Abstract 5261: Platelet-Depletion Ameliorates Cardiac Function and Disease Severity in Experimental Autoimmune Myocarditis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Martin Russ ◽  
Barbara Seliger ◽  
Steffen Hauptmann ◽  
Rene Marty ◽  
Jürgen Bukur ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Inflammatory Cardiomyopathy ◽  
Autoimmune Myocarditis ◽  
Severity Scores ◽  
Experimental Autoimmune Myocarditis ◽  
Platelet Depletion ◽  
Experimental Autoimmune

Introduction: Experimental Autoimmune Myocarditis (EAM) is a CD4+ T cell mediated model of inflammatory cardiomyopathy. Activated platelets express CD154, a molecule critical to adaptive immune responses, which has been implicated in platelet-mediated modulation of inflammation. Hypothesis: Platelets are critical for the generation of heart-specific, autoreactive T-cell responses in a model of experimental Autoimmune Myocarditis. Methods: BALB/c mice were immunized twice at day 0 and day 7 with 100μg alpha-MyHC-peptide (614–29) together with Complete Freund‘s adjuvant. Platelets were markedly depleted by i.v. injection of a GP1alpha antibody every 5th day (n=8). Control mice were injected with a non-depleting isotype antibody (n=8). Mice were assessed at day 28 for heart dimensions and cardiac function using echocardiography. After lethal anesthesia, hearts were removed and analyzed for heart weight/body weight ratio and histological severity scores. CD4+ T-cells were isolated from spleens, and analyzed for CD154 and IL-17 expression using FACS after in vitro re-stimulation on alpha-MyHC pulsed, irradiated antigen presenting cells. Results: Modest platelet depletion protected from left ventricular dilatation, and preserved left ventricular ejection fraction in immunized mice. Myocarditis prevalence and severity scores were significantly reduced in depleted animals. Relative numbers of spleen-derived CD4+ T-cells expressing CD154 or IL-17, were significantly reduced in the treatment group (table ). Conclusion: Our findings suggest that platelets might play a critical role in the development of heart-specific autoimmunity and cardiomyopathy. Further studies are needed to confirm these findings, which suggest a novel treatment approach for inflammatory cardiomyopathy. Echocardiography - Histology - FACS

Abstract 129: Suppressor of Cytokine Signaling 1 in Dendritic Cells Inhibits Myocardial Inflammation in Experimental Autoimmune Myocarditis

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Kazuko Tajiri ◽  
Kyoko Imanaka-Yoshida ◽  
Michiaki Hiroe ◽  
Nobutake Shimojo ◽  
Satoshi Sakai ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytokine Signaling ◽  
Autoimmune Myocarditis ◽  
Dc Function ◽  
Autoreactive T Cell ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Introduction: Autoimmunity is considered to play an important role in the development of myocarditis and dilated cardiomyopathy. Recent reports have indicated that a subgroup of myocarditis patients may benefit from immune-targeted therapies. Suppressor of cytokine signaling1 (SOCS1) is an intracellular, cytokine-inducible protein that regulates the responses of immune cells to cytokines. We therefore hypothesized that overexpression of SOCS1 may inhibit the inflammation of myocarditis and cardiomyopathy. Methods and Results: Myocarditis was induced by subcutaneous immunization with cardiac specific peptides derived from α-myosin heavy chain in BALB/c mice on days 0 and 7. Plasmid DNA encoding SOCS1 (pSOCS1) was injected intraperitoneally into mice on days 0, 5 and 10. pSOCS1 treatment significantly decreased heart-to-body weight ratios and the number of infiltrating cells in the heart. Echocardiography showed preserved contractile function in pSOCS1-treated mice. Although autoimmune myocarditis is a CD4+ T cell-mediated disease, pSOCS1 treatment does not have a direct suppressive effect on autoreactive T-cell activation. The introduced pSOCS1 suppressed proinflammatory cytokine production and STAT1 phosphorylation in dendritic cells (DCs). In addition, the proliferative responses of autoreactive CD4+ T cells co-cultured with DCs from pSOCS1-treated mice were much weaker than those of cells cultured with DCs from control plasmid-injected mice. These results suggested that the inoculated pSOCS1 may have been transfected into DCs and impaired DC function in vivo. Conclusion: The administration of pSOCS1 protected mice from the development of experimental autoimmune myocarditis, which was mediated by the inhibition of DC function that in turn reduced the activation of autoreactive CD4+ T cells.

scholarly journals Transplantation of Fibroblast Sheets with Blood Mononuclear Cell Culture Exerts Cardioprotective Effects by Enhancing Anti-Inflammation and Vasculogenic Potential in Rat Experimental Autoimmune Myocarditis Model

Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 106
Author(s):  
Kaori Sekine ◽  
Akira T. Kawaguchi ◽  
Masaki Miyazawa ◽  
Haruo Hanawa ◽  
Shinichi Matsuda ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Mononuclear Cells ◽  
Therapeutic Option ◽  
Cell Sheet ◽  
Left Ventricular ◽  
Fulminant Myocarditis ◽  
Autoimmune Myocarditis ◽  
Experimental Autoimmune Myocarditis ◽  
Anti Inflammatory ◽  
Experimental Autoimmune

Fulminant myocarditis causes impaired cardiac function, leading to poor prognosis and heart failure. Cell sheet engineering is an effective therapeutic option for improving cardiac function. Naïve blood mononuclear cells (MNCs) have been previously shown to enhance the quality and quantity of cellular fractions (QQMNCs) with anti-inflammatory and vasculogenic potential using the one culture system. Herein, we investigated whether autologous cell sheet transplant with QQMNCs improves cardiac function in a rat model with experimental autoimmune myocarditis (EAM). Fibroblast sheets (F-sheet), prepared from EAM rats, were co-cultured with or without QQMNCs (QQ+F sheet) on temperature-responsive dishes. QQ+F sheet induced higher expression of anti-inflammatory and vasculogenic genes (Vegf-b, Hgf, Il-10, and Mrc1/Cd206) than the F sheet. EAM rats were transplanted with either QQ+F sheet or F-sheet, and the left ventricular (LV) hemodynamic analysis was performed using cardiac catheterization. Among the three groups (QQ+F sheet, F-sheet, operation control), the QQ+F sheet transplant group showed alleviation of end-diastolic pressure–volume relationship on a volume load to the same level as that in the healthy group. Histological analysis revealed that QQ+F sheet transplantation promoted revascularization and mitigated fibrosis by limiting LV remodeling. Therefore, autologous QQMNC-modified F-sheets may be a beneficial therapeutic option for EAM.

scholarly journals Heart non-specific effector CD4+ T cells protect from postinflammatory fibrosis and cardiac dysfunction in experimental autoimmune myocarditis

2019 ◽  
Vol 115 (1) ◽  
Author(s):  
Martina Zarak-Crnkovic ◽  
Gabriela Kania ◽  
Agnieszka Jaźwa-Kusior ◽  
Marcin Czepiel ◽  
Winandus J. Wijnen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Cardiac Dysfunction ◽  
Smooth Muscle Actin ◽  
Cell Subset ◽  
Autoimmune Myocarditis ◽  
Th17 Response ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

AbstractHeart-specific CD4+ T cells have been implicated in development and progression of myocarditis in mice and in humans. Here, using mouse models of experimental autoimmune myocarditis (EAM) we investigated the role of heart non-specific CD4+ T cells in the progression of the disease. Heart non-specific CD4+ T cells were obtained from DO11.10 mice expressing transgenic T cell receptor recognizing chicken ovalbumin. We found that heart infiltrating CD4+ T cells expressed exclusively effector (Teff) phenotype in the EAM model and in hearts of patients with lymphocytic myocarditis. Adoptive transfer experiments showed that while heart-specific Teff infiltrated the heart shortly after injection, heart non-specific Teff effectively accumulated during myocarditis and became the major heart-infiltrating CD4+ T cell subset at later stage. Restimulation of co-cultured heart-specific and heart non-specific CD4+ T cells with alpha-myosin heavy chain antigen showed mainly Th1/Th17 response for heart-specific Teff and up-regulation of a distinct set of extracellular signalling molecules in heart non-specific Teff. Adoptive transfer of heart non-specific Teff in mice with myocarditis did not affect inflammation severity at the peak of disease, but protected the heart from adverse post-inflammatory fibrotic remodelling and cardiac dysfunction at later stages of disease. Furthermore, mouse and human Teff stimulated in vitro with common gamma cytokines suppressed expression of profibrotic genes, reduced amount of α-smooth muscle actin filaments and decreased contraction of cardiac fibroblasts. In this study, we provided a proof-of-concept that heart non-specific Teff cells could effectively contribute to myocarditis and protect the heart from the dilated cardiomyopathy outcome.

scholarly journals Cardiosphere-Derived Cells Attenuate Inflammation, Preserve Systolic Function, and Prevent Adverse Remodeling in Rat Hearts With Experimental Autoimmune Myocarditis

2018 ◽  
Vol 24 (1) ◽  
pp. 70-77 ◽  
Author(s):  
E. Nana-Leventaki ◽  
M. Nana ◽  
N. Poulianitis ◽  
D. Sampaziotis ◽  
D. Perrea ◽  
...  
Keyword(s):  
T Cell ◽  
Systolic Function ◽  
Acute Myocarditis ◽  
Left Ventricular ◽  
Cell Infiltration ◽  
Myocardial Inflammation ◽  
Autoimmune Myocarditis ◽  
T Cell Infiltration ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Background: Cardiosphere-derived cells (CDCs) have yielded promising efficacy signals in early-phase clinical trials of ischemic and nonischemic cardiomyopathy. The potential efficacy of CDCs in acute myocarditis, an inflammatory cardiomyopathy without effective therapy, remains unexplored. Given that CDCs produce regenerative, cardioprotective, anti-inflammatory, and anti-fibrotic effects (all of which could be beneficial in acute myocarditis), we investigated the efficacy of intracoronary delivery of CDCs in a rat model of experimental autoimmune myocarditis. Methods: Lewis rats underwent induction of experimental autoimmune myocarditis by subcutaneous footpad injection of purified porcine cardiac myosin supplemented with Mycobacterium tuberculosis on days 1 and 7. On day 10, rats were randomly assigned to receive global intracoronary delivery of 500 000 CDCs or vehicle. Global intracoronary delivery was performed by injection of cells or vehicle into the left ventricular (LV) cavity during transient occlusion of the aortic root. Rats were euthanized 18 days after infusion. Cardiac volumes and systolic function were assessed by serial echocardiography, performed on days 1, 10, and 28. Myocardial inflammation, T-cell infiltration, and cardiac fibrosis were evaluated by histology. Results: Experimental autoimmune myocarditis was successfully induced in 14/14 rats that completed follow-up. Left ventricular ejection fraction (LVEF) and volumes were comparable on days 1 and 10 between groups. CDC infusion resulted in increased LVEF (81.5% ± 3% vs 65.4% ± 8%, P < .001) and decreased LV end-systolic volume (43 ± 15 vs 100 ± 24 μL, P < .001) compared to placebo administration at 18 days post-infusion. Cardiosphere-derived cell infusion decreased myocardial inflammation (7.4% ± 7% vs 20.7% ± 4% of myocardium, P = .007), cardiac fibrosis (16.6% ± 13% vs 38.1% ± 3% of myocardium, P = .008), and myocardial T-cell infiltration (30.4 ± 29 vs 125.8 ± 49 cells per field, P = .005) at 18 days post-infusion compared to placebo administration. Conclusion: Intracoronary delivery of CDCs attenuates myocardial inflammation, T-cell infiltration, and fibrosis while preventing myocarditis-induced systolic dysfunction and adverse remodeling in rats with experimental autoimmune myocarditis.

scholarly journals Programmed Death-Ligand 2 Deficiency Exacerbates Experimental Autoimmune Myocarditis in Mice

2021 ◽  
Vol 22 (3) ◽  
pp. 1426
Author(s):  
Siqi Li ◽  
Kazuko Tajiri ◽  
Nobuyuki Murakoshi ◽  
DongZhu Xu ◽  
Saori Yonebayashi ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Myocardial Inflammation ◽  
Autoimmune Myocarditis ◽  
Inflammatory Infiltration ◽  
Programmed Death ◽  
Experimental Autoimmune Myocarditis ◽  
Deficient Mice ◽  
Experimental Autoimmune

Programmed death ligand 2 (PD-L2) is the second ligand of programmed death 1 (PD-1) protein. In autoimmune myocarditis, the protective roles of PD-1 and its first ligand programmed death ligand 1 (PD-L1) have been well documented; however, the role of PD-L2 remains unknown. In this study, we report that PD-L2 deficiency exacerbates myocardial inflammation in mice with experimental autoimmune myocarditis (EAM). EAM was established in wild-type (WT) and PD-L2-deficient mice by immunization with murine cardiac myosin peptide. We found that PD-L2-deficient mice had more serious inflammatory infiltration in the heart and a significantly higher myocarditis severity score than WT mice. PD-L2-deficient dendritic cells (DCs) enhanced CD4+ T cell proliferation in the presence of T cell receptor and CD28 signaling. These data suggest that PD-L2 on DCs protects against autoreactive CD4+ T cell expansion and severe inflammation in mice with EAM.

Abstract 14723: Autoreactive T Lymphocytes Activate Cardiac Endothelium Independently of Tnf-α and Cause Endothelial Dysfunction Through Exosomes in Experimental Autoimmune Myocarditis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Filip Rolski ◽  
Marcin Czepiel ◽  
Kazimierz Weglarczyk ◽  
Maciej Siedlar ◽  
Gabriela Kania ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Dysfunction ◽  
T Lymphocytes ◽  
Conditioned Medium ◽  
Autoimmune Myocarditis ◽  
Autoreactive T Cells ◽  
Tnf Α ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune ◽  
Stimulation Of

Background: Inflammatory heart diseases represent an important clinical problem, nonetheless data regarding activation of cardiac microvascular endothelial cells (MVECs) are limited. Aim: To examine influence of TNF-α and exosomes produced by heart-reactive CD4+ T lymphocytes on activation of cardiac MVECs. Methods: Experimental autoimmune myocarditis (EAM) was induced in wild-type (WT) and TNF-α-deficient (TNF-KO) mice. CD4+ T lymphocytes were isolated from EAM mice at day 21 and activated in vitro to produce conditioned medium and exosomes. Activation of MVECs was assessed by specific assays and leukocyte-to-endothelial adhesion was analysed under shear flow condition using the BioFlux microfluidic system. Results: TNF-KO mice showed lower prevalence of myocarditis when compared to WT mice (50% vs. 90%). Stimulation of MVECs with secretome of antigen-activated autoreactive T cells resulted in upregulation of adhesion molecules (ICAM-1, VCAM-1 and P-selectin), increased ROS and decreased NO production. Addition of anti-TNF-α neutralizing antibodies effectively blocked adhesion of leukocytes to MVECs activated with the conditioned medium. Endothelial activation and dysfunction induced by the conditioned medium were independent of TNF-α produced by T cells. Stimulation of MVECs with T cell-derived exosomes increased ROS and decreased levels of NO and eNOS activation, but exosomes neither increased expression of adhesion molecules in MVECs nor induced their ability to bind leukocytes. Conclusions: TNF-α promotes MVEC activation and EAM development. In this model, autoreactive T cells activate MVECs, and TNF-a produced by MVECs rather than T cells is essential in this process. On the other hand, endothelial dysfunction caused by T cells seems to be mediated mainly by exosomes.

Sign in / Sign up

Export Citation Format

Share Document