Induction of hepatitis B virus surface antigen‐specific cytotoxic T lymphocytes can be up‐regulated by the inhibition of indoleamine 2, 3‐dioxygenase activity

Cytotoxic T lymphocytes (CTLs) are thought to be major effectors involved in viral clearance during acute infections, including hepatitis B virus (HBV) infection. A persistent HBV infection is characterized by a lack of or a weak CTL response to HBV, which may be reflective of tolerance to HBV. Efficient induction of HBV‐specific CTLs leads to the clearance of HBV in patients with a chronic HBV infection. Previously, we reported that α‐galactosylceramide (α‐GalCer), a specific natural killer T (NKT) cell agonist, enhanced the induction of HBV surface antigen (HBsAg)‐specific CTLs. In the present study, we found that inhibition of indoleamine 2,3‐dioxygenase (IDO) activity enhanced the induction of HBsAg‐specific CTLs after immunization with HBsAg and α‐GalCer. The administration of HBsAg and α‐GalCer increased the production of interleukin‐2 and interleukin‐12b, which are crucial for the induction of HBsAg‐specific CTLs. The production of these cytokines was more strongly enhanced in IDO knockout mice compared with wild‐type mice. In addition, α‐GalCer induced the production of IDO in CD11b⁺ cells, and these cells inhibited proliferation of HBsAg‐specific CTLs. Our results lead to strategies for improving the induction of HBsAg‐specific CTLs.     

Up‐regulation of Rac1 in the bronchial smooth muscle of murine experimental asthma

There has been considerable research on the involvement of RhoA/Rho kinase signalling in smooth muscle contractions. However, only a few reports have addressed the specific role of Rac1, which is a member of the Rho GTPase superfamily. Therefore, this study investigated the role of Rac1‐related pathways in bronchial smooth muscle (BSM) contractions. Bronchial rings isolated from mice were suspended in an organ bath, and the isometric contractions of circular smooth muscles were monitored. The phosphorylation of myosin light chains (MLCs) was analysed by immunoblotting. The Rac1 inhibitor EHT1864 inhibited carbachol (CCh)‐induced BSM contractions, although high K⁺ depolarization‐induced BSM contractions were not significantly attenuated by EHT1864. Moreover, high K⁺‐ and phorbol 12,13‐dibutyrate (PDBu; PKC activator)‐induced contractions were not attenuated by Rac1 inhibition, whereas sodium fluoride (NaF)‐induced force development was inhibited by EHT1864. The gene and protein expression of Rac1 was increased in the BSM of a murine model with antigen‐induced airway hyper‐responsiveness (AHR). In addition, an increased force of the BSM contractions in AHR was suppressed by EHT1864 treatment, suggesting that the up‐regulation of Rac1 is involved in AHR. These findings suggest that an increase in Rac1‐mediated signalling is involved in the augmented contractions of BSMs in antigen‐induced AHR mice.     

Correlation between circulating fibrocytes, and activity and progression of interstitial lung diseases

Background and objective: Interstitial lung diseases (ILD) are characterized by progressive interstitial pulmonary fibrosis and a decline in lung function. Fibrocytes are bone marrow‐derived mesenchymal progenitor cells that may play a role in the pathogenesis of pulmonary fibrosis. Circulating fibrocyte numbers have been correlated with the prognosis of patients with idiopathic pulmonary fibrosis. The aim of the present study was to evaluate the relationship between circulating fibrocytes, and parameters of disease activity and progression in several groups of patients with ILD. Methods: The study population comprised 41 patients with ILD and seven healthy control subjects. Circulating CD45⁺ collagen‐I⁺ fibrocytes were evaluated by flow cytometry. Results: The number of circulating fibrocytes was significantly increased in all patients with ILD and particularly in patients with idiopathic interstitial pneumonitis and interstitial pneumonitis associated with collagen vascular disease as compared with healthy control subjects. The numbers of circulating fibrocytes were significantly correlated with pulmonary function test parameters and with serum levels of sialylated carbohydrate antigen, a marker of disease activity. Temporal changes in circulating fibrocyte numbers were evaluated in two patients, and the results suggested that these changes correlated with the activity of ILD. Conclusions: The results from this study provide further evidence for the role of circulating fibrocytes in fibrotic lung diseases.