Characteristics of Chronic Rejection in Heart Transplantation:  Important Elements of Pathogenesis and Future Treatments

Suzuki, Jun–ichi; Isobe, Mitsuaki; Morishita, Ryuichi; Nagai, Ryozo

doi:10.1253/circj.cj-09-0809

Cited by 49 publications

(19 citation statements)

References 79 publications

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“…Within the tunica media, smooth muscle cells become activated and, together with myofibroblasts derived from the adventitia, transmigrate in luminal direction to the endothelial cell layer. As a result of this complex interplay between cells and ECM components, a concentric hyperplasia of the tunica intima develops which distinctly differs from classic atherosclerosis in which eccentric plaque formation is typical [8]. Over time, a progressive vessel occlusion occurs and represents the histo-pathologic substrate of PAP elevation leading to the clinical manifestations of the disease [2, 9].…”

Section: Introductionmentioning

confidence: 99%

“…Over time, a progressive vessel occlusion occurs and represents the histo-pathologic substrate of PAP elevation leading to the clinical manifestations of the disease [2, 9]. The histo-pathological features of pulmonary vascular remodelling resemble the phenomenon of allograft vasculopathy (CAV) as it occurs in cardiac transplants [2, 8]. In CAV, reorganisation of the ECM, in particular the re-expression of fetal variants of certain cell adhesion modulating proteins like fibronectin or tenascin-C as well as the impact of fibroblast to myofibroblast transdifferentiation and vascular smooth muscle cell activation has been extensively described [10–14].…”

Section: Introductionmentioning

confidence: 99%

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Lung tissue remodelling in MCT-induced pulmonary hypertension: a proposal for a novel scoring system and changes in extracellular matrix and fibrosis associated gene expression

Franz

Grün

Betge³

et al. 2016

Oncotarget

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Pulmonary hypertension (PH) is associated with vasoconstriction and remodelling. We studied lung tissue remodelling in a rat model of PH with special focus on histology and extracellular matrix (ECM) remodelling. After induction of PH by monocrotaline, lung tissue was analysed histologically, by gene expression analysis and immunofluorescence labelling of ED-A domain containing fibronectin (ED-A + Fn), B domain containing tenascin-C (B + Tn-C) as well as alpha-smooth muscle actin (α-SMA). Serum concentrations of ED-A + Fn were determined by ELISA. Systolic right ventricular pressure (RVPsys) values were significantly elevated in PH ( n = 18; 75 ± 26.4 mmHg) compared to controls ( n = 10; 29 ± 19.3 mmHg; p = 0.015). The histological sum-score was significantly increased in PH (8.0 ± 2.2) compared to controls (2.5 ± 1.6; p < 0.001). Gene expression analysis revealed relevant induction of several key genes of extracellular matrix remodelling. Increased protein deposition of ED-A + Fn but not of B + Tn-C and α-SMA in lung tissue was found in PH (2.88 ± 3.19 area%) compared to controls (1.32 ± 0.16 area%; p = 0.030). Serum levels of ED-A + Fn were significantly higher in PH ( p = 0.007) positively correlating with RVPsys (r = 0.618, p = 0.019). We here present a novel histological scoring system to assess lung tissue remodelling in PH. Gene expression analysis revealed induction of candidate genes involved in collagen matrix turnover, fibrosis and vascular remodelling. The stable increased tissue deposition of ED-A + Fn in PH as well as its dynamics in serum suggests a role as a promising novel biomarker and potential therapeutic target.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lung tissue remodelling in MCT-induced pulmonary hypertension: a proposal for a novel scoring system and changes in extracellular matrix and fibrosis associated gene expression

Franz

Grün

Betge³

et al. 2016

Oncotarget

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“…However, even with efficient immunosuppressive therapy to prevent acute rejection in the early stage after transplantation, chronic allograft rejection is the major obstacle to the long-term survival of heart transplant recipients [2]. The principal phenomena causing chronic allograft rejection are coronary allograft vasculopathy (CAV) [3] and leukocytes from recipients infiltrating into allografts [4]. Previous studies have demonstrated that an immune mechanism participates in chronic allograft rejection.…”

Section: Introductionmentioning

confidence: 99%

“…The classically activated macrophage (CAM)/alternatively activated macrophage (AAM) ratio in allografts has been considered to play a key role in the immune response to transplantation [10]. Within the complex mechanism of chronic allograft rejection, both T cells and macrophages participate in the lesion of allografts [3]. These cells are immunotherapy targets in chronic allograft rejection.…”

Section: Introductionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ Deficiency in T Cells Accelerates Chronic Rejection by Influencing the Differentiation of CD4+ T Cells and Alternatively Activated Macrophages

et al. 2014

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BackgroundIn a previous study, activation of the peroxisome proliferator–activated receptor γ (PPARγ) inhibited chronic cardiac rejection. However, because of the complexity of chronic rejection and the fact that PPARγ is widely expressed in immune cells, the mechanism of the PPARγ - induced protective effect was unclear.Materials and MethodsA chronic rejection model was established using B6.C-H-2bm12KhEg (H-2bm12) mice as donors, and MHC II-mismatched T-cell-specific PPARγ knockout mice or wild type (WT) littermates as recipients. The allograft lesion was assessed by histology and immunohistochemistry. T cells infiltrates in the allograft were isolated, and cytokines and subpopulations were detected using cytokine arrays and flow cytometry. Transcription levels in the allograft were measured by RT-PCR. In vitro, the T cell subset differentiation was investigated after culture in various polarizing conditions. PPARγ-deficient regularory T cells (Treg) were cocultured with monocytes to test their ability to induce alternatively activated macrophages (AAM).ResultsT cell-specific PPARγ knockout recipients displayed reduced cardiac allograft survival and an increased degree of pathology compared with WT littermates. T cell-specific PPARγ knockout resulted in more CD4+ T cells infiltrating into the allograft and altered the Th1/Th2 and Th17/Treg ratios. The polarization of AAM was also reduced by PPARγ deficiency in T cells through the action of Th2 and Treg. PPARγ-deficient T cells eliminated the pioglitazone-induced polarization of AAM and reduced allograft survival.ConclusionsPPARγ-deficient T cells influenced the T cell subset and AAM polarization in chronic allograft rejection. The mechanism of PPARγ activation in transplantation tolerance could yield a novel treatment without side effects.

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“…Another consequence of chronic rejection and inflammation is cardiac fibrosis accompanied by increased stiffness of the heart and diminished contractility [5]. Ultimately, these fibrotic reactions can result in myocardial infarction or sudden death [4,6]. …”

Section: Introductionmentioning

confidence: 99%

IL-13 signaling via IL-13Rα2 triggers TGF-β1-dependent allograft fibrosis

Brunner¹,

Schiechl²,

Kesselring³

et al. 2013

Transplant Res

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BackgroundAllograft fibrosis still remains a critical problem in transplantation, including heart transplantation. The IL-13/TGF-β1 interaction has previously been identified as a key pathway orchestrating fibrosis in different inflammatory immune disorders. Here we investigate if this pathway is also responsible for allograft fibrosis and if interference with the IL-13/TGF-β1 interaction prevents allograft fibrosis.MethodsFVB or control DBA/1 donor hearts were transplanted heterotopically into DBA/1 recipient mice and hearts were explanted at day 60 and 100 post-transplantation. Cardiac tissue was examined by Masson’s trichrome staining and immunohistochemistry for CD4, CD8, CD11b, IL-13, Fas ligand, matrix metalloproteinase (MMP)-1, MMP-13, β2-microglobulin, and Gremlin-1. Graft-infiltrating cells were isolated and analyzed by flow cytometry. IL-13 and TGF-β1 levels were determined by enzyme-linked immunosorbent assay (ELISA) and the amount of collagen was quantified using a Sircol assay; IL-13Rα2 expression was detected by Western blotting. In some experiments IL-13/ TGF-β1 signaling was blocked with specific IL-13Rα2 siRNA. Additionally, a PCR array of RNA isolated from the allografts was performed to analyze expression of multiple genes involved in fibrosis.ResultsBoth groups survived long-term (>100 days). The allogeneic grafts were infiltrated by significantly increased numbers of CD4+ (P <0.0001), CD8+ (P <0.0001), and CD11b+ cells (P = 0.0065) by day 100. Furthermore, elevated IL-13 levels (P = 0.0003) and numbers of infiltrating IL-13+ cells (P = 0.0037), together with an expression of IL-13Rα2, were detected only within allografts. The expression of IL-13 and IL-13Rα2 resulted in significantly increased TGF-β1 levels (P <0.0001), higher numbers of CD11bhighGr1intermediateTGF-β1+ cells, and elevated cardiac collagen deposition (P = 0.0094). The allograft fibrosis found in these experiments was accompanied by upregulation of multiple profibrotic genes, which was confirmed by immunohistochemical stainings of allograft tissue. Blockage of the IL-13/TGF-β1 interaction by IL-13Rα2 siRNA led to lower numbers of CD11bhighGr1intermediateTGF-β1+, CD4+, CD8+, and CD11b+ cells, and prevented collagen deposition (P = 0.0018) within these allografts.ConclusionsIL-13 signaling via IL-13Rα2 induces TGF-β1 and causes allograft fibrosis in a murine model of chronic transplant rejection. Blockage of this IL-13/TGF-β1 interaction by IL-13Rα2 siRNA prevents cardiac allograft fibrosis. Thus, IL-13Rα2 may be exploitable as a future target to reduce allograft fibrosis in organ transplantation.

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Characteristics of Chronic Rejection in Heart Transplantation: Important Elements of Pathogenesis and Future Treatments

Cited by 49 publications

References 79 publications

Lung tissue remodelling in MCT-induced pulmonary hypertension: a proposal for a novel scoring system and changes in extracellular matrix and fibrosis associated gene expression

Lung tissue remodelling in MCT-induced pulmonary hypertension: a proposal for a novel scoring system and changes in extracellular matrix and fibrosis associated gene expression

Peroxisome Proliferator-Activated Receptor γ Deficiency in T Cells Accelerates Chronic Rejection by Influencing the Differentiation of CD4+ T Cells and Alternatively Activated Macrophages

IL-13 signaling via IL-13Rα2 triggers TGF-β1-dependent allograft fibrosis

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