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1.
Transplant Proc ; 52(3): 958-966, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32146023

ABSTRACT

BACKGROUND: Lung transplantation (LTx) is a last treatment option for patients with an end-stage pulmonary disease. Chronic lung allograft dysfunction, which generally manifests as bronchiolitis obliterans syndrome (BOS), is a major long-term survival limitation. During injury, inflammation and BOS monocytes are recruited. We determined whether changes in count, subset distribution, and functionality by surface marker expression coincided with BOS development. METHODS: Fresh whole-blood samples were analyzed from 44 LTx patients, including 17 patients diagnosed with BOS, and compared with 10 age-matched healthy controls and 9 sarcoidosis patients as positive controls. Monocytes were quantified and analyzed using flow cytometry. Based on surface marker expression, classical, intermediate, and nonclassical subsets were determined, and functional phenotypes were investigated. RESULTS: The absolute count of monocytes was decreased in LTx and slightly increased in BOS patients. The relative count shifted toward classical monocytes at the expense of nonclassical monocytes in LTx and BOS. Surface marker expression was highest on intermediate monocytes. The expression of both CD36 and CD163 was significantly increased in the LTx and BOS cohort. The difference between the BOS cohort and the LTx cohort was only subtle, with a significant decrease in HLA-DR expression on nonclassical monocytes in BOS. CONCLUSIONS: Monocyte subsets and surface marker expression changed significantly in transplantation patients, while BOS-specific changes were understated. More research is needed to determine whether and how monocytes influence the disease process and how current immunosuppressants affect their normal function in vivo.


Subject(s)
Bronchiolitis Obliterans/immunology , Lung Transplantation/adverse effects , Monocytes/immunology , Adult , Bronchiolitis Obliterans/pathology , Female , Humans , Male , Middle Aged , Phenotype
2.
Clin Exp Immunol ; 185(2): 263-70, 2016 08.
Article in English | MEDLINE | ID: mdl-27158798

ABSTRACT

Sarcoidosis is a systemic granulomatous disease of unknown aetiology that most commonly affects the lungs. Although elevated levels of regulatory T cells (Tregs ) have been reported, the extent to which they play a role in sarcoidosis pathogenesis remains unclear. Tumour necrosis factor (TNF) is thought to be one of the driving forces behind granuloma formation, illustrated by the efficacy of infliximab in severe sarcoidosis. Tregs express TNF receptor 2 (TNFR2) highly. Here, we examined the influence of infliximab therapy on Tregs and (soluble) TNFR2 levels in sarcoidosis, and correlated these with response to therapy. We observed that relative frequencies of Tregs were significantly higher in patients (n = 54) compared to healthy controls (n = 26; median 6·73 versus 4·36%; P < 0·001) and decreased following therapy (4·95; P < 0·001). Baseline TNFR2 expression on Tregs was increased significantly in patients versus controls (99·4 versus 96·2%; P = 0·031), and also in responders to therapy versus non-responders (99·6 versus 97·3%; P = 0·012). Furthermore, baseline soluble TNFR2 (sTNFR2) was higher in responders than in non-responders (mean 174 versus 107 pg/ml; P = 0·015). After treatment, responders showed a significant reduction in sTNFR2 levels in peripheral blood (-44·7 pg/ml; P < 0·001), in contrast to non-responders (+3·59 pg/ml). Our results demonstrated that Treg frequencies and TNFR2 expression on Tregs are increased in sarcoidosis, followed by a decline during infliximab therapy, suggesting a pathophysiological role of this T cell subset. Interestingly, sTNFR2 levels at baseline differed significantly between responders and non-responders, making it a potential marker in predicting which patients might benefit from infliximab.


Subject(s)
Infliximab/therapeutic use , Receptors, Tumor Necrosis Factor, Type II/blood , Receptors, Tumor Necrosis Factor, Type II/genetics , Sarcoidosis/drug therapy , T-Lymphocytes, Regulatory/immunology , Adult , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Prospective Studies , Sarcoidosis/diagnosis , Sarcoidosis/immunology , Sarcoidosis/physiopathology , Solubility , T-Lymphocyte Subsets/immunology , Tumor Necrosis Factor-alpha/immunology
3.
Clin Exp Immunol ; 167(3): 523-31, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22288596

ABSTRACT

Bronchoalveolar lavage (BAL) is widely accepted as a key diagnostic procedure in interstitial lung diseases (ILD). We performed a study to obtain reference intervals of differential cell patterns in BAL fluid with special attention to the origin of lavage fluid, e.g. bronchial/alveolar, to atopy and smoking status and to age of the healthy people. We performed bronchoalveolar lavage in 55 healthy subjects with known atopy status (age: 18-64 years, non-smokers/smokers: 34/21) and determined differential cell counts and lymphocyte subsets in BAL fluid and blood. Moreover, in a subgroup of non-smoking healthy individuals we measured the expression of the regulatory T cell marker forkhead box protein 3 (FoxP3) on blood and BAL fluid lymphocytes in addition to a comprehensive set of activation markers. Differential cell counts from the alveolar lavage fraction differed significantly from calculated pooled fractions (n = 11). In contrast, marginal differences were found between atopic and non-atopic subjects. Interestingly, the BAL fluid CD4(+) /CD8(+) ratio correlated strongly with age (r(2) = 0·50, P < 0·0001). We consider the bronchial and alveolar fraction to be lavage fluid from fundamentally different compartments and recommend analysis of the alveolar fraction in diagnostic work-up of ILD. In addition, our data suggest that age corrected BAL fluid CD4(+) /CD8(+) ratios should be used in the clinical evaluation of patients with interstitial lung diseases.


Subject(s)
Bronchoalveolar Lavage Fluid/cytology , Lung/cytology , Adolescent , Adult , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , CD4-CD8 Ratio , Female , Forkhead Transcription Factors/blood , Forkhead Transcription Factors/metabolism , Humans , Hypersensitivity, Immediate/immunology , Hypersensitivity, Immediate/metabolism , Hypersensitivity, Immediate/pathology , Leukocyte Count , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/immunology , Lung Diseases, Interstitial/metabolism , Lung Diseases, Interstitial/pathology , Lymphocyte Activation , Lymphocyte Subsets/cytology , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Male , Middle Aged , Reference Values , Smoking/metabolism , Smoking/pathology , Young Adult
4.
Brain ; 125(Pt 5): 952-60, 2002 May.
Article in English | MEDLINE | ID: mdl-11960885

ABSTRACT

One of the characteristics of multiple sclerosis is the unpredictable occurrence of exacerbations and remissions. These fluctuations in disease activity are related to alterations in (auto-)immune activity. Exacerbations lead to short-term morbidity, but may also influence long-term disability. This longitudinal study in 73 patients with relapsing-remitting multiple sclerosis assessed the contribution of systemic infections to the natural course of exacerbations. In addition, we analysed whether infections lead to an increase in the number of gadolinium-enhancing lesions. A total of 167 infections and 145 exacerbations were observed during 6466 patient weeks. During a predefined at-risk period (ARP) of 2 weeks before until 5 weeks after the onset of a clinical infection (predominantly upper airway infections), there was an increased risk of exacerbations (rate ratio 2.1), which is in accordance with previous studies. Exacerbations with onset during the ARP led more frequently to sustained deficit [increase of > or =1 Expanded Disability Status Scale (EDSS) point or > or =0.5 above EDSS 5.5 for >3 months] than exacerbations with onset outside the ARP, with a rate ratio of 3.8. Minor and major exacerbations were equally distributed between the ARP and non-ARP onset groups. ARP exacerbations were associated with significantly higher plasma levels of the inflammatory marker soluble intracellular adhesion molecule 1 than non-ARP exacerbations, indicating relatively enhanced immune activation during ARP relapses. Three serial MRI scans were performed after the onset of an infection over a 6-week period. There was no difference in the number of gadolinium-enhancing lesions between the three time points. In conclusion, exacerbations in the context of a systemic infection lead to more sustained damage than other exacerbations. There is no indication that this effect occurs through enhanced opening of the blood-brain barrier.


Subject(s)
Infections/complications , Multiple Sclerosis, Relapsing-Remitting/complications , Adult , Cytokines/blood , Female , Gastrointestinal Diseases/complications , Humans , Infections/epidemiology , Intercellular Adhesion Molecule-1/blood , Interferon-beta/therapeutic use , Interleukin-12/blood , Longitudinal Studies , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/epidemiology , Multiple Sclerosis, Relapsing-Remitting/pathology , Prospective Studies , Respiratory Tract Infections/complications , Risk Factors , Urinary Tract Infections/complications
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