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Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis

Tara L Spivey123, Lorenzo Uccellini14, Maria Libera Ascierto156, Gabriele Zoppoli57, Valeria De Giorgi1, Lucia Gemma Delogu8, Alyson M Engle1, Jaime M Thomas1, Ena Wang1, Francesco M Marincola1* and Davide Bedognetti159*

Author Affiliations

1 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

2 Clinical Research Training Program (CRTP), National Institutes of Health, Bethesda, Maryland, 20892, USA

3 Rush University Medical Center, Rush Medical College, Chicago, Illinois, 60612, USA

4 Luigi Sacco Hospital, Via G.B. Grassi, 20157 Milano, Italy

5 Department of Internal Medicine (DiMI), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy

6 Center of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy

7 Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda Maryland, 20892, USA

8 University of Sassari, Department of Drug Sciences, Via Muroni 23 A, 07100, Sassari, Italy

9 Department of Oncology, Biology, and Genetics, University of Genoa, and National Cancer Research Institute, Largo Rosanna Benzi 10, 16132 Genoa, Italy

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Journal of Translational Medicine 2011, 9:174  doi:10.1186/1479-5876-9-174

Published: 12 October 2011


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.