title: Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection.
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.
authors.affiliation: Department of Nephrology, Charité University Hospital, Berlin, Germany. duska.dragun@charite.de
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Müller
authors.forename: Jan Hinrich
authors.initials: JH
authors.lastname: Bräsen
authors.forename: Lutz
authors.initials: L
authors.lastname: Fritsche
authors.forename: Melina
authors.initials: M
authors.lastname: Nieminen-Kelhä
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
authors.forename: Birgit
authors.initials: B
authors.lastname: Rudolph
authors.forename: Johan
authors.initials: J
authors.lastname: Hoebeke
authors.forename: Diana
authors.initials: D
authors.lastname: Eckert
authors.forename: Istvan
authors.initials: I
authors.lastname: Mazak
authors.forename: Ralph
authors.initials: R
authors.lastname: Plehm
authors.forename: Constanze
authors.initials: C
authors.lastname: Schönemann
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.forename: Hans-Hellmut
authors.initials: HH
authors.lastname: Neumayer
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Gerd
authors.initials: G
authors.lastname: Wallukat
mesh_terms: 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
chemical_list: 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