title: Graft inflammation and histologic indicators of kidney chronic allograft failure: low-expressing interleukin-10 genotypes cannot be ignored.
abstract: BACKGROUND
  Infiltration of inflammatory cells into the renal allograft interstitium is the biologic hallmark of alloimmune responses that leads to tubulointerstitial injury and subsequent interstitial fibrosis and chronic allograft failure. The proliferation, stimulation, and infiltration of these inflammatory cells are governed by various proinflammatory and regulatory cytokines. We assessed whether the differences in the genes encoding cytokines (producing low, moderate, or high expression profiles) may affect the infiltration of inflammatory cells into the renal allograft and the histologic changes characteristics of chronic allograft failure.
  
  
  METHODS
  A total of 218 kidney transplant recipients were genotyped for 15 single-nucleotide polymorphisms located in the gene promoter or exonic regions of 10 different cytokines or their receptors. Six- to 12-month posttransplant surveillance biopsies were scored using 11 individual histologic parameters and the combined grade of interstitial fibrosis and tubular atrophy (IF/TA). B-cell, T-cell, and macrophage infiltrates were quantified by immunostaining.
  
  
  RESULTS
  The low-expressing interleukin (IL)-10 gene promoter genotypes were found significantly associated with high IF/TA grade (IL-10 -819 TT; P=0.035; odds ratio=3.27; 95% confidence interval 1.1-9.8). At individual histologic indices, recipients carrying low-expressing IL-10 genotypes showed 2.5-fold higher scores for interstitial fibrosis, inflammation, and tubular atrophy. High infiltration of T cells and macrophages but not B cells into the renal allograft interstitium was found strongly associated with the carriage of low-expressing IL-10 genotypes.
  
  
  CONCLUSIONS
  The results suggest that renal transplant recipients genetically predisposed to low expression of the regulatory cytokine IL-10 are more susceptible to high grades of IF/TA scores, graft inflammation, and high influx of inflammatory cells into the graft interstitium.
authors.affiliation: Calgary Laboratory Services, Calgary, AB, Canada. Faisal.Khan@Cls.ab.ca
authors.forename: Faisal
authors.initials: F
authors.lastname: Khan
authors.forename: Aylin
authors.initials: A
authors.lastname: Sar
authors.forename: Ipek
authors.initials: I
authors.lastname: Gonul
authors.forename: Hallgrimur
authors.initials: H
authors.lastname: Benediktsson
authors.forename: Jagdeep
authors.initials: J
authors.lastname: Doulla
authors.forename: Serdar
authors.initials: S
authors.lastname: Yilmaz
authors.forename: Noureddine
authors.initials: N
authors.lastname: Berka
mesh_terms: D000328:Adult; D001706:Biopsy; D016207:Cytokines / Q000235:genetics; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D007371:Interferon-gamma / Q000235:genetics; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics; D007375:Interleukin-1 / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics*; D016030:Kidney Transplantation / Q000473:pathology*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D014184:Transplantation, Homologous / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma