Th2 cells as effectors in postirradiation pulmonary damage preceding fibrosis in the rat

Westermann, W.; Schöbl, R; Rieber, Ernst Peter; Frank, K H

doi:10.1080/095530099140276

Cited by 75 publications

(19 citation statements)

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“…Vice-versa, increased apoptosis of peripheral blood lymphocytes, particularly CD8+ T cells, after curative radiation therapy is associated with reduced late toxicity [29]. In line with these findings, depletion of CD4+ T cells during pneumonitis decreased radiation-induced lung fibrosis in preclinical investigations in rats [16]. These findings indicate that infiltration of CD4+ T cells is a common feature of radiation-induced pneumonitis and that these cells may play a role for disease progression.…”

Section: Discussionmentioning

confidence: 84%

“…It is known from preclinical and clinical investigations that CD4+ and CD8+ T-lymphocytes constitute a significant part of the immune cell infiltrate in the lung tissue of irradiated breast and lung cancer patients with a predominance of the CD4+ subset [12-16]. Of note, the increase in numbers of activated CD4+ T-lymphocytes in the BALF is more pronounced in symptomatic patients than in asymptomatic patients [13,15].…”

Section: Discussionmentioning

confidence: 99%

“…A radiation-induced increase in T-lymphocytes in the lung tissue, particularly CD4+ T-lymphocytes, during the pneumonitic phase was confirmed in rodent models [7,16,17]. Of note, depletion of CD4+ T cells during the pneumonitic phase decreased radiation-induced lung fibrosis pointing to a contribution of these cells to disease pathogenesis [16]. In contrast, lung fibrosis upon whole thorax irradiation was aggravated in recombination-activating gene 2 (RAG2)-deficient mice; these mice lack mature T- and B-lymphocytes suggesting that lymphocytes may also have beneficial effects in radiation-induced lung disease [18].…”

Section: Introductionmentioning

confidence: 98%

“…Even more important, the presence of CD4+ T-lymphocytes in the bronchioalveolar lavage fluid (BALF) of irradiated breast or lung cancer patients correlated with a pneumonitic reaction [13,15]. A radiation-induced increase in T-lymphocytes in the lung tissue, particularly CD4+ T-lymphocytes, during the pneumonitic phase was confirmed in rodent models [7,16,17]. Of note, depletion of CD4+ T cells during the pneumonitic phase decreased radiation-induced lung fibrosis pointing to a contribution of these cells to disease pathogenesis [16].…”

Section: Introductionmentioning

confidence: 99%

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Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells

et al. 2014

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BackgroundLymphocyte infiltration is a common feature of radiation-induced pneumonitis and fibrosis, but their contribution to the pathogenic processes is still unclear. Here, we addressed the impact of thorax irradiation on the T cell compartment with a focus on immunosuppressive regulatory T cells (Treg).MethodsC57BL/6 wild type mice (WT) received anesthesia only (sham controls, 0 Gy) or were exposed to a single dose of whole thorax irradiation (15 Gy). Immune cells from lung tissue, spleen, and cervical lymph nodes were collected 10 to 84 days post-irradiation and phenotypically characterized by flow cytometry.ResultsWhole thorax irradiation provoked an increased influx of CD3+ T cells at 42 and 84 days post-irradiation. In contrast, local irradiation caused a sustained reduction in CD3+ T cells in peripheral lymphoid tissues. Interestingly, we observed a significant local and systemic increase in the fraction of CD4+ T cells expressing the transcription factor forkhead box P3 (FoxP3), the phenotypic marker for murine Treg, at day 21 post-irradiation. The accumulation of Treg was associated with increased levels of T cells expressing surface proteins characteristic for recruitment and immunosuppressive activity, e.g. CD103, CTLA-4 and CD73. Importantly, Treg isolated at this time point were able to suppress CD4+ effector T cells to a similar extent as Treg isolated from control mice.ConclusionsThe response of the adaptive immune system to whole thorax irradiation is characterized by local immunoactivation and systemic immunosuppression. The transient accumulation of immunosuppressive CD4+ FoxP3+ Treg may be required to protect the lung against excessive inflammation-induced tissue damage. Further investigations shall define the mechanisms underlying the accumulation of Treg and their role for the pathogenesis of radiation-induced lung disease.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells

et al. 2014

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“…Our selection includes cytokines previously associated with the lung response to radiation in both mice and humans such as Il6 and Tnfα [15,16,37,38]) as well as pulmonary fibrosis-promoting Il1β, Il13 and Il17 [39,40]) and anti-fibrotic mediators Il10 and Ifnγ [41]. Radiation exposure produced minimal changes in the cytokine profiles of these strains when assessed at acute time points (Additional file 6: Figure S6).…”

Section: Resultsmentioning

confidence: 99%

Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice

2015

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BackgroundThe lung response to radiation exposure can involve an immediate or early reaction to the radiation challenge, including cell death and an initial immune reaction, and can be followed by a tissue injury response, of pneumonitis or fibrosis, to this acute reaction. Herein, we aimed to determine whether markers of the initial immune response, measured within days of radiation exposure, are correlated with the lung tissue injury responses occurring weeks later.MethodsInbred strains of mice known to be susceptible (KK/HIJ, C57BL/6J, 129S1/SvImJ) or resistant (C3H/HeJ, A/J, AKR/J) to radiation-induced pulmonary fibrosis and to vary in time to onset of respiratory distress post thoracic irradiation (from 10–23 weeks) were studied. Mice were untreated (controls) or received 18 Gy whole thorax irradiation and were euthanized at 6 h, 1d or 7 d after radiation treatment. Pulmonary CD4+ lymphocytes, bronchoalveolar cell profile & cytokine level, and serum cytokine levels were assayed.ResultsThoracic irradiation and inbred strain background significantly affected the numbers of CD4+ cells in the lungs and the bronchoalveolar lavage cell differential of exposed mice. At the 7 day timepoint greater numbers of pulmonary Th1 and Th17 lymphocytes and reduced lavage interleukin17 and interferonγ levels were significant predictors of late stage fibrosis. Lavage levels of interleukin-10, measured at the 7 day timepoint, were inversely correlated with fibrosis score (R = −0.80, p = 0.05), while serum levels of interleukin-17 in control mice significantly correlated with post irradiation survival time (R = 0.81, p = 0.04). Lavage macrophage, lymphocyte or neutrophil counts were not significantly correlated with either of fibrosis score or time to respiratory distress in the six mouse strains.ConclusionSpecific cytokine and lymphocyte levels, but not strain dependent lavage cell profiles, were predictive of later radiation-induced lung injury in this panel of inbred strains.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-015-0359-y) contains supplementary material, which is available to authorized users.

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Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients

Luzina¹,

Atamas²,

Wise³

et al. 2003

Arthritis & Rheumatism

108

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Objective. Pulmonary fibrosis is a major cause of death in scleroderma patients. Previous studies have shown an increase in CD8؉ T cells in the lungs of scleroderma patients. In the present study, we sought to determine whether activated CD8؉ T cells contribute to pulmonary fibrosis in scleroderma patients through the production and activation of profibrotic mediators.Methods. CD8؉ cells were isolated from bronchoalveolar lavage fluid obtained from 19 scleroderma patients and 7 healthy subjects. The phenotype of these cells was determined using DNA array technology. Expression of selected genes was confirmed in real-time polymerase chain reaction and enzyme-linked immunosorbent assay experiments.

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Th2 cells as effectors in postirradiation pulmonary damage preceding fibrosis in the rat

Abstract: The results suggest a critical role for Th2 CD4+ T-lymphocytes in the pathogenesis of radiation-induced pneumonitis preceding lung fibrosis.

Cited by 75 publications

References 45 publications

Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells

Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells

Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice

Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients

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