Dual therapy with corticosteroid ablates the beneficial effect of DP2 antagonism in chronic experimental asthma.

Prostaglandin D2 (PGD2) signals via the DP1 and DP2 receptors. In Phase II trials, DP2 antagonism decreased airway inflammation and airway smooth muscle (ASM) area in moderate-to-severe asthma patients. However, in Phase III, DP2 antagonism failed to lower the rate of exacerbations, and DP2 as a target was shelved.

Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD.

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded.

IL-33-induced neutrophilic inflammation and NETosis underlie rhinovirus-triggered exacerbations of asthma.

Rhinovirus-induced neutrophil extracellular traps (NETs) contribute to acute asthma exacerbations; however, the molecular factors that trigger NETosis in this context remain ill-defined. Here, we sought to implicate a role for IL-33, an epithelial cell-derived alarmin rapidly released in response to infection. In mice with chronic experimental asthma (CEA), but not naïve controls, rhinovirus inoculation induced an early (1 day post infection; dpi) inflammatory response dominated by neutrophils, neutrophil-associated cytokines (IL-1α, IL-1β, CXCL1), and NETosis, followed by a later, type-2 inflammatory phase (3-7 dpi), characterised by eosinophils, elevated IL-4 levels, and goblet cell hyperplasia.

Maternal diet modulates the infant microbiome and intestinal Flt3L necessary for dendritic cell development and immunity to respiratory infection.

Poor maternal diet during pregnancy is a risk factor for severe lower respiratory infections (sLRIs) in the offspring, but the underlying mechanisms remain elusive. Here, we demonstrate that in mice a maternal low-fiber diet (LFD) led to enhanced LRI severity in infants because of delayed plasmacytoid dendritic cell (pDC) recruitment and perturbation of regulatory T cell expansion in the lungs. LFD altered the composition of the maternal milk microbiome and assembling infant gut microbiome.

The BAFF-APRIL System in Cancer.

B cell-activating factor (BAFF; also known as CD257, TNFSF13B, BLyS) and a proliferation-inducing ligand (APRIL; also known as CD256, TNFSF13) belong to the tumor necrosis factor (TNF) family. BAFF was initially discovered as a B-cell survival factor, whereas APRIL was first identified as a protein highly expressed in various cancers. These discoveries were followed by over two decades of extensive research effort, which identified overlapping signaling cascades between BAFF and APRIL, controlling immune homeostasis in health and driving pathogenesis in autoimmunity and cancer, the latter being the focus of this review.

Synergism and Antagonism of Bacterial-Viral Coinfection in the Upper Respiratory Tract.

Streptococcus pneumoniae (the pneumococcus) is a leading cause of pneumonia in children under 5 years of age. Coinfection by pneumococci and respiratory viruses enhances disease severity. Little is known about pneumococcal coinfections with respiratory syncytial virus (RSV).

Targeting the P2Y Receptor Suppresses IL-33 and HMGB1 Release and Ameliorates Experimental Asthma.

The alarmins IL-33 and HMGB1 (high mobility group box 1) contribute to type 2 inflammation and asthma pathogenesis. To determine whether P2Y-R (P2Y receptor), a purinergic GPCR (G protein-coupled receptor) and risk allele for asthma, regulates the release of IL-33 and HMGB1. Bronchial biopsy specimens were obtained from healthy subjects and subjects with asthma.

DP1 prostanoid receptor activation increases the severity of an acute lower respiratory viral infection in mice via TNF-α-induced immunopathology.

Respiratory syncytial virus (RSV) bronchiolitis is a leading cause of infant hospitalization and mortality. We previously identified that prostaglandin D2 (PGD2), released following RSV infection of primary human airway epithelial cells or pneumonia virus of mice (PVM) infection of neonatal mice, elicits pro- or antiviral innate immune responses as a consequence of D-type prostanoid receptor 2 (DP2) or DP1 activation, respectively. Here, we sought to determine whether treatment with the DP1 agonist BW245c decreases the severity of bronchiolitis in PVM-infected neonatal mice.

ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation an ATF6-UPR-Autophagy-Dependent Pathway.

Antigen (Ag)-mediated mast cell activation plays a critical role in the immunopathology of IgE-dependent allergic diseases. Restraining the signaling cascade that regulates the release of mast cell-derived inflammatory mediators is an attractive therapeutic strategy to treat allergic diseases. Orosomucoid-like-3 (ORMDL3) regulates the endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) and autophagy.

Respiratory Syncytial Virus Infection Promotes Necroptosis and HMGB1 Release by Airway Epithelial Cells.

: Respiratory syncytial virus (RSV) bronchiolitis causes significant infant mortality. Bronchiolitis is characterized by airway epithelial cell (AEC) death; however, the mode of death remains unknown.: To determine whether necroptosis contributes to RSV bronchiolitis pathogenesis via HMGB1 (high mobility group box 1) release.

PAG1 limits allergen-induced type 2 inflammation in the murine lung.

Background: Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) is a transmembrane adaptor protein that affects immune receptor signaling in T and B cells. Evidence from genome-wide association studies of asthma suggests that genetic variants that regulate the expression of PAG1 are associated with asthma risk. However, it is not known whether PAG1 expression is causally related to asthma pathophysiology.

Phase I Trial of Inducible Caspase 9 T Cells in Adult Stem Cell Transplant Demonstrates Massive Clonotypic Proliferative Potential and Long-term Persistence of Transgenic T Cells.

Purpose: Inducible caspase 9 () is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of -transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies.

Patients And Methods: Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.

Th17 plasticity and transition toward a pathogenic cytokine signature are regulated by cyclosporine after allogeneic SCT.

T-helper 17 (Th17) cells have been widely implicated as drivers of autoimmune disease. In particular, Th17 cytokine plasticity and acquisition of an interleukin-17A(IL-17A)interferon γ(IFNγ) cytokine profile is associated with increased pathogenic capacity. Donor Th17 polarization is known to exacerbate graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT); however, donor Th17 cytokine coexpression and plasticity have not been fully characterized.

Eomesodermin promotes the development of type 1 regulatory T (T1) cells.

Type 1 regulatory T (T1) cells are Foxp3 interleukin-10 (IL-10)-producing CD4 T cells with potent immunosuppressive properties, but their requirements for lineage development have remained elusive. We show that T1 cells constitute the most abundant regulatory population after allogeneic bone marrow transplantation (BMT), express the transcription factor Eomesodermin (Eomes), and are critical for the prevention of graft-versus-host disease. We demonstrate that Eomes is required for T1 cell differentiation, during which it acts in concert with the transcription factor B lymphocyte-induced maturation protein-1 (Blimp-1) by transcriptionally activating IL-10 expression and repressing differentiation into other T helper cell lineages.

RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma.

Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown.

Functional Reconstitution of Natural Killer Cells in Allogeneic Hematopoietic Stem Cell Transplantation.

Natural killer (NK) cells are the first lymphocyte population to reconstitute following allogeneic hematopoietic stem cell transplantation (HSCT) and are important in mediating immunity against both leukemia and pathogens. Although NK cell numbers generally reconstitute within a month, the acquisition of mature NK cell phenotype and full functional competency can take 6 months or more, and is influenced by graft composition, concurrent pharmacologic immunosuppression, graft-versus-host disease, and other clinical factors. In addition, cytomegalovirus infection and reactivation have a dominant effect on NK cell memory imprinting following allogeneic HSCT just as it does in healthy individuals.

Allergen-induced IL-6 trans-signaling activates γδ T cells to promote type 2 and type 17 airway inflammation.

Background: A variant in the IL-6 receptor (IL-6R) gene increases asthma risk and is predicted to decrease IL-6 classic signaling and increase IL-6 trans-signaling. This suggests that inhibition of IL-6 trans-signaling, but not classic signaling, might suppress allergic airway inflammation.

Objectives: We sought to determine whether IL-6 signaling contributes to (1) acute experimental asthma induced by clinically relevant allergens and (2) variation in asthma clinical phenotypes in asthmatic patients.

Receptor for advanced glycation end products and its ligand high-mobility group box-1 mediate allergic airway sensitization and airway inflammation.

Background: The receptor for advanced glycation end products (RAGE) shares common ligands and signaling pathways with TLR4, a key mediator of house dust mite (Dermatophagoides pteronyssinus) (HDM) sensitization. We hypothesized that RAGE and its ligand high-mobility group box-1 (HMGB1) cooperate with TLR4 to mediate HDM sensitization.

Objectives: To determine the requirement for HMGB1 and RAGE, and their relationship with TLR4, in airway sensitization.

RAGE: a new frontier in chronic airways disease.

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically.

Relative bioavailability and pharmacokinetic study of two trimetazidine modified release formulations in healthy Bangladeshi male volunteers.

Trimetazidine (CAS 5011-34-7) is an effective and well-tolerated antianginal drug that possesses protective properties against ischemia-induced heart injury. The relative bioavailability and pharmacokinetic characteristics of two modified release formulations of 35 mg trimetazidine, one as the test product (Metacard MR) and one as the reference product, were compared in healthy Bangladeshi male volunteers. The randomized, two-way crossover study was conducted in 24 healthy male volunteers after administration of a single 35 mg dose of each modified release formulation after 12-h overnight fasting, with a washout period of two weeks.

Genotypes and phenotypes of CYP3A in Bangladeshi population.

Background: To investigate whether interindividual variation in CYP3A levels can partly be explained by genetic polymorphisms, this study was designed to phenotype 200 healthy Bangladeshi subjects by measuring urinary ratio of 6β-hydroxy-cortisol/cortisol and to genotype all the subjects for the presence of CYP3A4*1B, *2, *4, *5, *6, *10 and *18 and CYP3A5*3 alleles.

Methods: For phenotyping, cortisol and 6β-hydroxy-cortisol were extracted and quantified by HPLC from morning spot urine samples (n=200). Genotyping was done using the extracted genomic DNA from all the subjects followed by amplification of target alleles by PCR.

Relative bioavailability and pharmacokinetic properties of two different enteric formulations of esomeprazole in healthy Bangladeshi male volunteers: An open-label, single-dose, randomized-sequence, two-way crossover study.

Background: In Bangladesh, a number of generic oral formulations of esomeprazole are marketed. Study of the relative bioavailability of these generic formulations has yet to be conducted in a Bangladeshi population.

Objectives: The aims of this study were to assess the relative bioavailability and pharmacokinetic properties of 2 formulations (test and reference) of esomeprazole 40 mg.

Immunoglobulin levels of vitiligo patients.

In the present study, the serum immunoglobulin profiles of vitiligo patients were compared with that of cohort control and evaluated the correlation between immunoglobulin level with their socioeconomic factors and nutritional status. Thirty vitiligo patients were recruited randomly from the Department of Dermatology and Venereology, Bangabandhu Sheikh Mujib Medical University Hospital, Dhaka, Bangladesh for this study. Thirty healthy individuals as control group matched by age, sex, education and socioeconomic factors to the patient group were selected.