Animal models of systemic sclerosis: their utility and limitations

Artlett, Carol M.

doi:10.2147/oarrr.s50009

Cited by 24 publications

(31 citation statements)

References 172 publications

(183 reference statements)

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“…In a second set of experiments, the efficacy of CM-101 was tested using a treatment model where CM-101 was administered only after the onset of fibrotic signs, 8 days following the first BLM injection 32. Histological assessment of skin lesions stained with H&E and Masson’s trichrome revealed significant elevation of dermal thickness and collagen deposition following 21 days of BLM administration.…”

Section: Resultsmentioning

confidence: 99%

Blockade of CCL24 with a monoclonal antibody ameliorates experimental dermal and pulmonary fibrosis

Mor

Segal-Salto²,

Katav

et al. 2019

Ann Rheum Dis

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ObjectivesWe aimed to assess the expression of the CCL24 chemokine in systemic sclerosis (SSc) and to evaluate the possible pathogenic implications of the CCL24/CCR3 axis using both in vitro and in vivo models. We further investigated the efficacy of an anti-CCL24 monoclonal antibody (mAb), CM-101, in inhibiting cell activation as well as dermal and pulmonary inflammation and fibrosis in experimental animal models.MethodsWe used ELISA and fluorescence immunohistochemistry to determine CCL24 levels in serum and CCL24/CCR3 expression in skin biopsies of SSc patients. Skin fibroblasts and endothelial cells treated with CCL24 or SSc serum with or without CM-101 were used to follow cell activation and differentiation. Prevention and treatment in vivo bleomycin (BLM)-induced models were used to evaluate experimental dermal and pulmonary fibrosis progression following treatment with the CM-101 mAb.ResultsCCL24 circulating levels were significantly elevated in SSc patients. CCL24/CCR3 expression was strongly increased in SSc skin. Blockade of CCL24 with CM-101 significantly reduced the activation of dermal fibroblasts and their transition to myofibroblasts induced by SSc serum. CM-101 was also able to significantly inhibit endothelial cell activation induced by CCL24. In BLM-induced experimental animal models, CM-101 profoundly inhibited both dermal and pulmonary fibrosis and inflammation.ConclusionsCCL24 plays an important role in pathological processes of skin and lung inflammation and fibrosis. Inhibition of CCL24 by CM-101 mAb can be potentially beneficial for therapeutic use in SSc patients.

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Section: Resultsmentioning

confidence: 99%

Blockade of CCL24 with a monoclonal antibody ameliorates experimental dermal and pulmonary fibrosis

Mor

Segal-Salto²,

Katav

et al. 2019

Ann Rheum Dis

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“…Due to inherent challenges of studying SSc in patients, many inducible and genetic animal models have been developed for the study of initial events, genes, and other influences on manifestation of the disease [ 9 , 46 , 51 ] . Despite the multitude of animal models that simulate selective aspects of SSc, a lack of models encompassing the disease’s full clinical heterogeneity has hindered the development of successful therapies [ 9 , 31 , 46 ] .…”

Section: Animal Models For Systemic Sclerosismentioning

confidence: 99%

“…Despite the multitude of animal models that simulate selective aspects of SSc, a lack of models encompassing the disease’s full clinical heterogeneity has hindered the development of successful therapies [ 9 , 31 , 46 ] . For example, tight skin 1 mice ( Tsk1 +/+ ) with a homozygous lethal mutation that causes thickened skin firmly bound to the subcutaneous tissue have proven useful for studying the efficacy of drugs that target fibrosis, but the model does not address the etiology of SSc [ 51 ] . Many animal models effectively display the pro-fibrotic features of SSc without reflecting the vascular characteristics that frequently precede fibrosis [ 9 , 47 , 52 ] .…”

Section: Animal Models For Systemic Sclerosismentioning

confidence: 99%

“…For this reason, new genetic animal models have been developed in order to reproduce the pathophysiological cascades of SSc that lead to its key features, rather than only mimicking selective features. For example, the Fos-related antigen-2 (FRA-2) transgenic mouse model expresses key features of the disease that result from abnormalities of vasculature [ 51 , 53 ] . Both microangiopathy and progressive skin fibrosis are displayed in FRA-2 transgenic mice [ 51 ] .…”

Section: Animal Models For Systemic Sclerosismentioning

confidence: 99%

“…For example, the Fos-related antigen-2 (FRA-2) transgenic mouse model expresses key features of the disease that result from abnormalities of vasculature [ 51 , 53 ] . Both microangiopathy and progressive skin fibrosis are displayed in FRA-2 transgenic mice [ 51 ] . The FRA-2 gene belongs to the activator protein-1 (AP-1) family of transcriptional regulators that control a multitude of downstream effects in response to cellular stress [ 51 , 53 ] .…”

Section: Animal Models For Systemic Sclerosismentioning

confidence: 99%

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Transforming growth factor-β signaling in systemic sclerosis

Ayers¹,

Sun²,

Chen³

2018

J Biomed Res

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Systemic sclerosis (SSc) is a complex, multiorgan autoimmune disease of unknown etiology. Manifestation of the disease results from an interaction of three key pathologic features including irregularities of the antigen-specific immune system and the non-specific immune system, resulting in autoantibody production, vascular endothelial activation of small blood vessels, and tissue fibrosis as a result of fibroblast dysfunction. Given the heterogeneity of clinical presentation of the disease, a lack of universal models has impeded adequate testing of potential therapies for SSc. Regardless, recent research has elucidated the roles of various ubiquitous molecular mechanisms that contribute to the clinical manifestation of the disease. Transforming growth factor β (TGF-β) has been identified as a regulator of pathological fibrogenesis in SSc. Various processes, including cell growth, apoptosis, cell differentiation, and extracellular matrix synthesis are regulated by TGF-β, a type of cytokine secreted by macrophages and many other cell types. Understanding the essential role TGF-β pathways play in the pathology of systemic sclerosis could provide a potential outlet for treatment and a better understanding of this severe disease.

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Phage Immunoprecipitation‐Sequencing Reveals CDHR5 Autoantibodies in Select Patients With Interstitial Lung Disease

Upadhyay,

Yoon,

Vazquez

et al. 2024

ACR Open Rheumatology

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ObjectiveInterstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases. Establishing autoimmunity in ILD impacts prognosis and treatment. Patients with ILD are screened for autoimmunity by measuring antinuclear autoantibodies, rheumatoid factors, and other nonspecific tests. However, this approach may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD.MethodsWe use Phage Immunoprecipitation‐Sequencing (PhIP‐Seq) to conduct an autoantibody discovery screen of patients with ILD and controls. We screened for novel autoantigen candidates using PhIP‐Seq. We next developed a radio‐labeled binding assay and validated the leading candidate in 398 patients with ILD recruited from two academic medical centers and 138 blood bank individuals that formed our reference cohort.ResultsPhIP‐Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among the 17 candidates, we validated CDHR5 and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, patients not previously diagnosed with autoimmunity. Using survival and transplant free–survival data available from one of the two centers, patients with CDHR5 autoantibodies showed worse survival compared with other patients with connective tissue disease ILD.ConclusionWe used PhIP‐Seq to define a novel CDHR5 autoantibody in a subset of select patients with ILD. Our data complement a recent study showing polymorphisms in the CDHR5‐IRF7 gene locus strongly associated with titer of anticentromere antibodies in systemic sclerosis, creating a growing body of evidence suggesting a link between CDHR5 and autoimmunity.

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Animal models of systemic sclerosis: their utility and limitations

Cited by 24 publications

References 172 publications

Blockade of CCL24 with a monoclonal antibody ameliorates experimental dermal and pulmonary fibrosis

Blockade of CCL24 with a monoclonal antibody ameliorates experimental dermal and pulmonary fibrosis

Transforming growth factor-β signaling in systemic sclerosis

Phage Immunoprecipitation‐Sequencing Reveals CDHR5 Autoantibodies in Select Patients With Interstitial Lung Disease

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