title: Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis.
abstract: In humans, the role and relationship between molecular pathways that lead to tissue destruction during acute allograft rejection are not fully understood. Based on studies conducted in humans, we recently hypothesized that different immune-mediated tissue destruction processes (i.e. cancer, infection, autoimmunity) share common convergent final mechanisms. We called this phenomenon the "Immunologic Constant of Rejection (ICR)." The elements of the ICR include molecular pathways that are consistently described through different immune-mediated tissue destruction processes and demonstrate the activation of interferon-stimulated genes (ISGs), the recruitment of cytotoxic immune cells (primarily through CXCR3/CCR5 ligand pathways), and the activation of immune effector function genes (IEF genes; granzymes A/B, perforin, etc.). Here, we challenge the ICR hypothesis by using a meta-analytical approach and systematically reviewing microarray studies evaluating gene expression on tissue biopsies during acute allograft rejection. We found the pillars of the ICR consistently present among the studies reviewed, despite implicit heterogeneity. Additionally, we provide a descriptive mechanistic overview of acute allograft rejection by describing those molecular pathways most frequently encountered and thereby thought to be most significant. The biological role of the following molecular pathways is described: IFN-γ, CXCR3/CCR5 ligand, IEF genes, TNF-α, IL-10, IRF-1/STAT-1, and complement pathways. The role of NK cell, B cell and T-regulatory cell signatures are also addressed.
authors: Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Tara L
authors: TL
authors: Spivey
authors: Lorenzo
authors: L
authors: Uccellini
authors: Maria Libera
authors: ML
authors: Ascierto
authors: Gabriele
authors: G
authors: Zoppoli
authors: Valeria
authors: V
authors: De Giorgi
authors: Lucia Gemma
authors: LG
authors: Delogu
authors: Alyson M
authors: AM
authors: Engle
authors: Jaime M
authors: JM
authors: Thomas
authors: Ena
authors: E
authors: Wang
authors: Francesco M
authors: FM
authors: Marincola
authors: Davide
authors: D
authors: Bedognetti
mesh_terms: D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D018448:Models, Immunological; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000235:genetics; D014184:Transplantation, Homologous