Immunomodulation by adoptive regulatory T‐cell transfer improves Coxsackievirus B3‐induced myocarditis

Pappritz, Kathleen; Savvatis, Konstantinos; Miteva, Kapka; Kerim, Bahtiyar; Dong, Fengquan; Fechner, Henry; Müller, Irene; Brandt, Christine; López, Begoña; González, Arantxa; Ravassa, Susana; Klingel, Karin; Dı́ez, Javier; Reinke, Petra; Volk, Hans‐Dieter; Linthout, Sophie Van; Tschöpe, Carsten

doi:10.1096/fj.201701408r

Cited by 46 publications

(47 citation statements)

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“…Although we found an overall reduction of CD4 + T cells in the heart in siCSF-1 treated mice, we cannot conclude on the influence of silencing the CSF-1 axis on CD4 + T cell differentiation e.g., into regulatory T cells or Th1 and Th17 cells. From our data we cannot conclude on possible additional effects e.g., of regulatory CD4 + T cells that are known to mitigate the inflammatory tissue damage in the heart ( 43 , 44 ). CSF-1 facilitates myeloid cell differentiation, monocyte survival, and macrophage proliferation.…”

Section: Discussionmentioning

confidence: 69%

Silencing the CSF-1 Axis Using Nanoparticle Encapsulated siRNA Mitigates Viral and Autoimmune Myocarditis

et al. 2018

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Myocarditis is an inflammatory disease of the heart muscle most commonly caused by viral infection and often maintained by autoimmunity. Virus-induced tissue damage triggers chemokine production and, subsequently, immune cell infiltration with pro-inflammatory and pro-fibrotic cytokine production follows. In patients, the overall inflammatory burden determines the disease outcome. Following the aim to define specific molecules that drive both immunopathology and/or autoimmunity in inflammatory heart disease, here we report on increased expression of colony stimulating factor 1 (CSF-1) in patients with myocarditis. CSF-1 controls monocytes originating from hematopoietic stem cells and subsequent progenitor stages. Both, monocytes and macrophages are centrally involved in mediating tissue damage and fibrotic scarring in the heart. CSF-1 influences monocytes via engagement of CSF-1 receptor, and it is also produced by cells of the mononuclear phagocyte system themselves. Based on this, we sought to modulate the virus-triggered inflammatory response in an experimental model of Coxsackievirus B3-induced myocarditis by silencing the CSF-1 axis in myeloid cells using nanoparticle-encapsulated siRNA. siCSF-1 inverted virus-mediated immunopathology as reflected by lower troponin T levels, a reduction of accumulating myeloid cells in heart tissue and improved cardiac function. Importantly, pathogen control was maintained and the virus was efficiently cleared from heart tissue. Since viral heart disease triggers heart-directed autoimmunity, in a second approach we investigated the influence of CSF-1 upon manifestation of heart tissue inflammation during experimental autoimmune myocarditis (EAM). EAM was induced in Balb/c mice by immunization with a myocarditogenic myosin-heavy chain-derived peptide dissolved in complete Freund's adjuvant. siCSF-1 treatment initiated upon established disease inhibited monocyte infiltration into heart tissue and this suppressed cardiac injury as reflected by diminished cardiac fibrosis and improved cardiac function at later states. Mechanistically, we found that suppression of CSF-1 production arrested both differentiation and maturation of monocytes and their precursors in the bone marrow. In conclusion, during viral and autoimmune myocarditis silencing of the myeloid CSF-1 axis by nanoparticle-encapsulated siRNA is beneficial for preventing inflammatory tissue damage in the heart and preserving cardiac function without compromising innate immunity's critical defense mechanisms.

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Section: Discussionmentioning

confidence: 69%

Silencing the CSF-1 Axis Using Nanoparticle Encapsulated siRNA Mitigates Viral and Autoimmune Myocarditis

et al. 2018

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“…Furthermore, Sacerdote et al only investigated splenocyte proliferation, NK activity and IL-2 production to determine the immunosuppressive potential of the used opioids [ 37 , 47 , 48 , 49 ]. Especially in models of inflammatory disease, like CVB3-induced myocarditis, it is well established that the extent of the immune response is not mediated by only one cell population or cytokine but rather by an orchestra of innate and adaptive immunity components [ 10 , 11 , 50 ].…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, previous own studies investigated the impact of various cell populations in the context of CVB3-induced heart failure [ 11 , 65 ], including monocytes/macrophages, NK cells, and DCs [ 50 , 66 , 67 ]. With respect to opioid administration, Filipczak-Bryniarska and colleagues intensively reported modulation of monocytes/macrophages and NK cells, and corresponding release of pro-inflammatory cytokines by LPS-stimulated macrophages [ 33 , 64 , 68 ].…”

Section: Resultsmentioning

confidence: 99%

“…In addition, generation of reactive oxygen species (ROS) also occurs, which promotes the further death of cardiac cells [ 10 ]. In parallel, inflammatory processes trigger the accumulation of collagen and extracellular matrix in the heart, resulting in left ventricle (LV) stiffening and finally in a reduction of cardiac function [ 11 , 12 ]. Besides the well-described direct infection of the heart in the context of experimental CVB3-induced myocarditis, there is cumulative evidence reporting primarily infection of lymphatic organs [ 13 ], including the pancreas [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Opioid-Induced Immunomodulation: Consequences for the Experimental Coxsackievirus B3-Induced Myocarditis Model

Pappritz

Linthout

2020

Biology

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Myocarditis is an inflammatory disorder of the heart predominantly caused by infectious agents. Since more than sixty years, the Coxsackievirus B3 (CVB3)-induced myocarditis mouse model is the experimental model used to investigate viral myocarditis. The pathogenesis of viral myocarditis is conceptually a multiphase process, initiated by the infection of cardiomyocytes, followed by activation of the immune system, and resulting in myocardial fibrosis and left ventricular dysfunction. In parallel to the direct infection of the heart, CVB3 replicates in lymphatic organs such as the pancreas. Due to infection of the pancreas, the model of experimental CVB3-induced myocarditis is estimated as a severe burden for the challenged animals. Application of analgesics in frame of the animal welfare act (European directive 2010/63/EU) is more and more becoming a matter of debate. For this purpose, we summarized published studies for 13 different opioids and discussed their potential impact on CVB3-induced myocarditis. In addition, with this summary we also want to provide guidance for researchers beyond the myocarditis field to estimate the impact of opioids on the immune system for their specific model. In the literature, both immunosuppressive as well as immune-activating effects of opioids have been described, but examinations in experimental CVB3-induced myocarditis have still not been reported so far. Based on the existing publications, administration of opioids in experimental CVB3-induced myocarditis might result in more severe disease progression, including higher mortality, or a less pronounced myocarditis model, failing to be used for the establishment of new treatment options. Taken together, the applicability of opioids in experimental CVB3-induced myocarditis and in inflammatory models in general needs to be carefully evaluated and further investigated.

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“…CD4 + T lymphocytes are globally expanded and activated in chronic ischemic HF, with Th2 (vs. Th1) and Th17 (vs. Treg) predominance in failing hearts . In contrast, a wealth of evidence from experimental and clinical studies has indicated that CD4CD25FOXP3+ Tregs might have an important role in protecting against cardiovascular disease, including MI, myocarditis, dilated cardiomyopathy, and HF . In HF, Tregs are qualitatively and quantitatively impaired independently of the etiology and are consequently ineffective in regaining immune homeostasis.…”

Section: Antiinflammatory and Immunomodulatory Strategiesmentioning

confidence: 99%

The Quest for Antiinflammatory and Immunomodulatory Strategies in Heart Failure

Linthout

Tschöpe

2019

Clin Pharma and Therapeutics

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Intensive research over the last 3 decades has unequivocally demonstrated the relevance of inflammation in heart failure (HF). Despite our current and ever increasing knowledge about inflammation, the clinical success of antiinflammatory and immunomodulatory therapies in HF is still limited. This review outlines the complexity and diversity of inflammation, its reciprocal interaction with HF, and addresses future perspectives, calling for immunomodulatory therapies that are specific for factors that activate the immune system without the risk of nonspecific immune suppression.

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Immunomodulation by adoptive regulatory T‐cell transfer improves Coxsackievirus B3‐induced myocarditis

Cited by 46 publications

References 47 publications

Silencing the CSF-1 Axis Using Nanoparticle Encapsulated siRNA Mitigates Viral and Autoimmune Myocarditis

Silencing the CSF-1 Axis Using Nanoparticle Encapsulated siRNA Mitigates Viral and Autoimmune Myocarditis

Opioid-Induced Immunomodulation: Consequences for the Experimental Coxsackievirus B3-Induced Myocarditis Model

The Quest for Antiinflammatory and Immunomodulatory Strategies in Heart Failure

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