N-octanoyl Dopamine Attenuates the Development of Transplant Vasculopathy in Rat Aortic Allografts Via Smooth Muscle Cell Protective Mechanisms

Wedel, Johannes; Hottenrott, Maximilia; Bulthuis, Marian; Huitema, S.; Yard, Benito A.; Hillebrands, Jan-Luuk

doi:10.1097/tp.0000000000000870

Cited by 5 publications

(3 citation statements)

References 47 publications

(50 reference statements)

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“…The NOD concentrations used in the current study were based on previous in vitro studies 22,43 , yet the a fast blood clearance, predominantly via renal and hepatobiliary elimination 46 does not allow plasma NOD concentrations to reach the in vitro concentrations used in our current study. Despite this short-coming, in vivo studies demonstrated that NOD is highly efficacious in the treatment of brain dead donors on early post-transplant renal and heart function 47,48 , in ameliorating inflammation in ischemic acute kidney injury 33 and in attenuating the development of transplant vasculopathy in rat aortic allografts 49 . Nonetheless, it remains to be elucidated to what extent the in vivo efficacy of NOD is mediated by its ability to inhibit IFNγ mediated gene expression.…”

Section: Discussionmentioning

confidence: 99%

N-Octanoyl-Dopamine inhibits cytokine production in activated T-cells and diminishes MHC-class-II expression as well as adhesion molecules in IFNγ-stimulated endothelial cells

Hofmann

Krapp

et al. 2019

Sci Rep

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IFNγ enhances allograft immunogenicity and facilitates T-cell mediated rejection. This may cause interstitial fibrosis and tubular atrophy (IFTA), contributing to chronic allograft loss. We assessed if inhibition of T-cell activation by N-octanoyl dopamine (NOD) impairs adherence of activated T-cells to endothelial cells and the ability of activated T-cells to produce IFNγ. We also assessed if NOD affects IFNγ mediated gene expression in endothelial cells. The presence of NOD during T-cell activation significantly blunted their adhesion to unstimulated and cytokine stimulated HUVEC. Supernatants of these T-cells displayed significantly lower concentrations of TNFα and IFNγ and were less capable to facilitate T-cell adhesion. In the presence of NOD VLA-4 (CD49d/CD29) and LFA-1 (CD11a/CD18) expression on T-cells was reduced. NOD treatment of IFNγ stimulated HUVEC reduced the expression of MHC class II transactivator (CIITA), of MHC class II and its associated invariant chain CD74. Since IFTA is associated with T-cell mediated rejection and IFNγ to a large extent regulates immunogenicity of allografts, our current data suggest a potential clinical use of NOD in the treatment of transplant recipients. Further in vivo studies are warranted to confirm these in vitro findings and to assess the benefit of NOD on IFTA in clinically relevant models.

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Section: Discussionmentioning

confidence: 99%

N-Octanoyl-Dopamine inhibits cytokine production in activated T-cells and diminishes MHC-class-II expression as well as adhesion molecules in IFNγ-stimulated endothelial cells

Hofmann

Krapp

et al. 2019

Sci Rep

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“…NK cells may also play a role in damping chronic inflammatory responses by killing donor-derived tissue-resident CD4 T cells that provide help to host B cells that produce DSAs (37••). Graft-derived molecules including vanin (38) and N-octanoyl dopamine (39) may promote AV by enhancing macrophage vessel infiltration and apoptosis of SMCs, respectively.…”

Section: The Roles Of Innate Immune Cells In Avmentioning

confidence: 99%

Recent advances in allograft vasculopathy

Merola

Jane‐wit²,

Pober³

2017

Current Opinion in Organ Transplantation

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Purpose of review Despite considerable advances in controlling acute rejection, the longevity of cardiac and renal allografts remains significantly limited by chronic rejection in the form of allograft vasculopathy (AV). This review discusses recently reported mechanistic insights of AV pathogenesis as well recent clinical evaluations of new therapeutic approaches. Recent findings Although adaptive immunity is the major driver of AV, natural killer cells mediate vasculopathic changes in a transplanted mouse heart following treatment with donor-specific antibody (DSA). However, NK cells may also dampen chronic inflammatory responses by killing donor-derived tissue-resident CD4 T cells that provide help to host B cells, the source of DSA. DSA may directly contribute to vascular inflammation by inducing intracellular signaling cascades that upregulate leukocyte adhesion molecules, facilitating recruitment of neutrophils and monocytes. DSA-mediated complement activation additionally enhances endothelial alloimmunogenicity through activation of non-canonical NF-κB signaling. New clinical studies evaluating mTOR and proteasome inhibitors to target these pathways have been reported. Summary AV is a pathology resultant from several innate and adaptive alloimmune responses. Mechanistic insights from preclinical studies have identified agents that are currently being investigated in clinical trials.

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“…A new way for attenuating SMC proliferation was proposed by Wedel et al 44 who tested the influence of Noctanoyl dopamine (NOD) infusion on the development of CAV in a rat aortic transplantation model. Continuous treatment for up to 4 weeks resulted in significantly reduced neointima formation with a respective reduction in SMCs.…”

Section: Treatment Options Primarily Targeting Smooth Muscle Cellsmentioning

confidence: 99%

New Targets for the Prevention of Chronic Rejection after Thoracic Organ Transplantation

Heim

Gocht

Weyand

et al. 2017

Thorac cardiovasc Surg

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The gold standard for the treatment of terminal heart failure and irreversible lung diseases includes thoracic organ transplantation. The major obstacle for long-term survival after successful transplantation is chronic rejection, an ongoing immunomodulatory disease so far without effective therapy. Therefore, the aim of this review is to elucidate scientific efforts targeting different new mechanisms of cardiac allograft vasculopathy (CAV) and chronic lung allograft dysfunction (CLAD). For this purpose, we performed a systematic review of the literature to assess recent strategies in transplant immunology research. We searched MEDLINE from 2015 up to date for articles addressing the following keywords: CAV, transplant vasculopathy, transplant arteriosclerosis, CLAD, bronchiolitis obliterans transplant, and obliterative bronchiolitis transplant. All articles including experimental models in the field of transplant immunology addressing new aspects for the prevention of chronic rejection after heart and lung transplantation were included in this review. The prevention of chronic rejection would clearly improve the survival of patients after heart and lung transplantation. Interesting targets were addressed in recent research, but further research is necessary to effectively treat this life-threatening disease in transplant recipients.

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N-octanoyl Dopamine Attenuates the Development of Transplant Vasculopathy in Rat Aortic Allografts Via Smooth Muscle Cell Protective Mechanisms

Abstract: This study identified NOD as potential treatment modality to attenuate TV. Our data clearly support a vasculoprotective effect of NOD by reducing smooth muscle cell proliferation and inflammation-induced apoptosis.

Cited by 5 publications

References 47 publications

N-Octanoyl-Dopamine inhibits cytokine production in activated T-cells and diminishes MHC-class-II expression as well as adhesion molecules in IFNγ-stimulated endothelial cells

N-Octanoyl-Dopamine inhibits cytokine production in activated T-cells and diminishes MHC-class-II expression as well as adhesion molecules in IFNγ-stimulated endothelial cells

Recent advances in allograft vasculopathy

New Targets for the Prevention of Chronic Rejection after Thoracic Organ Transplantation

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