A novel model of rheumatoid arthritis-associated interstitial lung disease in SKG mice

Keith, Rebecca C.; Powers, Jennifer; Redente, Elizabeth F.; Sergew, Amen; Martin, Richard J.; Gizinski, Alison M.; Holers, V. Michael; Sakaguchi, Shimon; Riches, David W. H.

doi:10.3109/01902148.2011.636139

Cited by 43 publications

(61 citation statements)

References 43 publications

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“…Our findings are in contrast to two other models of autoimmune arthritis that reported an association with autoimmune arthritis-related inflammation and fibrotic lung disease (34,40,41). These models promoted autoimmune arthritis via different mechanisms, one through altering T-cell signaling with a mutation in zeta chain-associated protein kinase 70 (ZAP-70) (SKG mice), and the other via aberrant MHC Class II expression.…”

contrasting

confidence: 54%

“…These data suggest that the lung may be a reservoir for cells inducing arthritis, but not a critical mediator of arthritis pathology. This conclusion is supported by a study of another autoimmune arthritis model that found lung injury alone was not a sufficient stimulus to promote arthritis in susceptible mice, whereas an injection of the fungal b-glucan, zymosan, was sufficient (33,34). Although RA-related lung disease occurs in older adults, we did not find a correlation with age.…”

supporting

confidence: 33%

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Autoreactive T and B Cells Induce the Development of Bronchus-Associated Lymphoid Tissue in the Lung

Shilling¹,

Williams²,

Perera³

et al. 2013

Am J Respir Cell Mol Biol

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Rheumatoid arthritis-related interstitial lung disease (RA-ILD) is associated with significant morbidity and mortality. Studies in humans have found that the incidence of bronchus-associated lymphoid tissue (BALT) correlates with the severity of lung injury. However, the mechanisms underlying the development of BALT during systemic autoimmunity remain unknown. We have determined whether systemic autoimmunity in a murine model of autoimmune arthritis can promote the development of BALT by generating a novel murine model derived from K/BxN mice. Transgenic mice with the KRN T-cell receptor specific for the autoantigen, glucose-6-phosphate isomerase (GPI), were crossed with GPI-specific immunoglobulin heavy and light chain knock-in mice, producing mice with a majority of T and B cells specific for the same autoantigen. We found that 67% of these mice demonstrated lymphocytic infiltration in the lungs, localized to either the perivascular or peribronchial regions. Fifty percent of the mice with lymphocytic infiltration manifested lymphoid-like lesions resembling BALT, with distinct T and B cell follicles. The lungs from mice with lymphoid infiltrates had increased numbers of cytokine-producing T cells, including IL-17A1 T cells and increased major histocompatibility complex Class II expression on B cells. Interestingly, challenge with bleomycin failed to elicit a significant fibrotic response, compared with wild-type control mice. Our data suggest that systemic autoreactivity promotes ectopic lymphoid tissue development in the lung through the cooperation of autoreactive T and B cells. However, these BALT-like lesions may not be sufficient to promote fibrotic lung disease at steady state or after inflammatory challenge.

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contrasting

confidence: 54%

supporting

confidence: 33%

Autoreactive T and B Cells Induce the Development of Bronchus-Associated Lymphoid Tissue in the Lung

Shilling¹,

Williams²,

Perera³

et al. 2013

Am J Respir Cell Mol Biol

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“…There is also evidence of interstitial lung disease in the zymosaninduced SKG model. Arthritic mice also develop pulmonary fibrosis that is similar to the interstitial lung disease found in some RA patients (Keith et al, 2012). There is limited understanding of whether these additional manifestations are responsive to anti-arthritic treatments and there is scope to further investigate multiple tissue pathology in these models.…”

Section: How Do Animal Models Compare Pathologically To Human Ra?mentioning

confidence: 99%

Animal models of rheumatoid arthritis: How informative are they?

McNamee

Williams

Seed

2015

European Journal of Pharmacology

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Animal models of arthritis are widely used to de-convolute disease pathways and to identify novel drug targets and therapeutic approaches. However, the high attrition rates of drugs in Phase II/III rates means that a relatively small number of drugs reach the market, despite showing efficacy in pre-clinical models. There is also increasing awareness of the ethical issues surrounding the use of animal models of disease and it is timely, therefore, to review the relevance and translatability of animal models of arthritis. In this paper we review the most commonly used animal models in terms of their pathological similarities to human rheumatoid arthritis as well as their response to drug therapy. In general, the ability of animal models to predict efficacy of biologics in man has been good. However, the predictive power of animal models for small molecules has been variable, probably because of differences in the levels of target knockdown achievable in vivo.3

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“…SKG mice, a mutant of the gene encoding ZAP70, spontaneously develop CD4 + T cell-mediated autoimmune arthritis and also develop extra-articular manifestations, including ILD (11,12). For this point, ILD in SKG mice could be a good candidate of a murine CTD-ILD model.…”

mentioning

confidence: 99%

GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice

Shiomi

Usui

Ishikawa

et al. 2014

The Journal of Immunology

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Interstitial lung disease (ILD) is a common complication and sometimes a prognostic factor of connective tissue diseases (CTDs) in humans. However, suitable animal model of severe CTD-associated ILD (CTD-ILD) has been limited. In this study, we showed that zymosan-treated SKG mice developed not only arthritis but also chronic–progressive ILD with high mortality over several months. The pathological and clinical features of ILD in zymosan-treated SKG mice were similar to that of human severe CTD-ILD. ILD in this mouse was characterized by massive infiltration of Th17 cells, GM-CSF–producing CD4+ T cells, and CD11b+ Gr1+ neutrophils with fibrosis. Naive SKG T cells were skewed to differentiate into GM-CSF–producing cells, and GM-CSF secreted by T cells enhanced IL-6 and IL-1β production by macrophages, which in turn enhanced differentiation of IL-17A– and/or GM-CSF–producing T cells and infiltration of neutrophils into lung. Neutralization of GM-CSF completely blocked the development of this ILD, and the blocking of IL-6 signaling resulted in partial prevention of it, whereas neutralization of IL-17A did not. In contrast, the progression of arthritis was inhibited by the neutralization of GM-CSF and slightly by the neutralization of IL-17A, but not by the blocking of IL-6 signaling. These data suggested zymosan-treated SKG mice could be a useful mouse model of severe CTD-ILD, and GM-CSF, rather than IL-17A or IL-6, contributed to the development of ILD in zymosan-treated SKG mice, indicating that neutralization of GM-CSF would be a useful therapeutic strategy for severe CTD-ILD.

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A novel model of rheumatoid arthritis-associated interstitial lung disease in SKG mice

Cited by 43 publications

References 43 publications

Autoreactive T and B Cells Induce the Development of Bronchus-Associated Lymphoid Tissue in the Lung

Autoreactive T and B Cells Induce the Development of Bronchus-Associated Lymphoid Tissue in the Lung

Animal models of rheumatoid arthritis: How informative are they?

GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice

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