Review: The transcripts associated with organ allograft rejection

Abstract

The molecular mechanisms operating in human organ transplant rejection are best inferred from the mRNAs expressed in biopsies because the corresponding proteins often have low expression and short half-lives, while small non-coding RNAs lack specificity. Associations should be characterized in a population that rigorously identifies T cell-mediated (TCMR) and antibody-mediated rejection (ABMR). This is best achieved in kidney transplant biopsies, but the results are generalizable to heart, lung, or liver transplants. Associations can be universal (all rejection), TCMR-selective, or ABMR-selective, with universal being strongest and ABMR-selective weakest. Top universal transcripts are IFNG-inducible (eg, CXCL11 IDO1, WARS) or shared by effector T cells (ETCs) and NK cells (eg, KLRD1, CCL4). TCMR-selective transcripts are expressed in activated ETCs (eg, CTLA4, IFNG), activated (eg, ADAMDEC1), or IFNG-induced macrophages (eg, ANKRD22). ABMR-selective transcripts are expressed in NK cells (eg, FGFBP2, GNLY) and endothelial cells (eg, ROBO4, DARC). Transcript associations are highly reproducible between biopsy sets when the same rejection definitions, case mix, algorithm, and technology are applied, but exact ranks will vary. Previously published rejection-associated transcripts resemble universal and TCMR-selective transcripts due to incomplete representation of ABMR. Rejection-associated transcripts are never completely rejection-specific because they are shared with the stereotyped response-to-injury and innate immunity.

The relationship between pathologic lesions of active and chronic antibody-mediated rejection in renal allografts

“…15 Indeed, Aubert et al, 21 in comparing patients with ABMR related to preexisting versus de novo DSAs, found the latter to be associated with higher mean scores for TG (Banff cg) and IFTA F I G U R E 2 Proposed model of clinical, serologic, molecular, and pathologic findings leading up to and following development of de novo donor-specific antibodies (DSA) in a renal allograft recipient. 16 Note also the latent period between the initial development of de novo DSAs and the onset of active ABMR (biopsy 2). This hypothetical patient had an early episode of acute TCMR (biopsy 1), which is a predisposing factor for subsequent development of de novo DSAs.…”

The regulation of interferon type I pathway‐related genes RSAD2 and ETV7 specifically indicates antibody‐mediated rejection after kidney transplantation

“…Established and approved methods for the specific determination of ABMR are not only invasive, but also costly and time‐consuming, whereas measuring serum creatinine and calculating the glomerular filtration rate for kidney function assessment are neither ABMR specific nor predictive. The search for stable and predictive biomarkers for ABMR is currently ongoing, and progress has been made in the genomics and proteomics field . Some new ABMR classifiers in biopsy material have been introduced as potentially useful addition to histology and DSA identification .…”

“…Some new ABMR classifiers in biopsy material have been introduced as potentially useful addition to histology and DSA identification . Additionally, the molecular mechanisms involved in ABMR have been further elucidated by associating the gene expression and regulation in graft material with this type of rejection . The discovery and further analysis of robust markers regulated during ABMR after KTx cannot only lead to the development of new diagnostic or monitoring tools, but also to the essential extension of the insufficient understanding of the mechanisms and pathways involved in ABMR allowing the identification of therapeutic targets.…”

“…The search for stable and predictive biomarkers for ABMR is currently ongoing, and progress has been made in the genomics and proteomics field. 19,20 Some new ABMR classifiers in biopsy material have been introduced as potentially useful addition to histology and DSA identification. 21,22 Additionally, the molecular mechanisms involved in ABMR have been further elucidated by associating the gene expression and regulation in graft material with this type of rejection.…”

“…21,22 Additionally, the molecular mechanisms involved in ABMR have been further elucidated by associating the gene expression and regulation in graft material with this type of rejection. 20 The discovery and further analysis of robust markers regulated during ABMR after KTx cannot only lead to the development of new diagnostic or monitoring tools, but also to the essential extension of the insufficient understanding of the mechanisms and pathways involved in ABMR allowing the identification of therapeutic targets. An ideal specific marker or marker combining set for ABMR would preferably be rapidly determinable in a noninvasively obtained material, like blood or urine.…”