Philip F Halloran1, Konrad Famulski, Jeff Reeve. 1. aAlberta Transplant Applied Genomics Centre bDivision of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, Canada.
Abstract
PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: Microarray assessment provides a new dimension in biopsy assessment for diagnosis that offers mechanistic insights and sometimes challenges histology assessments.
PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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 donorhuman 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. SUMMARY: Microarray assessment provides a new dimension in biopsy assessment for diagnosis that offers mechanistic insights and sometimes challenges histology assessments.
Authors: Weijia Zhang; Zhengzi Yi; Chengguo Wei; Karen L Keung; Zeguo Sun; Caixia Xi; Christopher Woytovich; Samira Farouk; Lorenzo Gallon; Madhav C Menon; Ciara Magee; Nader Najafian; Milagros D Samaniego; Arjang Djamali; Stephen I Alexander; Ivy A Rosales; Rex Neal Smith; Philip J O'Connell; Robert Colvin; Paolo Cravedi; Barbara Murphy Journal: JCI Insight Date: 2019-06-06
Authors: Masatoshi Matsunami; Ivy A Rosales; Benjamin A Adam; Tetsu Oura; Michael Mengel; Rex-Neal Smith; Hang Lee; A Benedict Cosimi; Robert B Colvin; Tatsuo Kawai Journal: Transplantation Date: 2019-11 Impact factor: 4.939
Authors: S M Kurian; E Velazquez; R Thompson; T Whisenant; S Rose; N Riley; F Harrison; T Gelbart; J J Friedewald; J Charette; S Brietigam; J Peysakhovich; M R First; M M Abecassis; D R Salomon Journal: Am J Transplant Date: 2017-04-03 Impact factor: 8.086
Authors: Katelynn S Madill-Thomsen; Georg A Böhmig; Jonathan Bromberg; Gunilla Einecke; Farsad Eskandary; Gaurav Gupta; Luis G Hidalgo; Marek Myslak; Ondrej Viklicky; Agnieszka Perkowska-Ptasinska; Philip F Halloran Journal: J Am Soc Nephrol Date: 2021-07-12 Impact factor: 10.121