Synthetic di-sulfated iduronic acid attenuates asthmatic response by blocking T-cell recruitment to inflammatory sites

Identification of carbohydrate sequences that determine affinity to specific chemokines is a critical step for strategies to interfere with chemokine-mediated leukocyte trafficking. Here, we first characterized the development of allergic asthma in Tie2-dependent and inducible Ext1-knockout (Tie2-Ext1^iKO) mice. We showed that heparan sulfate is essential for leukocyte recruitment in the peribronchial region and bronchoalveolar lavage fluid (BALF), and is crucial for induction of airway hyperresponsiveness. Our glycan microarray showed a unique affinity profile of chemokine CCL20 to substructures of heparin and heparin-like oligo/di/monosaccharides. Among them, we identified a synthetic and not naturally occurring monosaccharide, 2,4-O-di-sulfated iduronic acid (Di-S-IdoA), as a potential inhibitor for CCL20–heparan sulfate interaction. Mice injected with Di-S-IdoA via tail vain or nasal inhalation showed attenuated leukocyte recruitment into inflammatory sites and BALF. These results demonstrate a critical role of chemokine–heparan sulfate interaction in the asthma development and Di-S-IdoA as a potential drug for asthma treatment.Asthma is a common allergic disease characterized by chronic airway inflammation, mucus hypersecretion, and airway hyperreactivity to inhaled allergens (1). Despite the importance of T lymphocytes in adaptive immunity and host defense, their accumulation in airway in allergic asthma causes Th2-mediated pulmonary inflammation. The asthmatic inflammatory response is orchestrated by T-cell trafficking network among lung, blood circulation, secondary lymphoid organ, and peripheral tissue (2). Of note, the significant increase of T cells in the airway in asthma is mostly due to T-cell recruitment from regional lymph nodes rather than their proliferation at the inflamed site (3). Therefore, a therapeutic approach that shuts off the trafficking pathway of pathogenic T cells should significantly inhibit the Th2-mediated inflammation in allergic asthma.It is well known that the destination of T-cell trafficking pathway is tightly restricted by the profile of chemokines, lipid chemoattractants, and T-cell chemokine receptors. As a part of immune surveillance, naïve T cells and central memory T cells constantly access secondary lymphoid organs from blood circulation via specialized high endothelial venules (HEVs). The interaction between T cells and HEV cells includes in a stepwise manner (4, 5), L-selectin–dependent tethering and rolling, activation, firm arrest, and transendothelial migration. Besides 6-sulfo sialyl Lewis X as a L-selectin ligand, HEVs constitutively express chemokine CCL21 and CCL19 and attract T cells that express its cognate receptor CCR7 (5). In contrast to this homeostatic homing, circulating T cells interact with inflamed blood vessels in lung after asthmatic exposure to an inhaled allergen. Among numerous combinations of chemokines and their receptors, there is considerable evidence that CCL20 and its cognate receptor CCR6 may contribute to the pathogenesis of asthma (6). CCL20-CCR6 plays a key role in the recruitment of Th17 (7) cells and Th2 cells (8). Indeed, CCL20 is highly enriched on inflammatory epithelium (9) and CCR6 is expressed on memory T cells infiltrated in the lung during allergic inflammation (7). In addition, CCR6-deficient mice have decreased airway responsiveness, and reduced recruitment of eosinophils into lung (10, 11). These findings suggest that CCL20-CCR6 axis is a putative target for the treatment of asthma.Cumulative evidence in vivo and in vitro indicates that chemokines cannot be functionally active in HEVs and inflamed sites without their interaction with heparan sulfate (12). Heparan sulfate protects chemokines from proteolysis, immobilizes them on the endothelium surface and produces chemokine gradients in the vasculature. Heparan sulfate is composed of repeating disaccharide units of uronic acid [glucuronic acid (GlcA) or iduronic acid (IdoA)] and N-acetylglucosamine (GlcNAc) carbohydrates. Some of GlcA (or IdoA) carbohydrates are subsequently O-sulfated, and GlcNAc carbohydrates are partially modified with N-deacetylation and N-sulfation (13). Previous reports have indicated that the sulfation patterns in heparan sulfate are more restricted than expected (14), and the sulfation is associated with respiratory distress (15) and asthma (16). It is believed that there are specific interactions between heparan sulfate and chemokines (17). Nevertheless, the nontemplate nature of long carbohydrate chains (<25,000 disaccharide units) and conformational plasticity still make it difficult to identify the common sequences of heparan sulfate that display affinity to specific chemokines. In this regard, our previously established glycan microarray system (18, 19) is a powerful tool to define the selectivity in heparan sulfate–chemokine interactions.Recently, we established the exostoses-1 (Ext1) gene conditional knockout Tie2-Ext1^iKO mouse model, in which GlcA/IdoA-GlcNAc repeat of heparan sulfate can be abrogated in endothelial cells in a tetracycline-inducible manner (20). In this study, Tie2-Ext1^iKO mouse showed significant reduction of both leukocyte recruitment to lung tissues and of airway hyperresponsiveness in ovalbumin (OVA) asthma model. Moreover, glycan microarray analysis surprisingly identified that an unnatural and synthetic monosaccharide, 2,4-O-di-sulfated iduronic acid (Di-S-IdoA) has a high affinity to recombinant CCL20. Intravenous and inhalation challenges of Di-S-IdoA significantly inhibited the leukocyte infiltration in bronchoalveolar lavage fluid (BALF). Our finding that even a monosaccharide can attenuate airway inflammation suggests its potential use as an antiasthma therapy that can be administered by inhalation.     

Coordination-based vapochromic behavior of a luminescent Pt(ii) complex with potassium ions

Vapochromic Pt(ii) complexes that exhibit color and luminescence changes induced by the presence of vapor molecules have drawn considerable attention because of their potential use as vapor sensors. Generally, the vapochromic responsiveness of Pt(ii)-based complexes is difficult to envisage, because a typical molecular design facilitates the stabilization of a vapor-adsorbed form through weak intermolecular interactions. Herein, we investigate the vapochromic behavior of a Pt(ii) complex with potassium ions, which act as vapor coordination sites, by strongly stabilizing the vapor-adsorbed form. Upon exposure to N,N-dimethylacetamide and N,N-dimethylformamide vapors, the complex exhibits crystal structural transformation with luminescence spectral changes. Crystal structural analysis indicates that the vapor molecules are coordinated to the potassium ions after vapor exposure. This study suggests the possibility of inducing Pt(ii)-based vapochromic responsiveness through establishing potassium-ion-based vapor coordination sites.

A luminescent Pt(ii) complex with potassium ions was successfully synthesized and its coordination-based vapochromic behavior was investigated.     

Corrosion Behavior of Ultrafine-Grained CoCrFeMnNi High-Entropy Alloys Fabricated by High-Pressure Torsion

The influence of the nanocrystalline structure produced by severe plastic deformation (SPD) on the corrosion behavior of CoCrFeMnNi alloys with Cr contents ranging from 0 to 20 at.% was investigated in aqueous 0.5 M H₂SO₄ and 3.5% NaCl solutions. The resistance to general corrosion and pitting became higher in both the solutions, with higher passivation capability observed with increasing Cr content, and it is believed that the high corrosion resistance of CoCrFeMnNi alloys can be attributed to the incorporation of the Cr element. However, the impact of the nanocrystalline structure produced by SPD on the corrosion behavior was negligibly small. This is inconsistent with reports on nanocrystalline binary Fe–Cr alloys and stainless steels processed by SPD, where grain refinement by SPD results in higher corrosion resistance. The small change in the corrosion behavior with respect to grain refinement is discussed, based on the passivation process of Fe–Cr alloys and on the influence of the core effects of HEAs on the passivation process.     

Outcome of allogeneic hematopoietic stem cell transplantation for mycosis fungoides and Sézary syndrome

Although allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to provide prolonged remission of relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS), its role has not been fully evaluated. Here, the outcomes of allogeneic HSCT for patients with MF/SS were retrospectively evaluated by using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Forty-eight patients were evaluable and enrolled in the analysis. Median age was 45.5 years. Eighteen patients (38%) received myeloablative conditioning, and 33 (69%) received HSCT from an alternative donor. Disease status was complete or partial response in 25% of the patients and relapsed or refractory in the others. At the time of analysis, 18 patients were alive, with a median follow-up of 31.0 months (range, 3.8-31.1). Three-year overall survival (OS) and progression-free survival (PFS) were 30% (95%CI, 16-45%) and 19% (95%CI, 9-31%), respectively. Disease progression was not observed later than 17 months after transplantation. Both disease status and performance status at transplant significantly affected OS and PFS. Although our findings suggest that allogeneic HSCT provides long-term PFS in patients with MF/SS, the timing of transplantation should be decided carefully based on the disease status and the patient's condition in order to improve the outcome.     

Prognostic impact of count of extratumoral lymphatic permeation in lung adenocarcinoma and its relation to the immune microenvironment

Extratumoral lymphatic permeation (ly‐ext) has been reported as an independent poor prognostic factor for lung adenocarcinoma, but whether or not the number of ly‐ext foci is associated with prognosis and its relationship to the immune microenvironment is unclear. We counted the number of ly‐ext foci on pathological slides from patients with completely resected lung adenocarcinoma with ly‐ext, and divided them into two groups: a group with a high number of ly‐ext foci (ly‐ext high) and one with a low number of ly‐ext foci (ly‐ext low). Among the patients with ly‐ext, only a high number of ly‐ext foci was an independent poor prognostic factor. The 3‐year recurrence‐free survival (RFS) rate of the ly‐ext high group was significantly lower than that of the ly‐ext low group (14.7% vs. 50.0%, P < 0.01). Then, we analyzed the immune microenvironment of pT1 lung adenocarcinoma with ly‐ext (13 cases of ly‐ext high and 11 cases of ly‐ext low tumor) by immunohistochemistry using antibodies for stem cell markers (aldehyde dehydrogenase 1 A1 and CD44), tumor‐promoting mucin (MUC1), tumor‐infiltrating lymphocytes (CD4, CD8, FOXP3, and CD79a), and tumor‐associated macrophages (CD204). The number of CD8+ TILs within the primary lesion was significantly lower and the number of FOXP3+ TILs within the primary lesion was significantly higher in the ly‐ext high group (P < 0.05 and P < 0.01, respectively). Our results indicated that a high number of ly‐ext foci was an independent poor prognostic factor. Moreover, tumors with high numbers of ly‐ext foci had a more immunosuppressive microenvironment.