Recipient-Derived Neoangiogenesis of Arterioles and Lymphatics in Quilty Lesions of Cardiac Allografts

Jonigk, Danny; Lehmann, Ulrich; Stuht, Stephan; Wilhelmi, Michaela; Haverich, Axel; Kreipe, Hans; Mengel, Michael

doi:10.1097/01.tp.0000287458.72440.75

Cited by 28 publications

(20 citation statements)

References 37 publications

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“…13 In addition, lymphatic vessels have been detected in association with subendocardial lymphonodular aggregates (Quilty lesions), 25,26 and alteration of lymphatic EC markers has been observed during the first year after heart transplantation. 27 Here, we found that chronic rejection increased lymphangiogenesis in rat cardiac allografts.…”

Section: Discussionmentioning

confidence: 99%

Targeting Lymphatic Vessel Activation and CCL21 Production by Vascular Endothelial Growth Factor Receptor-3 Inhibition Has Novel Immunomodulatory and Antiarteriosclerotic Effects in Cardiac Allografts

Nykänen

Sandelin²,

Krebs³

et al. 2010

Circulation

136

129

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Background— Lymphatic network and chemokine-mediated signals are essential for leukocyte traffic during the proximal steps of alloimmune response. We aimed to determine the role of lymphatic vessels and their principal growth signaling pathway, vascular endothelial growth factor (VEGF)-C/D/VEGFR-3, during acute and chronic rejection in cardiac allografts. Methods and Results— Analysis of heterotopically transplanted rat cardiac allografts showed that chronic rejection increased VEGF-C + inflammatory cell and hyaluronan receptor-1 (LYVE-1) + lymphatic vessel density. Allograft lymphatic vessels were VEGFR-3 + , contained antigen-presenting cells, and produced dendritic cell chemokine CCL21. Experiments with VEGFR-3/LacZ mice or mice with green fluorescent protein–positive bone marrow cells as cardiac allograft recipients showed that allograft lymphatic vessels originated almost exclusively from donor cells. Intraportal adenoviral VEGFR-3-Ig (Ad.VEGFR-3-Ig/VEGF-C/D-Trap) perfusion was used to inhibit VEGF-C/D/VEGFR-3 signaling. Recipient treatment with Ad.VEGFR-3-Ig prolonged rat cardiac allograft survival. Ad.VEGFR-3-Ig did not affect allograft lymphangiogenesis but was linked to reduced CCL21 production and CD8 + effector cell entry in the allograft. Concomitantly, Ad.VEGFR-3-Ig reduced OX62 + dendritic cell recruitment and increased transcription factor Foxp3 expression in the spleen. In separate experiments, treatment with a neutralizing monoclonal VEGFR-3 antibody reduced arteriosclerosis, the number of activated lymphatic vessels expressing VEGFR-3 and CCL21, and graft-infiltrating CD4 + T cells in chronically rejecting mouse cardiac allografts. Conclusions— These results show that VEGFR-3 participates in immune cell traffic from peripheral tissues to secondary lymphoid organs by regulating allograft lymphatic vessel CCL21 production and suggest VEGFR-3 inhibition as a novel lymphatic vessel–targeted immunomodulatory therapy for cardiac allograft rejection and arteriosclerosis.

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Section: Discussionmentioning

confidence: 99%

Targeting Lymphatic Vessel Activation and CCL21 Production by Vascular Endothelial Growth Factor Receptor-3 Inhibition Has Novel Immunomodulatory and Antiarteriosclerotic Effects in Cardiac Allografts

Nykänen

Sandelin²,

Krebs³

et al. 2010

Circulation

136

129

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“…1b]) were isolated using a no-touch technique, essentially as described (Fig. 2) [10]. Approximately 1,000 cells were harvested from serial sections in each compartment.…”

Section: Light Microscopy and Immunohistochemistrymentioning

confidence: 99%

Obliterative airway remodelling in transplanted and non-transplanted lungs

et al. 2010

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Obliterative airway remodelling is a morphological sequence in a variety of pulmonary diseases. Notably, bronchiolitis obliterans represents one of the key complications of lung transplantation, induced by (immigrating) myofibroblasts. A comparative expression analysis of obliterative airway remodelling in transplanted and non-transplanted patients has not been reported so far. Obliterated and unremodelled airways from explanted lungs (n = 19) from patients suffering from chronic allograft dysfunction, infection, graft-versus-host disease and toxic exposure were isolated by laser-assisted microdissection. Airways from lung allografts harvested shortly before and after transplantation (n = 4) as well as fibroblastic foci from lungs with interstitial pulmonary fibrosis (n = 4) served as references. Pre-amplified cDNA was analysed by quantitative real-time RT-PCR for expression of fibrosis, inflammation and apoptosis-associated genes. Composition of infiltrating cells and protein expression were assessed by conventional histology and immunohistochemistry. Bronchiolitis obliterans in transplanted patients showed a significant increase of BMP-7 expression (p = 0.0141 compared with controls), while TGF-beta1 and FGF-2 as well as BMP-4 and BMP-7 were up-regulated in fibroblastic foci in interstitial pulmonary fibrosis (p < 0.0424 compared with controls). Regarding other fibrosis-associated genes (BMP-6, SMAD-3, CASP-3 and CASP-9, FASLG, NF-KB1, IL-1 and IL-2) as well as cellularity and cellular composition, no significant differences between obliterative airway remodelling in transplanted and non-transplanted patients could be shown. Obliterative airway remodelling in lung allografts and in non-transplanted patients share many morphological and genetic traits. BMPs, especially BMP-7, warrant further investigation as possible markers for the aggravation of airway remodelling.

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“…A set of 20 endogenous human genes, including two microRNAs, which are known to be associated with EBV infection and leiomyomatous tumorigenesis (43)(44)(45)(46)(47)(48) were analyzed by short tandem repeat (STR)-PCR, real-time PCR, immunohistochemistry and fluorescence in situ hybridization (FISH) (49)(50)(51). The retrospective analysis of archived tissue has been approved by our local ethics committee.…”

Section: Methodsmentioning

confidence: 99%

Molecular and Clinicopathological Analysis of Epstein-Barr Virus–Associated Posttransplant Smooth Muscle Tumors

Jonigk

Laenger

Maegel

et al. 2012

American Journal of Transplantation

174

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Epstein-Barr virus (EBV)-associated posttransplant smooth muscle tumors (PTSMT)are very rare complications. We aimed to provide a clinicopathological characterization which is based on our own case series (n = 5) as well as previously reported PTSMT cases (n = 63). Meta-analysis of PTSMT and molecular analysis of tumor cells from our cohort was performed. Most PTSMT developed in kidney-transplanted patients (n = 41/68, 60%). Liver/transplant liver was the main site of manifestation (n = 38/68, 56%). Tumors occurred after a median interval of 48 months (range 5-348) and developed earlier in children than in adults. Most tumors showed no marked cellular atypia, low mitosis rate and no tumor necrosis. Gene expression analysis of 20 EBV-related genes, including two microRNAs, revealed overexpression of MYC (p = 0.0357). Therapy was mainly based on surgical resection or reduced immunosuppression but no significant differences in overall survival were evident. Lower overall survival was associated with multiorgan involvement (n = 33/68, 48.5%) and particularly with intracranial PTSMT manifestation (n = 7/68, 10%; p < 0.02), but not transplant involvement (n = 11/68, 16%). In summary, PTSMT differ from conventional leiomyosarcomas by their lack of marked atypia, unusual sites of involvement and defining EBV association. Surgery and reduced immunosuppression show comparable clinical results and prognosis is associated with intracranial manifestation.

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Recipient-Derived Neoangiogenesis of Arterioles and Lymphatics in Quilty Lesions of Cardiac Allografts

Abstract: The inflammatory compartment of Quilty lesions is of recipient origin and shows chimeric neoangiogenesis of blood and lymphatic vessels. VEGF-alpha produced in the adjacent myocardium appears to stimulate the chimeric neoangiogenesis.

Cited by 28 publications

References 37 publications

Targeting Lymphatic Vessel Activation and CCL21 Production by Vascular Endothelial Growth Factor Receptor-3 Inhibition Has Novel Immunomodulatory and Antiarteriosclerotic Effects in Cardiac Allografts

Targeting Lymphatic Vessel Activation and CCL21 Production by Vascular Endothelial Growth Factor Receptor-3 Inhibition Has Novel Immunomodulatory and Antiarteriosclerotic Effects in Cardiac Allografts

Obliterative airway remodelling in transplanted and non-transplanted lungs

Molecular and Clinicopathological Analysis of Epstein-Barr Virus–Associated Posttransplant Smooth Muscle Tumors

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