T regulatory cells and attenuated bleomycin-induced fibrosis in lungs of CCR7-/- mice

Trujillo, Glenda; Hartigan, Adam J.; Hogaboam, Cory M.

doi:10.1186/1755-1536-3-18

Cited by 57 publications

(42 citation statements)

References 40 publications

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“…In the case of influenza infection, iBALT was found to be sufficient for survival because of the priming of influenza-specific T and B cells in the lungs (19). In agreement with our findings, C-C chemokine receptor type 7 knockout mice (CCR7 2/2 ), which have increased BALT formation, also have a diminished response to bleomycin- induced lung fibrosis (38). The increased BALT formation and the protection from bleomycin are associated with defects in T regulatory cell trafficking, which underlies the postnatal development of BALT in CCR7 2/2 mice (38, 39).…”

supporting

confidence: 80%

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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supporting

confidence: 80%

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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“…However, emerging data suggest that certain B- (12) and T-cell (13-15) populations participate in the immunopathogenesis of fibrosis. These reports are conflicting, with several studies suggesting that CD4 1 cells possessing suppressor or regulatory abilities either protect (14,16) or promote (15,17) fibrotic responses. Abnormalities in regulatory T cells (Tregs) are seen in the lungs and blood of patients with several forms of lung fibrosis (18), leading to the supposition that Tregs might impede fibrosis (16).…”

Section: Conclusion: Sema 7amentioning

confidence: 72%

Semaphorin 7a⁺ Regulatory T Cells Are Associated with Progressive Idiopathic Pulmonary Fibrosis and Are Implicated in Transforming Growth Factor-β1–induced Pulmonary Fibrosis

Reilkoff

Peng

Murray³

et al. 2013

Am J Respir Crit Care Med

117

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“…Patients with IPF and collagen vascular disease-associated pulmonary fibrosis demonstrate a reduced number and function of Tregs in BAL fluid and peripheral blood, compared with controls, suggesting that Tregs may play a role in fibroproliferation (27). However, conflicting data in the literature have emerged regarding Tregs in animal models of pulmonary fibrosis (31)(32)(33)(34), suggesting that the role of Tregs in regulating fibroproliferation may be both context-specific and site-specific. To our knowledge, the role of Tregs in the fibroproliferative response to ALI has not been described.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Garibaldi

D’Alessio

Mock

et al. 2013

Am J Respir Cell Mol Biol

155

135

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Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1 2/2 mice received intratracheal LPS. Fibroproliferation was characterized by histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1 2/2 mice received CD4 1 CD25 1 (Tregs) or CD4 1 CD252 Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1 2/2 mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1 2/2 mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1 2/2 mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.Keywords: acute lung injury; fibroproliferative ARDS; fibrocytes; regulatory T cells; lung injury resolution Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect 190,000 individuals in the United States each year, accounting for 75,000 deaths (1). The only treatment that improves outcomes involves a lung-protective strategy in patients on mechanical ventilation (2). Mortality from ALI/ARDS remains as high as 44% (3).ALI/ARDS is divided into an exudative phase marked by edema fluid, hyaline membrane formation, and neutrophilic infiltration, followed in some patients by a fibroproliferative phase (4). Fibroproliferation is part of the normal repair response, and is characterized by the intra-alveolar accumulation of fibroblasts and collagen deposition. If this process is ineffective or continues unabated, patients may develop fibrosis (5). Longer durations of ARDS correspond to increased lung collagen and fibrosis, and portend worse outcomes (6). Fibroproliferative changes on biopsy and computed tomography predict mortality (7,8). The determinants of prolonged fibroproliferation and factors that govern its resolution remain poorly understood.The fibroblast is a key cell ...

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T regulatory cells and attenuated bleomycin-induced fibrosis in lungs of CCR7-/- mice

Cited by 57 publications

References 40 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

Semaphorin 7a⁺ Regulatory T Cells Are Associated with Progressive Idiopathic Pulmonary Fibrosis and Are Implicated in Transforming Growth Factor-β1–induced Pulmonary Fibrosis

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

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T regulatory cells and attenuated bleomycin-induced fibrosis in lungs of CCR7-/- mice

Cited by 57 publications

References 40 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

Semaphorin 7a+ Regulatory T Cells Are Associated with Progressive Idiopathic Pulmonary Fibrosis and Are Implicated in Transforming Growth Factor-β1–induced Pulmonary Fibrosis

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

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Semaphorin 7a⁺ Regulatory T Cells Are Associated with Progressive Idiopathic Pulmonary Fibrosis and Are Implicated in Transforming Growth Factor-β1–induced Pulmonary Fibrosis