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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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