Non-HLA-antibodies targeting Angiotensin type 1 receptor and antibody mediated rejection

Abstract Antibody-mediated mechanisms directed against non-HLA related targets may exert negative impact on allograft function and survival. Angiotensin type 1 receptor (AT1 R) emerges as a functional target for non-HLA allo- and autoantibodies (AT1 R-Abs) comprising of IgG1 and IgG3 subclasses. Pro...

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Bibliographic Details
Published in:Human immunology 2012-12, Vol.73 (12), p.1282-1286
Main Authors: Dragun, Duska, Catar, Rusan, Kusch, Angelika, Heidecke, Harald, Philippe, Aurélie
Format: Article
Language:English
Subjects:
Allergy and Immunology
Antibody-Dependent Cell Cytotoxicity
Antigen-Antibody Complex - immunology
Autoantibodies - immunology
Graft Rejection - immunology
Graft Rejection - metabolism
Graft Rejection - therapy
HLA Antigens - immunology
Humans
Protein Binding
Receptor, Angiotensin, Type 1 - genetics
Receptor, Angiotensin, Type 1 - immunology
Receptor, Angiotensin, Type 1 - metabolism
Receptors, G-Protein-Coupled - immunology
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Summary:Abstract Antibody-mediated mechanisms directed against non-HLA related targets may exert negative impact on allograft function and survival. Angiotensin type 1 receptor (AT1 R) emerges as a functional target for non-HLA allo- and autoantibodies (AT1 R-Abs) comprising of IgG1 and IgG3 subclasses. Proof of concept for pathophysiologic relevance of AT1 R-Abs in antibody mediated rejection (AMR) in renal transplants was provided by passive transfer studies in animal model and therapeutic rescue of patients. Although AT1 R-Abs may belong to complement fixing IgG subclasses, C4d positivity in renal transplant biopsies was not frequently detected implicating complement independent mechanisms of injury. AT1 R-Abs exert direct effects on endothelial and vascular smooth muscle cells by induction of Erk1/2 signaling and increased DNA binding of transcription factors associated with pro-inflammatory and pro-coagulatory responses. Establishment of enzyme-linked immunosorbent assay employing extracts of cells overexpressing AT1 R in its native conformation was instrumental for recent studies in independent cohorts. Assessing the AT1 R-Ab-status along with the HLA-antibodies may help to identify patients at particular risk for irreversible acute or chronic allograft injuries and improve overall outcomes. This review summarizes the current state of research in AT1 R biology, development in diagnostic strategies, discusses recent clinical studies, and provides perspectives on further refinements in understanding AT1 R-Ab-actions.
ISSN:0198-8859
1879-1166
DOI:10.1016/j.humimm.2012.07.010