Epitopes described in "Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection."

Article Authors:Duska Dragun; Dominik N Müller; Jan Hinrich Bräsen; Lutz Fritsche; Melina Nieminen-Kelhä; Ralf Dechend; Ulrich Kintscher; Birgit Rudolph; Johan Hoebeke; Diana Eckert; Istvan Mazak; Ralph Plehm; Constanze Schönemann; Thomas Unger; Klemens Budde; Hans-Hellmut Neumayer; Friedrich C Luft; Gerd Wallukat
Article Title:Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection.
Reference Detail
Reference ID:1020089
Abstract:BACKGROUND: Antibodies against HLA antigens cause refractory allograft rejection with vasculopathy in some, but not all, patients. METHODS: We studied 33 kidney-transplant recipients who had refractory vascular rejection. Thirteen had donor-specific anti-HLA antibodies, whereas 20 did not. Malignant hypertension was present in 16 of the patients without anti-HLA antibodies, 4 of whom had seizures. The remaining 17 patients had no malignant hypertension. We hypothesized that activating antibodies targeting the angiotensin II type 1 (AT1) receptor might be involved. RESULTS: Activating IgG antibodies targeting the AT1 receptor were detected in serum from all 16 patients with malignant hypertension and without anti-HLA antibodies, but in no other patients. These receptor-activating antibodies are subclass IgG1 and IgG3 antibodies that bind to two different epitopes on the second extracellular loop of the AT1 receptor. Tissue factor expression was increased in renal-biopsy specimens from patients with these antibodies. In vitro stimulation of vascular cells with an AT1-receptor-activating antibody induced phosphorylation of ERK 1/2 kinase and increased the DNA binding activity of the transcription factors activator protein 1 (AP-1) and nuclear factor-kappaB. The AT1 antagonist losartan blocked agonistic AT1-receptor antibody-mediated effects, and passive antibody transfer induced vasculopathy and hypertension in a rat kidney-transplantation model. CONCLUSIONS: A non-HLA, AT1-receptor-mediated pathway may contribute to refractory vascular rejection, and affected patients might benefit from removal of AT1-receptor antibodies or from pharmacologic blockade of AT1 receptors.
Reference Type:Literature
PubMed ID:15703421
Journal:N Engl J Med
Journal Volume:352
Article Pages:558-69
Journal ISSN:1533-4406
Article Chemical List:Angiotensin II Type 1 Receptor Blockers;Autoantibodies;HLA Antigens;Immunoglobulin G;Immunoglobulins, Intravenous;Receptor, Angiotensin, Type 1;Transcription Factors;Mitogen-Activated Protein Kinase 3;Losartan
Article MeSH List:Angiotensin II Type 1 Receptor Blockers(pharmacology; therapeutic use); Animals; Autoantibodies(blood); Combined Modality Therapy; Disease Models, Animal; Female; Graft Rejection(immunology; pathology; therapy); HLA Antigens(immunology); Humans; Hypertension(immunology); Immunoglobulin G(blood); Immunoglobulins, Intravenous(therapeutic use); Kidney(blood supply; immunology; pathology); Kidney Transplantation(immunology); Losartan(pharmacology; therapeutic use); Male; Mitogen-Activated Protein Kinase 3(metabolism); Phosphorylation; Plasmapheresis; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptor, Angiotensin, Type 1(immunology); Transcription Factors(metabolism); Transplantation, Homologous(immunology)
Curation Last Updated:2016-04-11 21:12:01