title: The molecular phenotypes of rejection in kidney transplant biopsies.
abstract: OBJECTIVE
  The recent emergence of a system for distinguishing T-cell-mediated rejection (TCMR) from antibody-mediated rejection (ABMR), including C4d-negative ABMR, allows us to map the molecular features of these conditions.
  
  
  RESULTS
  The TCMR landscape is dominated by molecules expressed in effector T cells, antigen-presenting cells (macrophages, dendritic cells, B cells) and interferon-gamma (IFNG)-induced genes. A surprising finding is the association of transcripts for inhibitory molecules such as CTLA4 and PDL1 with TCMR, indicating that this tubulo-interstitial inflammatory compartment is actively controlled. ABMR is dominated by endothelial transcripts related to angiogenesis, reflecting endothelial injury; natural killer (NK)-cell transcripts; and selected IFNG-regulated transcripts. This suggests a cognate unit of NK cells engaging donor-specific antibody bound to donor human leukocyte antigen antigens through their CD16a (FCGR3A) Fc receptors, triggering IFNG release. TCMR and ABMR share many rejection-associated transcripts, mainly IFNG-induced genes and transcripts shared between NK cells and CD8 effector T cells (e.g., KLRD1). In addition, acute kidney injury transcripts, which reflect the parenchymal response to injury, are shared between different forms of rejection and are indicative of disease progression.
  
  
  CONCLUSIONS
  Microarray assessment provides a new dimension in biopsy assessment for diagnosis that offers mechanistic insights and sometimes challenges histology assessments.
authors.affiliation: aAlberta Transplant Applied Genomics Centre bDivision of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, Canada.
authors.forename: Philip F
authors.initials: PF
authors.lastname: Halloran
authors.forename: Konrad
authors.initials: K
authors.lastname: Famulski
authors.forename: Jeff
authors.initials: J
authors.lastname: Reeve
mesh_terms: D001706:Biopsy; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006801:Humans; D016030:Kidney Transplantation; D007694:Killer Cells, Natural / Q000276:immunology; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology