Peripheral T Cell Functions Correlate with the Severity of Chronic Obstructive Pulmonary Disease

Zhu, Xiashi; Gadgil, Aneal S.; Givelber, Rachel J.; George, M. Patricia; Stoner, Michael W.; Sciurba, Frank C.; Duncan, Steven R.

doi:10.4049/jimmunol.0802622

Cited by 82 publications

(68 citation statements)

References 43 publications

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“…In particular, reports on proportions of IFN-c+ CD8+ T-cells are confusing. Our finding of increased proportions of IFN-c+CD8+ T-cells in the circulation of COPD patients is in line with a number of other studies, including a large study in COPD patients with varying disease severity [24][25][26]. Moreover, this result is consistent with several reports investigating local inflammation in the lung showing increased IFN-c production by CD8+ T-cells [5,6].…”

Section: Effects Of Smoking On Cytokine Expressionsupporting

confidence: 82%

“…Our finding of increased TNF-a expression by CD8+ T-cells is supported by HODGE et al [24]; however, another group reported a decrease in COPD patients when compared with healthy controls [28]. Several studies have attempted to correlate lung function parameters to IFN-c and TNF-a production by T-cells in the circulation [26,28,30], but the results are still ambiguous. In our cohort, patients with more severe disease had lower proportions of both IFN-c+CD8+ and TNF-a+CD8+ T-cells when compared to patients with mild disease.…”

Section: Effects Of Smoking On Cytokine Expressionsupporting

confidence: 69%

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Systemic CD4+ and CD8+ T-cell cytokine profiles correlate with GOLD stage in stable COPD

et al. 2011

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Chronic obstructive pulmonary disease (COPD) is associated with pulmonary and systemic inflammation. Both CD4+ and CD8+ T-lymphocytes play a key role in COPD pathogenesis, but cytokine profiles in circulating T-lymphocytes have not been well characterised.Here we report the analysis of peripheral blood T-cells from 30 stable COPD patients and 10 healthy never-smokers for interferon (IFN)-c, interleukin (IL)-4, tumour necrosis factor (TNF)-a and the T-helper 17 cytokines IL-17A, IL-17F and IL-22 by intracellular flow cytometry.We found significantly increased proportions of IFN-c+ and TNF-a+ CD8+ T-cells in COPD patients, when compared with healthy controls. This was most evident in patients with less severe disease. In contrast, expression profiles in circulating CD4+ T-cells were similar in COPD patients and healthy controls for all cytokines tested, except for IL-17F. COPD patients with more severely reduced diffusing capacity had lower proportions of IL-17A+ CD4+ T-cells. Proportions of IL-22+ cells in the CD4+ memory T-cell population were significantly increased in active smokers, when compared with past smokers.Collectively, this comprehensive cytokine analysis of circulating T-cells in COPD patients revealed a correlation for CD8+ T-cells between Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage and IFN-c or TNF-a expression, but not for CD4+ T-cells.

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Section: Effects Of Smoking On Cytokine Expressionsupporting

confidence: 82%

Section: Effects Of Smoking On Cytokine Expressionsupporting

confidence: 69%

Systemic CD4+ and CD8+ T-cell cytokine profiles correlate with GOLD stage in stable COPD

et al. 2011

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“…However, the interpretation of these reports is limited by small samples sizes, the use of non-COPD smokers with unknown patient characteristics, or in vitro treatment of PBMCs with Cs extract (55,56). The only report directly examining NK cell function in COPD used cells derived from patients using inhaled steroids (56), a variable known to impair functional assays, particularly in COPD (57). It has also been suggested that CS may impair NK cell function, leading to enhanced tumor burden following tumor challenge (58).…”

Section: Discussionmentioning

confidence: 99%

Chronic Cigarette Smoke Exposure Primes NK Cell Activation in a Mouse Model of Chronic Obstructive Pulmonary Disease

Motz¹,

Eppert²,

Wortham³

et al. 2010

The Journal of Immunology

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Chronic obstructive pulmonary disease (COPD) is a debilitating, progressive lung disease punctuated by exacerbations of symptoms. COPD exacerbations are most often associated with viral infections, and exposure to cigarette smoke (CS) followed by viral infection has been shown experimentally to enhance lung inflammation, tissue destruction, and airway fibrosis. Despite this, however, the cellular mechanisms responsible for this effect are unknown. In this study, we examined NK cell function in a mouse model of COPD given the vital role of NK cells following viral infection. Ex vivo stimulation of lung leukocytes with poly(I:C), ssRNA40, or ODN1826 enhanced production of NK cell-derived IFN-γ in CS-exposed mice. NK cells from CS-exposed mice exhibited a novel form of priming; highly purified NK cells from CS-exposed mice, relative to NK cells from filtered air-exposed mice, produced more IFN-γ following stimulation with IL-12, IL-18, or both. Further, NK cell priming was lost following smoking cessation. NKG2D stimulation through overexpression of Raet1 on the lung epithelium primed NK cell responsiveness to poly(I:C), ssRNA40, or ODN1826 stimulation, but not cytokine stimulation. In addition, NK cells from CS-exposed mice expressed more cell surface CD107a upon stimulation, demonstrating that the NK cell degranulation response was also primed. Together, these results reveal a novel mechanism of activation of the innate immune system and highlight NK cells as important cellular targets in controlling COPD exacerbations.

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“…[13][14][15] In brief, cell-surface molecule expressions of freshly isolated cells were ascertained using anti-human fluorochrome-conjugated monoclonal antibodies (mAb) against the following cellsurface determinants: CD3, CD4, CD8, CD14, CD19, CD28, CD45, and HLA class II (DR) from BD Biosciences (San Jose, CA). 13 In some cases, cells were stained with anti-human T-cell antigen receptor variable ␤ chain (TCRBV) mAb with specificity for 2S1, 3S1, and 4S1 (Immunotech, Marseilles, France), as well as 5S1 and 8S1 (BD Biosciences).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Reagents for these determinations were purchased from BD Biosciences and were used according to the manufacturer's instructions, as described previously. 15 Quantitations were performed on Ն10,000 live cells and analyzed using a FACSCalibur system (BD Biosciences). [13][14][15] …”

Section: Flow Cytometrymentioning

confidence: 99%

A Human-Mouse Chimeric Model of Obliterative Bronchiolitis after Lung Transplantation

Xue

Zhu

George

et al. 2011

The American Journal of Pathology

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Obliterative bronchiolitis is a frequent, morbid, and usually refractory complication of lung transplantation. Mechanistic study of obliterative bronchiolitis would be aided by development of a relevant model that uses human immune effector cells and airway targets. Our objective was to develop a murine chimera model that mimics obliterative bronchiolitis of lung allograft recipients in human airways in vivo. Human peripheral blood mononuclear cells were adoptively transferred to immunodeficient mice lacking activity of T, B, and NK cells, with and without concurrent transplantations of human small airways dissected from allogeneic cadaveric lungs. Chimerism with human T cells occurred in the majority of recipient animals. The chimeric T cells became highly activated, rapidly infiltrated into the small human airway grafts, and caused obliterative bronchiolitis. In contrast, airways implanted into control mice that did not also receive human peripheral blood mononuclear cell transfers remained intact. In vitro proliferation assays indicated that the chimeric T cells had enhanced specific proliferative responses to donor airway alloantigens. This model confirms the critical role of T cells in development of obliterative bronchiolitis among human lung allograft recipients and provides a novel and easily implemented mechanism for detailed, reductionist in vivo studies of human T-cell responses to allogeneic human small airways. Chronic lung allograft rejection typically manifests with obliterative bronchiolitis (OB), a small airway fibroproliferative disease process characterized by varying degrees of airway luminal obliteration with fibrinous granulation tissue. 1 Lung transplant recipients with OB develop expiratory airflow obstruction, which is often inexorably progressive, and have increased predilection for infection. 2 Despite extensive investigation, as well as incremental advances in donor organ preservation, surgical techniques, immunosuppressive regimens, and infection prophylaxis, OB remains the single most frequent cause of late graft dysfunction and death after lung transplantation. 2 Current limitations in prevention and treatment of OB likely reflect incomplete understanding of the responsible immunopathogenic mechanisms. Accordingly, having a model to generate novel insights regarding the disease paradigm, and a ready means to test these hypotheses, could be a boon for the development of more effective modalities to prevent or counter this frequent complication of lung transplantation.Animal models have been immeasurably important in advancing our understanding of many disease processes, including allograft rejection mechanisms. 3 With particular respect to pulmonary transplantation, heterotopic tracheal allografts in mice undergo histological abnormalities that reproduce the progression of OB in humans, including an initial lymphocytic infiltration, followed by successive stages of epithelial metaplasia and denudation and, ultimately, intraluminal fibroproliferation. [3][4][5][6][7] Although this mo...

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Peripheral T Cell Functions Correlate with the Severity of Chronic Obstructive Pulmonary Disease

Cited by 82 publications

References 43 publications

Systemic CD4+ and CD8+ T-cell cytokine profiles correlate with GOLD stage in stable COPD

Systemic CD4+ and CD8+ T-cell cytokine profiles correlate with GOLD stage in stable COPD

Chronic Cigarette Smoke Exposure Primes NK Cell Activation in a Mouse Model of Chronic Obstructive Pulmonary Disease

A Human-Mouse Chimeric Model of Obliterative Bronchiolitis after Lung Transplantation

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