Oh Sasaki

High Expression of IL-22 Suppresses Antigen-Induced Immune Responses and Eosinophilic Airway Inflammation via an IL-10–Associated Mechanism

Allergic inflammation in the airway is generally considered a Th2-type immune response. However, Th17-type immune responses also play important roles in this process, especially in the pathogenesis of severe asthma. IL-22 is a Th17-type cytokine and thus might play roles in the development of allergic airway inflammation. There is increasing evidence that IL-22 can act as a proinflammatory or anti-inflammatory cytokine depending on the inflammatory context. However, its role in Ag-induced immune responses is not well understood. This study examined whether IL-22 could suppress allergic airway inflammation and its mechanism of action. BALB/c mice were sensitized and challenged with OVA-Ag to induce airway inflammation. An IL-22–producing plasmid vector was delivered before the systemic sensitization or immediately before the airway challenge. Delivery of the IL-22 gene before sensitization, but not immediately before challenge, suppressed eosinophilic airway inflammation. IL-22 gene delivery suppressed Ag-induced proliferation and overall cytokine production in CD4+ T cells, indicating that it could suppress Ag-induced T cell priming. Antagonism of IL-22 by IL-22–binding protein abolished IL-22–induced immune suppression, suggesting that IL-22 protein itself played an essential role. IL-22 gene delivery neither increased regulatory T cells nor suppressed dendritic cell functions. The suppression by IL-22 was abolished by deletion of the IL-10 gene or neutralization of the IL-10 protein. Finally, IL-22 gene delivery increased IL-10 production in draining lymph nodes. These findings suggested that IL-22 could have an immunosuppressive effect during the early stage of an immune response. Furthermore, IL-10 plays an important role in the immune suppression by IL-22.

Intratracheal Delivery of Hepatocyte Growth Factor Directly Attenuates Allergic Airway Inflammation in Mice

Hepatocyte growth factor (HGF) has an important role in many biological events such as angiogenesis and cell proliferation, as well as anti-fibrotic and anti-apoptotic effects. In addition, we found that HGF suppresses antigen-induced immune responses in the airway by suppressing dendritic cell functions, using a HGF-producing plasmid vector. In the present study, we examined whether delivery of the HGF protein in the lung attenuates allergic airway inflammation in a mouse model. Generally, HGF is rapidly cleared from organs. So, to achieve the efficient delivery of HGF, we prepared a slow-releasing form by mounting recombinant human (rh) HGF protein in biodegradable gelatin hydrogels. BALB/c mice were immunized and then challenged with ovalbumin (OVA) to induce eosinophilic airway inflammation. Intratracheal delivery of a very small amount of gelatin-coupled rhHGF (0.3 μg) just once before the inhalation of OVA significantly suppressed eosinophilic airway inflammation. In addition, cytokine production in thoracic lymph nodes and the antigen-presenting capacity of lung CD11c+ cells were reduced. In contrast, delivery of 1.0 μg of rhHGF did not exhibit any significantly suppressive effect. These results suggest that the controlled release of rhHGF protein can suppress antigen-induced allergic immune responses in the lung. Therefore, HGF could be a novel therapeutic option for asthma.

Alendronate Attenuates Eosinophilic Airway Inflammation Associated with Suppression of Th2 Cytokines, Th17 Cytokines, and Eotaxin-2

Bisphosphonates (BPs) have been widely used to treat osteoporosis. They act by inhibiting farnesyl diphosphate synthase in the mevalonate pathway. This resembles the action of statins, whose immune-modulating effect has recently been highlighted. In contrast, the effect of BPs on immune responses has not been elucidated well. In this study, we examined the effect of alendronate (ALN), a nitrogen-containing BP, on allergic airway inflammation in a mouse model. BALB/c mice were sensitized twice with OVA and challenged three times with nebulized OVA to induce eosinophilic airway inflammation. ALN was administered by an intragastric tube before each inhalation. ALN strongly suppressed airway eosinophilia and Th2, as well as Th17 cytokine production in the lung. ALN also attenuated eotaxin-2 production in the lung. Immunohistochemistry demonstrated that the major cell source of eotaxin-2 was peribronchial/perivascular macrophages, and flow cytometrical studies confirmed that ALN decreased eotaxin-2 expression in these macrophages. Furthermore, ALN attenuated eotaxin-2 production from mouse pleural macrophages and human monocyte/macrophage-like THP-1 cells in vitro. These results suggest that ALN suppressed Ag-induced airway responses in the mouse model. The suppression of eotaxin-2 production from macrophages appears to be one of ALN’s immunomodulatory effects, whereas the mechanism by which ALN suppressed Th2 and Th17 responses could not be fully elucidated in this study. Although a clinical study should be conducted, ALN could be a novel therapeutic option for asthma.

Upregulation of Lung Dendritic Cell Functions in Elastase-Induced Emphysema

Background: Chronic obstructive pulmonary disease (COPD) is now considered a chronic inflammatory disease. Although dendritic cells (DCs) are thought to play a key role in immune responses, studies investigating the role of DCs in COPD are quite limited. Methods: Porcine pancreas elastase was intratracheally administered to C57BL/6J mice on day 0. On days 2, 7 and 14, emphysema formation was evaluated by pressure-volume relationships and microscopic findings, including measurement of the mean linear intercept. Lung DCs were isolated on day 2, and their ability to stimulate allogeneic T cells and to produce cytokines was examined. Results: Pathologic emphysematous change was observed on day 2 and a significant increase in lung volume was observed on day 14. Lung DC function, such as the induction of T-cell proliferation and IL-10 production, was upregulated. Conclusions: Upregulation of DC function was observed in elastase-induced emphysema. Further investigation on the contribution to emphysema formation may provide a useful target for future therapy.

A Case of Polymyxin b-Immobilized Fiber Column Treatment for Rapidly Progressive Interstitial Pneumonia Associated with Clinically Amyopathic Dermatomyositis

We report a case of rapidly progressive interstitial pneumonia associated with clinically amyopathic dermatomyositis who responded to single course of polymyxin b-immobilized fiber column treatment. Initial treatment with pulsed corticosteroids and cyclophosphamide, intravenous immunoglobulin, and cyclosporine seemed to suppress the activity of interstitial lung disease temporarily, but signs of relapse were detected such as elevation of serum KL-6 level and progressing pulmonary shadows in chest computed tomography scan. After polymyxin b-immobilized fiber column treatment, the areas of pulmonary shadows drastically decreased. Gradually, arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio recovered, and serum ferritin level and KL-6 level decreased. These findings indicate that polymyxin b-immobilized fiber column treatment could be promising in combination with conventional therapy for rapidly progressive interstitial pneumonia associated with clinically amyopathic dermatomyositis, especially at the early phase of relapse.

Cardiopulmonary arrest after severe anaphylactic reaction to second infusion of infliximab in a patient with ankylosing spondylitis.

To the Editor: Infliximab is an anti-tumor necrosis factor-α (TNF-α) chimeric monoclonal antibody widely used to treat chronic inflammatory diseases such as rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis (AS), and psoriasis. Infusion reaction to infliximab occurs in approximately 5% of patients1. Although severe anaphylactic reactions including hypotension, arrhythmia, and bronchospasm have been reported, there is no report of cardiopulmonary arrest strongly connected with the infliximab infusion. We describe a patient with AS who developed cardiopulmonary arrest after an anaphylactic reaction to the second infliximab infusion. A 37-year-old man with no history of allergy or coronary artery event received infliximab infusion for AS at our hospital. His symptoms were refractory to nonsteroidal antiinflammatory drugs, and he had been treated with … Address correspondence to Dr. Fujio; E-mail: kfujio-tky{at}umin.ac.jp

Efficacy of intensive immunosuppression in exacerbated rheumatoid arthritis-associated interstitial lung disease

Abstract Objectives: Acute or subacute exacerbations are recognized as a severe complication of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Nevertheless, the role of intensive immunosuppression in RA-ILD remains elusive. We attempted to evaluate the clinical characteristics and efficacy of immunosuppressive treatment in exacerbated RA-ILD. Methods: Clinical data, including respiratory function, imaging, treatment, and prognosis, were retrospectively collected for 17 patients with RA-ILD who required hospitalization at the University of Tokyo Hospital due to an acute exacerbation (12 patients) or subacute exacerbation (5 patients). Results: Patients with RA-ILD demonstrated a significantly higher titers of anticyclic citrullinated peptide antibodies compared with RA patients in Japanese Ninja registry, suggesting the role of adaptive immunity. Immunosuppressive treatment suppressed the deterioration of pulmonary functions with improved ground grass opacity and consolidation. In particular, in patients with less fibrosis on computed tomography (CT) images showed a better response to treatment. Although five patients treated with combination therapy, including cyclophosphamide, showed a severely decreased lung volume, these intensive therapies provided a good prognosis without fatalities for the average observation period of 474 days. Conclusions: Immunosuppressive therapy is effective for exacerbations of RA-ILD. For severe cases with low respiratory function, intensive therapy, including cyclophosphamide, has a potential to improve the prognosis.

Perillyl alcohol suppresses antigen-induced immune responses in the lung.

Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4(+) T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.

Polymorphic lymphoproliferative disorders in patients with rheumatoid arthritis are associated with a better clinical outcome

Abstract Objectives: The characteristics of lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA) remain unclear. Therefore, we retrospectively analyzed the clinical characteristics of these patients in our department. Methods: Twenty RA patients who developed LPD between April 2003 and August 2016 in our department were analyzed. Results: All of the RA patients who developed LPD had been treated with methotrexate (MTX). The median weekly and total dosages of MTX were 6.8 mg/week and 2530 mg, respectively. The median duration of MTX administration was eight years. Nineteen patients (95%) achieved complete remission (CR) and 15 (75%) achieved CR with MTX cessation alone. Based on the pathological findings, we divided MTX-associated LPD patients into two groups (n = 16); polymorphic LPD (31%) and other groups. CR with MTX cessation alone was achieved in 5 (100%) and 6 (54.5%) patients in the polymorphic LPD and other groups, respectively (p = .12). Moreover, the duration from the cessation of MTX to CR was significantly shorter in the polymorphic LPD group than in the other group (5.3 months vs 12.6 months, p = .01, respectively). Conclusion: Polymorphic LPD, which was the most frequent pathological diagnosis in this cohort, was associated with a higher incidence of CR and a significantly shorter duration to CR.

Characteristics of antisynthetase syndrome patients with hyperferritinaemia

exchange chromatography. Synovial tissue (ST) samples were obtained during planned surgery or diagnostic arthroscopy from patients with RA or OA. Highresolution magic-angle spinning magnetic resonance spectroscopy (HRMAS MRS) (2) was used for the detection of metabolites in biopsies. The observed metabolic pattern in SF was similar in RA and OA, both according to QTOF MS and amino acid analysis (data not shown). This is probably because samples collected from patients with RA in the acute stage in general reflect acute inflammation. By contrast, HRMAS MRS revealed elevated levels of lactate and glutamine in RA synovia (p = 0.013 and 0.025, respectively; Figure 1A). Similar changes in lactate were present in tissue samples from RA females vs. OA females (p = 0.043, data not shown). Additionally, choline levels in RA females were increased compared to those in RA males (p = 0.027; Figure 1B). Although an elevated level of choline was not seen in all female RA patients examined here, the involvement of choline in the pathogenesis of RA has been demonstrated recently (3). Principal component analysis further supported increased heterogeneity in RA samples (data not shown), in accordance with published observations (4). Finally, we isolated cells from several RA biopsies to identify inflammatory components by flow cytometry. These samples contained large amounts of T cells, both CD8+ and CD4+, with a higher proportion of the latter subtype. A considerable proportion of the CD4+ T cells were long-lived memory cells (CD45RO+ and CD45RA+) expressing CD196 and CD161 (data not shown), suggesting a T-helper (Th) 17 phenotype (5). In summary, we have shown that, despite the need for invasive procedures, HRMAS MRS may be beneficial for the identification of unique metabolic targets to distinguish RA and hence may be used for accurate diagnosis and stratification of RA patient groups. This will further enable precise targeted treatment of RA. We expect this to result in a reduction in misand overmedication and an improvement in patients’ quality of life.