
CX3CR1 positive macrophages
 
CX3CR1 positive staining area
 
human renal transplant biopsies
 
human renal transplantation
 
normal renal allograft biopsies
 
outcome parameters
 
prognostic marker
 
worse clinical outcome 3