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Anti-CX3CL1 (fractalkine) monoclonal antibody attenuates lung and skin fibrosis in sclerodermatous graft-versus-host disease mouse model
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Anti-CX3CL1 (fractalkine) monoclonal antibody attenuates lung and skin fibrosis in sclerodermatous graft-versus-host disease mouse model
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Anti-CX3CL1 (fractalkine) monoclonal antibody attenuates lung and skin fibrosis in sclerodermatous graft-versus-host disease mouse model
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Journal Article
Anti-CX3CL1 (fractalkine) monoclonal antibody attenuates lung and skin fibrosis in sclerodermatous graft-versus-host disease mouse model
2024
Overview
Background
Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular injury and inflammation, followed by excessive fibrosis of the skin and other internal organs, including the lungs. CX3CL1 (fractalkine), a chemokine expressed on endothelial cells, supports the migration of macrophages and T cells that express its specific receptor CX3CR1 into targeted tissues. We previously reported that anti-CX3CL1 monoclonal antibody (mAb) treatment significantly inhibited transforming growth factor (TGF)-β1-induced expression of type I collagen and fibronectin 1 in human dermal fibroblasts. Additionally, anti-mouse CX3CL1 mAb efficiently suppressed skin inflammation and fibrosis in bleomycin- and growth factor-induced SSc mouse models. However, further studies using different mouse models of the complex immunopathology of SSc are required before the initiation of a clinical trial of CX3CL1 inhibitors for human SSc.
Methods
To assess the preclinical utility and functional mechanism of anti-CX3CL1 mAb therapy in skin and lung fibrosis, a sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) mouse model was analyzed with immunohistochemical staining for characteristic infiltrating cells and RNA sequencing assays.
Results
On day 42 after bone marrow transplantation, Scl-cGVHD mice showed increased serum CX3CL1 level. Intraperitoneal administration of anti-CX3CL1 mAb inhibited the development of fibrosis in the skin and lungs of Scl-cGVHD model, and did not result in any apparent adverse events. The therapeutic effects were correlated with the number of tissue-infiltrating inflammatory cells and α-smooth muscle actin (α-SMA)-positive myofibroblasts. RNA sequencing analysis of the fibrotic skin demonstrated that cGVHD-dependent induction of gene sets associated with macrophage-related inflammation and fibrosis was significantly downregulated by mAb treatment. In the process of fibrosis, mAb treatment reduced cGVHD-induced infiltration of macrophages and T cells in the skin and lungs, especially those expressing CX3CR1.
Conclusions
Together with our previous findings in other SSc mouse models, the current results indicated that anti-CX3CL1 mAb therapy could be a rational therapeutic approach for fibrotic disorders, such as human SSc and Scl-cGVHD.
Publisher
Springer Science and Business Media LLC,BioMed Central,BioMed Central Ltd,BMC
Subject
/ Analysis
/ Animals
/ Antibodies, Monoclonal - pharmacology
/ Antibodies, Monoclonal - therapeutic use
/ Chemokine CX3CL1 - antagonists & inhibitors
/ Chemokine CX3CL1 - metabolism
/ Collagen
/ Complications and side effects
/ Cutaneous manifestations of general diseases
/ CX3CL1
/ CXCR1
/ Diseases of the musculoskeletal system
/ Female
/ Fibrosis
/ Formulae, receipts, prescriptions
/ Graft vs Host Disease - drug therapy
/ Graft vs Host Disease - immunology
/ Graft vs Host Disease - pathology
/ Humans
/ Medicine
/ Mice
/ Pulmonary Fibrosis - drug therapy
/ Pulmonary Fibrosis - immunology
/ Pulmonary Fibrosis - pathology
/ Pulmonary Fibrosis - prevention & control
/ RNA
/ Scleroderma, Systemic - drug therapy
/ Scleroderma, Systemic - immunology
/ Scleroderma, Systemic - pathology
/ Skin
/ T cells
