Non-HLA Antibodies Targeting Vascular Receptors Enhance Alloimmune Response and Microvasculopathy After Heart Transplantation

Hiemann, N.E.; Meyer, Rudolf; Wellnhofer, Ernst; Schoenemann, Constanze; Heidecke, Harald; Lachmann, Nils; Hetzer, Roland; Dragun, Duska

doi:10.1097/tp.0b013e3182692ad2

Cited by 118 publications

(117 citation statements)

References 29 publications

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“…A following study detected a strong association between the presence of AT1R-Abs and AMR in kidney transplanted recipients whose sera contained no antibody to donor HLA or MICA [8]. A recent pilot study in a small cohort with 30 recipients in the first year after HTx showed a correlation of elevated levels of AT1R-Abs and ETAR-Abs with early onset of microvasculopathy at month 12, and graft loss following HTx, implicating relevant effects on post-transplant morbidity and mortality in that study [10]. Higher levels of AT1R-and ETAR-Abs were observed in patients with acute cellular rejection and antibodymediated rejection at months 1 and 12 post-HTx [10].…”

Section: Discussionmentioning

confidence: 99%

“…More recently, antibodies targeting against other non-HLA antigen like the angiotensin II type 1 receptor (AT1R) and the endothelin receptor A (ETAR), have shown to play a role in several severe alloimmune and autoimmune pathologies ranging from renal allograft rejection [8] to microvasculopathy in systemic sclerosis [9] and in cardiac transplants [10].…”

Section: Introductionmentioning

confidence: 99%

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Occurrence of HLA- and Non-HLA Antibodies after Heart Transplantation are Associated with Cardiac Allograft Vasculopathy

Barten¹,

Dieterlen²,

Garbade³

et al. 2014

Cardiometry

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AimsCardiac allograft vasculopathy (CAV) accounts for major morbidity and mortality late in the heart transplant (HTx) history. The role of antibodies (Abs) directed against human leukocyte antigens (HLA) and non-HLA antigens in the pathogenesis of CAV are still under investigation. Materials and methodsSera of 116 long-term HTx recipients with CAV (n=46) and without CAV (n=70) were analysed by (1) Luminex for Abs against both HLA classes and major histocompatibility complex class I-related chain A (MICA), and by (2) ELISA for Abs against angiotensin-type-1-receptor (AT1R) or endothelin-receptor-A (ETAR). Cellular rejection by endomyocardial biopsies and immunosuppressive drug therapy were analysed, too. ResultsHTx recipients developed higher levels of non-HLA-Abs than of Abs against HLA. CAV appeared more frequently in recipients with non-HLA-Abs (38.3% AT1R; 44.1% ETAR; 13.0% MICA) than in recipients with HLA-Abs (8.7% HLA class I; 8.7% HLA class II). Recipients with non-HLA-Abs developed CAV earlier (73.7±47.4months) than recipients without Abs (85.5±50.6months). ConclusionOccurrence of HLA-Abs and non-HLA-Abs contribute to CAV after HTx. Non-HLA-Abs were connected to an earlier and higher incidence of CAV. Recipients with subclinical cellular rejections and AT1R-Abs and ETAR-Abs as well as recipients with certain donor specific-Abs again HLA and MICA specifities are at risk to develop CAV.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Occurrence of HLA- and Non-HLA Antibodies after Heart Transplantation are Associated with Cardiac Allograft Vasculopathy

Barten¹,

Dieterlen²,

Garbade³

et al. 2014

Cardiometry

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“…Hiemann et al 5 reported in their pilot study that patients on assist device support before heart transplantation were more likely to develop high anti -AT1R antibody levels (43% of supported versus 18% of non -supported patients, P = 0.021) within 24 h after heart transplantation, implicating pre -transplant sensitization. Barten el al.…”

Section: Discussionmentioning

confidence: 99%

“…The negative impact of anti -HLA antibodies on post -transplant allograft function and survival has now been well documented. Recently, there has been accumulating evidence of various non -HLA antibodies involvement in decreased allograft and recipient survival [5][6][7][8][9][10] . While anti -HLA antibodies exert their negative effect via complement activation and antibody -mediated cytotoxicity, antibodies against AT1R, act as a natural allosteric receptor agonist.…”

Section: Discussionmentioning

confidence: 99%

“…Anti-AT1R antibodies exert their damaging effect by binding to the second extracellular loop of AT1R receptors present in endothelial and vascular smooth muscle cells, inducing endothelial activation and dysfunction. Previous reports have identified heart transplant recipients who developed anti-AT1R antibodies to be at increased risk of post-transplant rejection and cardiac allograft vasculopathy 4,5 . Apart from an effect on the vascular tone, these antibodies also lead to pro -inflammatory and pro -coagulatory responses.…”

Section: Introductionmentioning

confidence: 99%

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The impact of Angiotensin II Type 1 Receptor antibodies on morbidity and mortality in Heart Mate II supported recipients

Urban¹,

Slavčev²,

Gazdic³

et al. 2016

BIOMED PAP

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, Peter Ivak a , Ivan Netuka a Aims. One of the proposed limitations of left ventricular assist device (LVAD) therapy is high degree of sensitization. Apart from human leukocyte antigen (HLA), antibodies against Angiotensin II Type 1 Receptor (AT1R) have been associated with adverse outcomes. The purpose of this study was to compare complications and survival of anti -AT1R positive versus negative Heart Mate II (HMII) recipients. Methods. Altogether 96 patients received HMII at our institution between 2008 and 2012. These were stratified into three groups: antibody positive before implantation (AT1R+), antibody conversion during support (AT1R-/+) and patients who remained antibody negative (AT1R-). Survival, major on-device adverse events and post-transplant rejections were assessed with Kaplan-Meier and log-rank tests.Results. Two year on-device and overall survival was 78 ± 12% and 75 ± 10% in AT1R-, 60 ± 23% and 60 ± 15% in AT1R+ and 92 ± 6% and 87 ± 5% in AT1R-/+ group (P = 0.409, P = 0.185). Freedom from major adverse event at two years for AT1R-, AT1R+ and AT1R-/+ was 49 ± 14%, 53 ± 16% and 41 ± 11% (P = 0.875). Freedom from rejection was 63 ± 17% in patients who were both anti-AT1R and HLA negative and 65 ± 13% in those who were antibody positive (P = 0.788). Conclusion.Patients who were anti-AT1R antibody positive had similar on-device survival and rate of complications in comparison to those who were antibody negative. In transplanted patients, there were no differences in the overall survival and rejection between the groups.

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The Detection of Antibodies to the Angiotensin II-Type 1 Receptor in Transplantation

Dragun

2013

Methods in Molecular Biology

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The detection of auto-antibodies detection is a major aspect of patient's immunomonitoring. Antibodies directed against the heart and kidney Angiotensin II type 1 receptor (AT1R) play a major role in antibody mediated rejection after heart and kidney transplantation and in obliterative vasculopathy of autoimmune diseases. Here, a sandwich enzyme-linked immunosorbent assay (ELISA) is the reliable tool for the detection of auto-antibodies targeting AT1R.

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Non-HLA Antibodies Targeting Vascular Receptors Enhance Alloimmune Response and Microvasculopathy After Heart Transplantation

Abstract: Elevated levels of AT(1)R and ET(A)R Abs are associated with cellular and Ab-mediated rejection and early onset of microvasculopathy and should be routinely monitored after heart transplantation.

Cited by 118 publications

References 29 publications

Occurrence of HLA- and Non-HLA Antibodies after Heart Transplantation are Associated with Cardiac Allograft Vasculopathy

Occurrence of HLA- and Non-HLA Antibodies after Heart Transplantation are Associated with Cardiac Allograft Vasculopathy

The impact of Angiotensin II Type 1 Receptor antibodies on morbidity and mortality in Heart Mate II supported recipients

The Detection of Antibodies to the Angiotensin II-Type 1 Receptor in Transplantation

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