New models for analyzing mast cell functions in vivo

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-5324, USA.
Trends in Immunology (Impact Factor: 10.4). 11/2012; 33(12). DOI: 10.1016/
Source: PubMed


In addition to their well-accepted role as critical effector cells in anaphylaxis and other acute IgE-mediated allergic reactions, mast cells (MCs) have been implicated in a wide variety of processes that contribute to disease or help to maintain health. Although some of these roles were first suggested by analyses of MC products or functions in vitro, it is critical to determine whether, and under which circumstances, such potential roles actually can be performed by MCs in vivo. This review discusses recent advances in the development and analysis of mouse models to investigate the roles of MCs and MC-associated products during biological responses in vivo, and comments on some of the similarities and differences in the results obtained with these newer versus older models of MC deficiency.

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    • "We found that mast cell-deficient W/Wv mice exhibited reduced susceptibility to CIM as compared with WT mice (Figures 3 and 4) and that the reduced susceptibility of W/Wv mice was restored by the reconstitution of mast cells (Figure 6). Although we could not exclude the possibility that other abnormalities of W/Wv mice such as anemia and reduced numbers of neutrophils and basophils [1,26] are also involved in the reduced susceptibility to CIM, our results strongly suggest that mast cells in skeletal muscle play an important role in the development of CIM. "
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    ABSTRACT: In addition to the pivotal roles of mast cells in allergic diseases, recent data suggest that mast cells play crucial roles in a variety of autoimmune responses. However, their roles in the pathogenesis of autoimmune skeletal muscle diseases have not been clarified despite their distribution in skeletal muscle. Therefore, the objective of this study is to determine the roles of mast cells in the development of autoimmune skeletal muscle diseases. The number of mast cells in the affected muscle was examined in patients with dermatomyositis (DM) or polymyositis (PM). The susceptibility of mast cell-deficient WBB6F1-KitW/KitWv mice (W/Wv mice) to a murine model of polymyositis, C protein-induced myositis (CIM), was compared with that of wild-type (WT) mice. The effect of mast cell reconstitution with bone marrow-derived mast cells (BMMCs) on the susceptibility of W/Wv mice to CIM was also evaluated. The number of mast cells in the affected muscle increased in patients with PM as compared to patients with DM. W/Wv mice exhibited significantly reduced disease incidence and histological scores of CIM as compared with WT mice. The number of CD8+ T cells and macrophages in the skeletal muscles of CIM decreased in W/Wv mice compared to WT mice. Engraftment of BMMCs restored the incidence and histological scores of CIM in W/Wv mice. Vascular permeability in the skeletal muscle was elevated in WT mice but not in W/Wv mice upon CIM induction. Mast cells are involved in the pathogenesis of inflammatory myopathy.
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    • "However, these strains generally have loss of function mutations in the c-kit – SCF axis, complicating the picture with deficiencies in other c-kit expressing hematopoietic cells. More recently, new mouse models have been developed and will likely give a clearer picture of the functions unique to mast cells (Reber et al., 2012). "
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder of unknown etiology characterized by accumulation of lung fibroblasts and extracellular matrix deposition, ultimately leading to compromised tissue architecture and lung function capacity. IPF has a heterogeneous clinical course; however the median survival after diagnosis is only 3-5 years. The pharmaceutical and biotechnology industry has made many attempts to find effective treatments for IPF, but the disease has so far defied all attempts at therapeutic intervention. Clinical trial failures may arise for many reasons, including disease heterogeneity, lack of readily measurable clinical end points other than overall survival, and, perhaps most of all, a lack of understanding of the underlying molecular mechanisms of the progression of IPF. The precise link between inflammation and fibrosis remains unclear, but it appears that immune cells can promote fibrosis by releasing fibrogenic factors. So far, however, therapeutic approaches targeting macrophages, neutrophils, or lymphocytes have failed to alter disease pathogenesis. A new cell to garner research interest in fibrosis is the mast cell. Increased numbers of mast cells have long been known to be present in pulmonary fibrosis and clinically correlations between mast cells and fibrosis have been reported. More recent data suggests that mast cells may contribute to the fibrotic process by stimulating fibroblasts resident in the lung, thus driving the pathogenesis of the disease. In this review, we will discuss the mast cell and its physiological role in tissue repair and remodeling, as well as its pathological role in fibrotic diseases such as IPF, where the process of tissue repair and remodeling is thought to be dysregulated.
    Frontiers in Pharmacology 01/2013; 4:174. DOI:10.3389/fphar.2013.00174 · 3.80 Impact Factor
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    ABSTRACT: Mast cells are increasingly being recognized as effector cells in many cardiovascular conditions. Many mast-cell-derived products such as tryptase and chymase can, through their enzymic action, have detrimental effects on blood vessel structure while mast cell-derived mediators such as cytokines and chemokines can perpetuate vascular inflammation. Mice lacking mast cells have been developed and these are providing an insight into how mast cells are involved in cardiovascular diseases and, as knowledge increase, mast cells may become a viable therapeutic target to slow progression of cardiovascular disease.
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