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

Dragun, D.; Mueller, D.N.; Braesen, J.H.; Fritsche, L.; Nieminen-Kelhae, M.; Dechend, R.; Kintscher, U.; Rudolph, B.; Hoebeke, J.; Eckert, D.; Mazak, I.; Plehm, R.; Schoenemann, C.; Unger, T.; Budde, K.; Neumayer, H.H.; Luft, F.C.; Wallukat, G.

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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Item Type:	Article
Title:	Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection (authors reply inN Engl J Med. 2005 May 12;352(19):2027-8)
Creators Name:	Dragun, D., Mueller, D.N., Braesen, J.H., Fritsche, L., Nieminen-Kelhae, M., Dechend, R., Kintscher, U., Rudolph, B., Hoebeke, J., Eckert, D., Mazak, I., Plehm, R., Schoenemann, C., Unger, T., Budde, K., Neumayer, H.H., Luft, F.C. and Wallukat, G.
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.
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
Source:	New England Journal of Medicine
ISSN:	0028-4793
Publisher:	Massachusetts Medical Society
Volume:	352
Number:	6
Page Range:	558-569
Date:	1 January 2005
Official Publication:	https://doi.org/10.1056/NEJMoa035717
PubMed:	View item in PubMed

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