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

Heim, Christian; Gocht, A.; Weyand, Michael; Ensminger, Stephan

doi:10.1055/s-0037-1615290

Cited by 11 publications

(5 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…10,11 In summary, our findings affirm both in vitro-and in vivo-activated hPlts as an isolated factor responsible for the development of transplant arteriosclerosis in a humanized mouse artery xenograft model and support the therapeutic usage of the antiplatelet agents such as clopidogrel for effectively reducing transplant arteriosclerosis in experimental vascular grafts. 10,11 This humanized C57/Bl6-Rag2 −/− γc −/− mouse xenograft model may be useful to investigate further cell subpopulations required for the development of transplant arteriosclerosis and to test novel therapeutic strategies 46,47 as well as drug interactions altering the platelet response and ultimately to prevent the development of CAV in human patients.…”

Section: Discussionmentioning

confidence: 99%

Direct Impact of Human Platelets on the Development of Transplant Arteriosclerosis

et al. 2022

Self Cite

View full text Add to dashboard Cite

Background. Platelets play an important role in the pathogenesis of inflammatory and proliferative vascular changes. The aim of this study was to investigate whether human platelets are able to induce transplant arteriosclerosis in a humanized C57/Bl6-Rag2 −/− γc −/− mouse xenograft model. Methods. Nonactivated and in vitro-activated human platelets were analyzed and phenotyped for surface markers by flow cytometry. Side branches of human mammary arteries were implanted into the infrarenal aorta of recipients, followed by daily application of human platelets and histological analyzed on day 30 after transplantation. Results. Human platelets collected by apheresis had low levels of platelet activation markers. However, after in vitro activation, expression was markedly increased. Sixty minutes after injection in recipient mice, nonactivated human platelets become significantly activated. Increased adhesion of platelets to the vascular endothelium was detected by in vivo fluorescence microscopy. After intravenous injection of nonactivated or activated platelets, human xenografts showed pronounced intimal proliferation. Immunohistological analysis showed that the group treated with activated human platelets exhibited significantly increased intragraft protein expression of intracellular adhesion molecule-1 and platelet-derived growth factor receptor beta and smooth muscle cell migration into the neointima. Conclusions. These data demonstrate that an isolated daily application of both in vivo-and in vitro-activated human platelets results in the development of transplant arteriosclerosis in a humanized mouse transplantation model.

show abstract

Section: Discussionmentioning

confidence: 99%

Direct Impact of Human Platelets on the Development of Transplant Arteriosclerosis

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Cardiac allograft vasculopathy still is the most important long term complication after heart transplantation and many efforts are taken to find a way to prevent its development. 33 In the current study, we tested nintedanib, a tyrosine kinase inhibitor with antagonistic effects on different growth factor receptors, for its impact on CAV. Results of our study revealed that treatment with nintedanib (1) significantly reduced CAV development after allogeneic aortic transplantation in mice, (2) which was characterized by significantly reduced amounts of neointimal smooth muscle cells accompanied by a decreased immigration of DCs and T cells into the neointima, and (3) by reduced expression of PDGF receptors α and β as well as their ligand PDGF-B.…”

Section: Discussionmentioning

confidence: 99%

“… 5 , 7 , 34 Nintedanib significantly inhibited this process in our mouse model which can be explained by the effects of the targeted tyrosine kinase receptors (TKRs). PDGFRα + β strongly mediate SMC proliferation and migration after ligand binding, 11 , 30 , 31 while VEGFR1 + 2 only mediate cell migration, 32 , 33 but additionally seem to be able to potentiate the mitogenic effect of FGF. 32 FGF again is a very potent factor for SMC proliferation 34 via its receptors FGFR1 and FGFR2.…”

Section: Discussionmentioning

confidence: 99%

Small Molecule Tyrosine Kinase Inhibitor Nintedanib Reduces Development of Cardiac Allograft Vasculopathy in Murine Aortic Allografts

Gocht

Spriewald

Distler

et al. 2018

Transplantation Direct

Self Cite

View full text Add to dashboard Cite

BackgroundNintedanib is a small molecule tyrosine kinase inhibitor that blocks the action of the platelet-derived growth factor receptor (PDGFR), the vascular endothelial growth factor receptor (VEGFR) and the fibroblast growth factor receptor. All of these receptors have been shown to be involved in the development of cardiac allograft vasculopathy (CAV) after heart transplantation. We therefore hypothesized that blocking these tyrosine kinase receptors with nintedanib could prevent CAV.MethodsCBA/JRj (H2k) mice underwent an abdominal aortic transplantation with a graft derived from fully allogeneic C57BL/6JRj (H2b) mice. Nintedanib was given daily from the first day after transplantation until harvest on day 14 for polymerase chain reaction analysis of intragraft cytokine expression or harvest on day 30 for histological analysis of the graft.ResultsNintedanib treatment resulted in significantly reduced neointima formation in the aortic graft compared with untreated control allografts. Interestingly, the immigration of smooth muscle cells into the neointima was markedly reduced while graft infiltrating macrophages and T cells were not altered in nintedanib-treated animals. The expression of the growth factor PDGF was significantly reduced in the nintedanib group going along with a distinctly reduced expression of the corresponding receptors PDGFR α and -β.ConclusionsTreatment with nintedanib caused a significant reduction of CAV development after aortic transplantation in mice. We hypothesize the attenuated neointima formation in nintedanib-treated animals to be mediated by a direct inhibition of intimal smooth muscle cell proliferation via reduced expression of PDGF and the appropriate receptors PDGFR α + β.

show abstract

“…The endothelium plays a key role in the onset and progression of CAV [ 1 ]. Endothelial dysfunction is a typical feature of many cardiovascular diseases (CVDs) [ 8 ], and it is also an early feature of CAV, and it was found to progress with increasing time post-HTx [ 9 , 10 ]. Typically, coronary angiography is used to monitor the progress of CAV [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Both immunologic and nonimmunologic (CVD) risk factors contribute to the development of CAV [ 22 , 23 , 24 ]. Intriguingly, there appears to be a complex interplay between both factors, ultimately leading to endothelial injury and an exaggerated repair response [ 2 , 9 , 10 ]. Traditional risk factors for the development of both CVD and CAV include dyslipidemia, diabetes, and hypertension [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Nailfold Videocapillaroscopy for Non-Invasive Assessment of Microcirculation and Prognostic Correlation with Endothelial Dysfunction, Cardiovascular Risk Factors, and Non-HLA Antibodies in Heart Transplant Recipients: A Pilot Study

Sikorska

Kamińska

Catar

et al. 2023

JCM

View full text Add to dashboard Cite

Early identification of allograft vasculopathy and the concomitant elimination of adverse risk factors is essential for improving the long-term prognosis of heart transplant (HTx) recipients with underlying cardiovascular disease (CVD). The major aim of this pilot study was to conduct a non-invasive imaging evaluation of the HTx patient microcirculation by employing nailfold video-capillaroscopy (NVC) in a well-characterized patient and control cohort, and to correlate these data with endothelial cell function, accompanied by studies of traditional cardiovascular risk factors and non-HLA antibodies in HTx recipients. Ten patients undergoing HTx (mean age of 38 ± 14 years) were recruited for the study and compared to a control group of 12 well-matched healthy volunteers (mean age 35 ± 5 years) with normal body mass index (BMI). Detailed medical records were collected from all individuals. NVC was performed using CapillaryScope 200 MEDL4N microscope. For functional readout and correlation analysis, endothelial cell network formation in conjunction with measurements of patient serum levels of vascular endothelial growth factor (VEGF) and non-HLA autoantibodies directed against the angiotensin II type-1-receptor (anti-AT1R-Ab), endothelin-1 type-A-receptor (anti-ETAR-Ab), protease-activated receptor-1 (anti-PAR-1-Ab), and VEGF-A (anti-VEGF-A-Ab) were studied. Our NVC analysis found that the average apical loop diameter of nailfold capillaries was significantly increased in HTx recipients (p = 0.001). In addition, HTx patients with more prominent changes in capillaroscopic patterns were characterized by the presence of traditional cardiovascular risk factors, and HTx patients had increased levels of anti-AT1R-ab, anti-ETAR-ab, and anti-VEGF-A-Ab (p = 0.017, p = 0.025, and p = 0.003, respectively). Capillary diameters most strongly correlated with elevated serum levels of troponin T and triglycerides (R = 0.69, p = 0.028 and R = 0.81, p = 0.004, respectively). In conclusion, we found that an abnormal NVC pattern in HTx patients is associated with traditional CVD risk factors and that NVC is a useful non-invasive tool to conveniently monitor changes in the microvasculature of HTx patients.

show abstract

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

Cited by 11 publications

References 69 publications

Direct Impact of Human Platelets on the Development of Transplant Arteriosclerosis

Direct Impact of Human Platelets on the Development of Transplant Arteriosclerosis

Small Molecule Tyrosine Kinase Inhibitor Nintedanib Reduces Development of Cardiac Allograft Vasculopathy in Murine Aortic Allografts

Nailfold Videocapillaroscopy for Non-Invasive Assessment of Microcirculation and Prognostic Correlation with Endothelial Dysfunction, Cardiovascular Risk Factors, and Non-HLA Antibodies in Heart Transplant Recipients: A Pilot Study

Contact Info

Product

Resources

About