Kein Folientitel

1
Angiotensin II type 1 receptor agonistic
antibodies and refractory vascular rejection
Duska Dragun
NephrologyTransplantation, Charité Campus Mitte
Humboldt University Berlin, Germany
2
Acute humoral rejection (refractory acute
vascular rejection)

• 30 of acute rejection cases (10 overall)
• Pathogenesis
• donor-specific antibodies against HLA antigens
  (C4d)
• non-HLA antibodies against unidentified targets
  

3
Patients
9 cases with Banff III acute rejection refractory
to steroids and ATG 9/9 negative for HLA class I
and class II DSA
9/9 malignant hypertension, 4/9 seizures
4
Hypothesis
Angiotensin II like agonistic antibodies may
cause refractory vascular rejection and malignant
hypertension in non-presensitized patients?
5
Bioassay using neonatal rat cardiomyocytes
6
Agonistic activity of patients IgG
Steroid/ ATGrefract/ DSA neg
Increase in BPM
Patients
7
Agonistic activity of patients IgG
Steroid/ATG refract/DSA neg
Increase in BPM
Steroid/ATG sensit/ DSA neg
Patients
8
Agonistic activity of patients IgG
Steroid/ ATG-refract/DSA neg
Increase in BPM
Steroid/ ATG-refract/DSA pos
Steroid/ ATG-sensit/ DSA neg
Patients
9
Specificity of the AngII AT1R mediated agonistic
response
Increase in BPM
10
AT1
-
AA
AT1
-
Rc
IgG
11
AT1R-AA pos
AT1R-AA neg
12
AT1R-AA neg
AT1R-AA pos
13
(No Transcript)
14
TF
p65
c
-
fos
CD68
15
MCP-1 production by stimulated VSMCs
MCP-1(pg/ml)
Ang II
AT1-AA
control IgG
16
RANTES production by stimulated VSMCs
RANTES (pg/ml)
17
Hypothesis on action of AT1-AA
AT-1AA
AT1 receptor
NF-kB / AP-1/NF-AT
?
!
!
IL-2
tissue factor
MCP-1
RANTES
IFN-g
pro- coagulation
T-cell response
cell infiltration
Microangiopathy / rejection
18
AT1 receptor
19
Bioassay using neonatal rat cardiomyocytes
20
Epitope analysis
Increase in beat number/min
21
IgG subclass determination
Increase in beat number/min
22
AT1 receptor
IgG1
IgG3
23
Concluding remarks
We identified antibodies with agonistic activity
of IgG1 and IgG3 subclass targeting epitopes on
the second extracellular loop of the AT1
receptor. Agonistic activity of antibodies can be
blocked by AT1 receptor antagonist. AT1 receptor
antagonism should be attempted in a distinct
population of renal transplant patients with
malignant hypertension and acute vascular
rejection in the absence of HLA antibodies.
24
AT1-AA in renal transplantation Gerd
Wallukat Ralf Dechend Dominik N. Müller Jan
Hinrich Bräsen F.C. Luft
Diana Eckert Klemens Budde Lutz Fritsche Hans-H.
Neumayer
Constanze Schönemann Birgit Rudolph