Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection.
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.
Dragun
Duska
D
Department of Nephrology, Charité University Hospital, Berlin, Germany. duska.dragun@charite.de
Müller
Dominik N
DN
Bräsen
Jan Hinrich
JH
Fritsche
Lutz
L
Nieminen-Kelhä
Melina
M
Dechend
Ralf
R
Kintscher
Ulrich
U
Rudolph
Birgit
B
Hoebeke
Johan
J
Eckert
Diana
D
Mazak
Istvan
I
Plehm
Ralph
R
Schönemann
Constanze
C
Unger
Thomas
T
Budde
Klemens
K
Neumayer
Hans-Hellmut
HH
Luft
Friedrich C
FC
Wallukat
Gerd
G
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D006973:Hypertension / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007668:Kidney / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology*; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D010956:Plasmapheresis; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism; D014184:Transplantation, Homologous / Q000276:immunology
D047228:Angiotensin II Type 1 Receptor Blockers; D001323:Autoantibodies; D006680:HLA Antigens; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D044140:Receptor, Angiotensin, Type 1; D014157:Transcription Factors; D048052:Mitogen-Activated Protein Kinase 3; D019808:Losartan