title: Genes associated with antibody-dependent cell activation are overexpressed in renal biopsies from patients with antibody-mediated rejection.
abstract: BACKGROUND
  Antibody-mediated rejection (ABMR) is dependent on complement activating donor-specific anti-HLA antibodies (DSA). This is commonly detected by C4d deposition in allografts. However, recent data define a C4d negative ABMR phenotype suggesting a role for complement-independent DSA injury, antibody-dependent cellular cytotoxicity (ADCC).
  
  
  METHODS
  Here, we established an in vitro ADCC model that identified human ADCC-activated genes using microarray analysis. We subsequently interrogated renal allograft biopsies from patients with ABMR and controls for mRNA expression of the ADCC-activated gene set.
  
  
  RESULTS
  We identified 13 ADCC-activated genes. Six gene expression assays including 8 of the 13 genes (CCL3, CCL4/CCL4L1/CCL4L2, CD160, IFNG, NR4A3 and XCL1/XCL2) were analyzed in 127 kidney biopsies obtained from HLA-sensitized (HS), non-HS patients and control individuals. Most ADCC-activated genes showed significantly higher expression in the transplant samples compared to the controls (p<0.0005). The gene expression levels were significantly higher in HS and non-HS transplant patients who developed ABMR compared to those who did not (p=0.04-0.002). There was no difference in the gene expression levels between C4d positive and negative ABMR (p=0.26-0.99). Samples from high PRA (>80%) or positive DSA patients showed higher gene expression levels for the ADCC-activated genes compared to low PRA (<80%) and negative DSA patients (p=0.04-0.001).
  
  
  CONCLUSIONS
  ADCC pathways are active in transplant patients with ABMR, and likely mediate allograft injury, providing a potential mechanism for C4d negative ABMR.
authors.affiliation: Transplant Immunology Laboratory, Comprehensive Transplant Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA. Electronic address: elina.suviolahti@gmail.com.
authors.forename: Elina
authors.initials: E
authors.lastname: Suviolahti
authors.affiliation: Transplant Immunology Laboratory, Comprehensive Transplant Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
authors.forename: Shili
authors.initials: S
authors.lastname: Ge
authors.affiliation: Department of Pathology, Cedars-Sinai Medical Center/UCLA School of Medicine, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Nast
authors.affiliation: Biostatistics Core, Research Institute & General Clinical Research Center & Cardiothoracic Surgery, Cedars-Sinai Medical Center, 8797 Beverly Blvd., Suite 215, Los Angeles, CA 90048, USA.
authors.forename: James
authors.initials: J
authors.lastname: Mirocha
authors.affiliation: Transplant Immunology Laboratory, Comprehensive Transplant Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
authors.forename: Artur
authors.initials: A
authors.lastname: Karasyov
authors.affiliation: Transplant Immunology Laboratory, Comprehensive Transplant Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: White
authors.affiliation: Comprehensive Transplant Center, Cedars-Sinai Medical Center/UCLA School of Medicine, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Jordan
authors.affiliation: Transplant Immunology Laboratory, Comprehensive Transplant Center, Cedars-Sinai Medical Center/UCLA School of Medicine, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
authors.forename: Mieko
authors.initials: M
authors.lastname: Toyoda
mesh_terms: D064591:Allografts; D000920:Antibody-Dependent Cell Cytotoxicity; D001706:Biopsy; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007518:Isoantibodies; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D012333:RNA, Messenger / Q000276:immunology
chemical_list: D007518:Isoantibodies; D012333:RNA, Messenger
keywords: Anti-HLA antibody; Antibody-dependent cellular cytotoxicity; Antibody-mediated allograft rejection; Gene expression; Kidney biopsy; Natural killer cell