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Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection (authors reply inN Engl J Med. 2005 May 12;352(19):2027-8)

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Official URL:https://doi.org/10.1056/NEJMoa035717
PubMed:View item in PubMed
Creators Name:Dragun, D. and Mueller, D.N. and Braesen, J.H. and Fritsche, L. and Nieminen-Kelhae, M. and Dechend, R. and Kintscher, U. and Rudolph, B. and Hoebeke, J. and Eckert, D. and Mazak, I. and Plehm, R. and Schoenemann, C. and Unger, T. and Budde, K. and Neumayer, H.H. and Luft, F.C. and Wallukat, G.
Journal Title:New England Journal of Medicine
Journal Abbreviation:N Engl J Med
Volume:352
Number:6
Page Range:558-569
Date:1 January 2005
Keywords:Animal Disease Models, Angiotensin Type 1 Receptor, Angiotensin II Type 1 Receptor Blockers, Autoantibodies, Combined Modality Therapy, Graft Rejection, HLA Antigens, Homologous Transplantation, Hypertension, Immunoglobulin G, Inbred F344 Rats, Inbred Lew Rats, Intravenous Immunoglobulins, Kidney, Kidney Transplantation, Losartan, Mitogen-Activated Protein Kinase 3, Phosphorylation, Plasmapheresis, Transcription Factors, Animals, Rats
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-κB. 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 AT 1-receptor antibodies or from pharmacologic blockade of AT 1 receptors.
ISSN:0028-4793
Publisher:Massachusetts Medical Society (U.S.A.)
Item Type:Article

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