Induction of autoimmunity in a bleomycin-induced murine model of experimental systemic sclerosis: an important role for CD4+ T cells.

Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Journal of Investigative Dermatology (Impact Factor: 6.19). 02/2009; 129(7):1688-95. DOI: 10.1038/jid.2008.431
Source: PubMed

ABSTRACT Systemic sclerosis (SSc) is an autoimmune disease characterized by the excessive deposition of collagen in the skin or other organs and the production of specific antinuclear antibodies (ANAs). Recently, bleomycin (BLM)-induced experimental scleroderma was reported in a murine model. Here, we present further development of this model and suggest that it is appropriate for the analysis of human diffuse type SSc. BLM was injected into the shaved backs of C3H or BALB/c mice (100 microg/mouse) 5 days per week for 3 weeks. Skin fibrosis was confirmed and pathological changes were seen in the lower part of the esophagus and stomach similar to those seen in SSc. The sera from these mice had autoantibodies specific to the damaged tissues and ANAs. Transfer of CD4(+) T cells from BLM-treated BALB/c mice induced the same pathological changes and antibody production in untreated-BALB/c nude mice. Hence, tissue fibrosis and the production of ANAs are probably associated with CD4(+) T-cell activity in this model. In conclusion, this model will be valuable for investigating the relationship between tissue fibrosis and abnormalities of the immune system.

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    ABSTRACT: Tolerance to collagen structures has been shown to inhibit the progression of autoimmune scleroderma and rheumatoid arthritis. More recently, tolerance induction to collagen type V (colV) in experimental models of lung transplantation was shown to ameliorate the complex pathology known as "chronic rejection." The link between colV autoimmunity and progressive graft dysfunction and subsequent development of bronchiolitis obliterans syndrome (BOS) has been established in human lung transplant recipients. We hypothesized that intravenous injection of colV inhibits development of lung fibrosis in a bleomycin-induced lung injury mouse model. Experimental animals were injected intravenously with saline or colV 10 days before intratracheal instillation of bleomycin. Pulmonary inflammation was monitored and quantified for the presence of cells in the bronchoalveolar lavage (BAL) fluid by flow cytometry and histology of lung tissue. ColV-pre-treated animals showed a significant reduction in lung inflammation compared with non-treated animals, according to histology and morphometry. The number of inflammatory cells in the BAL fluid was significantly reduced and associated with a lower proportion of gammadelta T cells and CD4(+) T cells in the colV-pre-treated group. Matrix metalloproteinase-2 and -9 (MMP-2 and -9; also known as gelatinase A and gelatinase B, respectively) levels in the BAL fluid were significantly reduced in colV-pre-treated mice compared with the non-treated mice. In addition, intravenous injection of colV was associated with a significant reduction in the relative expression of interleukin (IL)-6, IL-17 and IL-22 in cells present in BAL fluid at 7 and 14 days after bleomycin instillation. Pre-treatment by intravenous injection of colV inhibits bleomycin-induced pulmonary fibrosis by inhibiting IL-6 and IL-17 production. Fibrosis treatment in this context therefore should target induction of colV tolerance and Th17 development.
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    ABSTRACT: Scleroderma is a fibrotic condition characterized by immunological abnormalities, vascular injury and increased accumulation of extracellular matrix proteins in the skin. Although the etiology of scleroderma has not yet been fully elucidated, a growing body of evidence suggests that extracellular matrix overproduction by activated fibroblasts results from a complex interaction among endothelial cells, lymphocytes, macrophages and fibroblasts, through a number of mediators, such as cytokines, chemokines and growth factors. For a better understanding of the pathophysiology of scleroderma, animal models are important tools. These models reproduce several histological as well as biochemical aspects of human scleroderma, and we can learn a lot through animal studies. On the other hand, it must be emphasized that studying animal models cannot answer all the problems of human scleroderma. In this review, I introduce current insights into the pathogenesis and also recent updates of therapeutic approaches using several animal models of SSc, and discuss their contribution to our understanding of the pathogenesis of, and treatments for, human scleroderma.
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