Ahmad Kasran

Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I

Background: Chronic obstructive pulmonary disease (COPD) is often associated with peripheral muscle weakness, which is caused by several factors. Acute exacerbations may contribute, but their impact on muscle force remains unclear. Correlations between peripheral muscle force and inflammatory and anabolic markers have never been studied in COPD. The effect of an acute exacerbation on quadriceps peak torque (QPT) was therefore studied in hospitalised patients, and the aforementioned correlations were examined in hospitalised and in stable patients. Methods: Lung function, respiratory and peripheral muscle force, and inflammatory and anabolic markers were assessed in hospitalised patients on days 3 and 8 of the hospital admission and 90 days later. The results on day 3 (n=34) were compared with those in clinically stable outpatients (n=13) and sedentary healthy elderly subjects (n=10). Results: Hospitalised patients had lowest mean (SD) QPT (66 (22)% predicted) and highest median (IQR) levels of systemic interleukin-8 (CXCL8, 6.1 (4.5 to 8.3) pg/ml). Insulin-like growth factor I (IGF-I) tended to be higher in healthy elderly subjects (p=0.09). QPT declined between days 3 and 8 in hospital (mean −5% predicted (95% CI −22 to 8)) and partially recovered 90 days after admission to hospital (mean 6% predicted (95% CI −1 to 23)). QPT was negatively correlated with CXCL8 and positively correlated with IGF-I and lung transfer factor in hospitalised and in stable patients. Conclusions: Peripheral muscle weakness is enhanced during an acute exacerbation of COPD. CXCL8 and IGF-I may be involved in the development of peripheral muscle weakness in hospitalised and in stable patients with COPD.

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4 + CD25 + FoxP3 + T cells

Graft-versus-host-disease (GVHD) is the most common cause of poor outcome after allogeneic stem cell transplantation (SCT). Of late, exploitation of FOXP3+ regulatory T-cell (TREG) function is emerging as a promising strategy in suppression of GVHD, while preserving graft-versus-leukemia (GVL). Cyclosporine and rapamycin reduce the expansion of effector T cells by blocking interleukin (IL)-2, but signaling by IL-2 is pivotal for TREG homeostasis. The resolution of GVHD is critically dependent on thymus-dependent reconstitution of the immunoregulatory system. Thus, there has been concern about the impact of blocking IL-2 signaling by immunosuppressive agents on TREG homeostasis. Here we demonstrate in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4+CD25+FoxP3+ T cells but also their homeostatic behavior in peripheral immune compartments. Treatment with cyclosporine resulted in a sharp reduction of peripheral CD25+FoxP3+ T cells in all immune compartments studied. Prolonged rapamycin treatment allowed for thymic generation of CD4+FoxP3+ T cells, whereas treatment with cyclosporine led to a reduced generation of these cells. In conclusion, cyclosporine and rapamycin differentially affect homeostasis of CD4+FoxP3+ TREG in vivo. As peripheral tolerance induction is a prerequisite for successful treatment outcome after allogeneic SCT, these findings are of potential clinical relevance.

Haptoglobin directly affects T cells and suppresses T helper cell type 2 cytokine release

T helper cell type 1 (Th1) and type 2 (Th2) immune responses are characterized by a different pattern of cytokine expression following T‐cell activation. Alterations of the ratio of Th1 to Th2 cells are important determinants of susceptibility to viral and parasitic infections, allergies, anti‐tumour responses, and autoimmunity. In this work we bring new evidence for an effect of haptoglobin (Hp), a positive acute‐phase protein, on T‐lymphocyte functions. We show that Hp specifically interacts with both resting and activated CD4+ and CD8+ T cells. This specific binding results in a strong suppression of induced T‐cell proliferation. In addition, Hp exhibits a strong in vitro inhibitory effect on Th2 cytokine release, while the production of interferon‐γ (IFN‐γ) and interleukin‐2 (IL‐2) is only slightly inhibited at high Hp doses. As a result, the presence of Hp promotes Th1 activation over Th2 activation in vivo as evidenced in Hp‐deficient mice. Anti‐CD3 monoclonal antibody injection indeed resulted in predominant IL‐4 production in Hp−/− mice, in contrast to predominant IFN‐γ production in Hp+/+ mice. We conclude that Hp plays a modulating role on the Th1/Th2 balance by promoting a dominant Th1 cellular response. This points to a role of acute‐phase proteins in balancing immune responses.

Skeletal muscle weakness in patients with sarcoidosis and its relationship with exercise intolerance and reduced health status

Background: Skeletal muscle weakness is assumed to be present in patients with sarcoidosis but has never been reported in a consecutive group of patients. Moreover, its relationship with previously observed exercise intolerance and reduced health status has never been studied in these patients. Methods: Pulmonary function, skeletal and respiratory muscle forces, peak and functional exercise capacity, health status, and the circulating levels of inflammatory and anabolic markers were determined in 25 patients with sarcoidosis who complained of fatigue (15 men) and in 21 healthy subjects (13 men). Results: Patients with sarcoidosis had lower respiratory and skeletal muscle forces, reduced exercise capacity and health status, higher anxiety and depression scores, and higher circulating levels of tumour necrosis factor-α than healthy subjects (all p⩽0.01). Its soluble receptor p75 tended to be higher (p = 0.04). Circulating levels of interleukin (IL)-6, IL-8, insulin-like growth factor I and its binding protein 3 were not significantly different between the two groups. Skeletal muscle weakness was related to exercise intolerance, depression, and reduced health status in patients with sarcoidosis, irrespective of age, sex, body weight and height (p⩽0.05). Quadriceps peak torque was inversely related to fatigue but not to the circulating levels of inflammatory or anabolic markers. The mean daily dose of corticosteroids received in the 6 month period before testing was related to quadriceps peak torque only in patients who received oral corticosteroids. Conclusion: Skeletal muscle weakness occurs in patients with sarcoidosis who complain of fatigue and is associated with reduced health status and exercise intolerance.

Haptoglobin dampens endotoxin-induced inflammatory effects both in vitro and in vivo

We report that haptoglobin, an acute‐phase protein produced by liver cells in response to interleukin‐6 (IL‐6), can modulate the inflammatory response induced by endotoxins. We provide evidence that haptoglobin has the ability to selectively antagonize lipopolysaccharide (LPS) effects in vitro by suppressing monocyte production of tumour necrosis factor‐α, IL‐10 and IL‐12, while it fails to inhibit the production of IL‐6, IL‐8 and IL‐1 receptor antagonist. In two animal models of LPS‐induced bronchopulmonary hyperreactivity and endotoxic shock, haptoglobin knockout mice were more sensitive to LPS effects compared to their wild‐type counterparts. The present data suggest that haptoglobin regulates monocyte activation following LPS stimulation. The increase in haptoglobin levels during an acute‐phase reaction may generate a feedback effect which dampens the severity of cytokine release and protects against endotoxin‐induced effects.

Progesterone increases airway eosinophilia and hyper‐responsiveness in a murine model of allergic asthma

Background Sex hormones might affect the severity and evolution of bronchial asthma. From existing literature, there exists, however, no convincing evidence for either exacerbation or improvement of allergic symptoms by progesterone.

Blockade of CTLA-4 enhances allergic sensitization and eosinophilic airway inflammation in genetically predisposed mice.

CTLA‐4 (CD152) expression is restricted to subsets of activated T lymphocytes and shares homology with CD28. CTLA‐4 and CD28 molecules both bind to B7 molecules on antigen‐presenting cells. Whereas CD28‐B7 interaction enhances T cell activation, cytokine production and survival, CTLA‐4 signaling down‐regulates T cell responses. Here, we studied the involvement of CTLA‐4 triggering in thepathogenesis of allergen‐induced airway inflammation in mice. Anti‐CTLA‐4 mAb were injected during i.p. sensitization with ovalbumin (OVA). This treatment favored OVA‐specific IgE production and augmented blood eosinophilia in BALB/c mice. In BALB/c mice, enhanced Th2 sensitization after anti‐CTLA‐4 mAb injections resulted in more severe airway inflammation, and increased airway hyperresponsiveness to metacholine, bronchial eosinophilia and IL‐4 and IL‐5 levels in broncho‐alveolar lavage (BAL) fluid following repeated allergen inhalations. Importantly, aggravation of airway inflammationand enhancement of Th2 responses were accompanied by a significant reduction of pulmonary TGF‐β levels at protein level in BAL fluid as well as on mRNA level in inflamed lung tissue. In contrast to BALB/c mice, blockade of CTLA‐4 did not alter IgE production nor the phenotype of airway inflammation or TGF‐β production in C57BL/6 mice. Our data suggest that CTLA‐4 triggering represents an important regulatory mechanism for Th2 sensitization in genetically predisposed mice by modulating TGF‐β production.

Eosinophilic rhinitis accompanies the development of lower airway inflammation and hyper‐reactivity in sensitized mice exposed to aerosolized allergen

Background Allergic rhinitis is a risk factor for the development of asthma. About 80% of asthmatic patients also have rhinitis. However, the pattern of induction of allergic rhinitis and asthma remains unclear.

Safety and tolerability of antagonist anti-human CD40 Mab ch5D12 in patients with moderate to severe Crohn's disease

Background:  The ligation of CD40 by CD154 is a critical step in the interaction between APC and T cells. In animals, antagonizing CD40L‐CD40 has been shown to reduce the severity of several autoimmune and inflammatory disorders, including experimental colitis.

Elevated expression of both mRNA and protein levels of IL-17A in sputum of stable Cystic Fibrosis patients

BackgroundT helper 17 (Th17) cells can recruit neutrophils to inflammatory sites through production of IL-17, which induces chemokine release. IL-23 is an important inducer of IL-17 and IL-22 production. Our aim was to study the role of Th17 cells in cystic fibrosis (CF) lung disease by measuring IL-17 protein and mRNA levels and IL-22 and IL-23 mRNA in sputum of clinically stable CF patients and by comparing these levels with healthy controls.MethodsSputum induction was performed in adult CF patients outside of an exacerbation and healthy control subjects. IL-17A protein levels were measured in supernatants with cytometric bead array (CBA) and RNA was isolated and quantitative RT-PCR was performed for IL-17A, IL-22 and IL-23.ResultsWe found significantly higher levels of IL-17A protein and mRNA levels (both: p < 0.0001) and IL-23 mRNA levels (p < 0.0001) in the sputum of CF group as compared to controls. We found very low levels of IL-22 mRNA in the CF group. The levels of IL-17 and IL-23 mRNA were higher in patients chronically infected with Pseudomonas aeruginosa (P. aeruginosa) as compared to those who were not chronically infected with P. aeruginosa. The presence of Staphylococcus aureus (S. aureus) on sputum did not affect the IL-17 or IL-23 levels. There was no correlation between IL-17 or IL-23 levels and FEV1 nor sputum neutrophilia.ConclusionThe elevated levels of IL-17 and IL-23 might indicate that Th17 cells are implicated in the persistent neutrophil infiltration in CF lung disease and chronic infection with P. aeruginosa.