A single-arm, open-label, phase 2 clinical trial evaluating disease response following treatment with BI-505, a human anti-intercellular adhesion molecule-1 monoclonal antibody, in patients with smoldering multiple myeloma.

Background: Smoldering multiple myeloma (SMM) is an indolent disease stage, considered to represent the transition phase from the premalignant MGUS (Monoclonal Gammopathy of Undetermined Significance) state towards symptomatic multiple myeloma (MM). Even though this diagnosis provides an opportunity for early intervention, few treatment studies have been done and the current standard of care is observation until progression. BI-505, a monoclonal antibody directed against intercellular adhesion molecule 1 (ICAM-1) with promising anti-myeloma activity in preclinical trials, is a possible treatment approach for this patient category with potential to eliminate tumor cells with minimal long-term side effects.

A Phase I Dose-Escalation Study of Antibody BI-505 in Relapsed/Refractory Multiple Myeloma.

Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients.

Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.

Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans.

Objectives: This study sought to determine whether splenic activation after acute coronary syndrome (ACS) is linked to leukocyte proinflammatory remodeling and whether splenic activity independently predicts the risk of cardiovascular disease (CVD) events.

Background: Pre-clinical data suggest the existence of a cardiosplenic axis, wherein activation of hematopoietic tissues (notably in the spleen) results in liberation of proinflammatory leukocytes and accelerated atherosclerotic inflammation. However, it is presently unknown whether a cardiosplenic axis exists in humans and whether splenic activation relates to CVD risk.

Inhalation of LPS induces inflammatory airway responses mimicking characteristics of chronic obstructive pulmonary disease.

Aim: Inhalation of lipopolysaccharide (LPS) produces both systemic and pulmonary inflammatory responses. The aim of this study was to further characterize the response to LPS in order to develop a human model suitable for early testing of drug candidates developed for the treatment for chronic obstructive pulmonary disease (COPD).

Materials: Blood and induced sputum were obtained 4, 24 and 48 h following inhalation of saline and LPS (5 and 50 μg).

CD4+ T cells have a key instructive role in educating dendritic cells in allergy.

Background: Dendritic cells (DCs) are central in allergy as regulators of the Th1/Th2 balance. We have recently demonstrated a unique transcriptional profile of DCs in patients with ongoing allergy compared with healthy subjects and shown that crosstalk between DCs and memory T cells affects the transcriptional profile of T cells. However, the transcriptional profile of DCs educated by T cells in allergy is unknown.

Effects of intranasal TNFalpha on granulocyte recruitment and activity in healthy subjects and patients with allergic rhinitis.

Background: TNFalpha may contribute to the pathophysiology of airway inflammation. For example, we have recently shown that nasal administration of TNFalpha produces late phase co-appearance of granulocyte and plasma exudation markers on the mucosal surface. The objective of the present study was to examine indices of granulocyte presence and activity in response to intranasal TNFalpha challenge.

Effects of TNFalpha on the human nasal mucosa in vivo.

Background: TNFalpha is a cytokine that may contribute to the pathophysiology of airway inflammation. Inhalation of TNFalpha produces granulocyte recruitment and airway hyperresponsiveness in man. Anti-TNFalpha treatment may inhibit allergen-induced plasma exudation in guinea-pig airways.

Clinical efficacy and pharmacokinetic profiles of intranasal and oral cetirizine in a repeated allergen challenge model of allergic rhinitis.

Background: Intranasal and oral antihistamines are effective in treating allergic rhinitis. Studies comparing these routes of administration of an antihistamine regarding efficacy and pharmacokinetic profile are lacking.

Objective: To compare topical and oral routes of administration of cetirizine regarding efficacy, plasma exudation, and systemic drug levels in a repeated allergen challenge model of allergic rhinitis.

Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation.

Background: Mast cell-derived prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology.

The human IgE-encoding transcriptome to assess antibody repertoires and repertoire evolution.

Upon encounter with antigen, the B lymphocyte population responds by producing a diverse set of antigen-specific antibodies of various isotypes. The vast size of the responding populations makes it very difficult to study clonal evolution and repertoire composition occurring during these processes in humans. Here, we have explored an approach utilizing the H-EPSILON-encoding transcriptome to investigate aspects of repertoire diversity during the season of antigen exposure.

Onset of action of a topical antihistamine as assessed by histamine challenge-induced plasma exudation responses.

Background: Although usually administered orally, antihistamines are available also for topical use in allergic rhinitis. Information on onset of action of these drugs is incomplete.

Objective: To examine onset of action of topical cetirizine-dinitrate on plasma exudation evoked by repeated nasal histamine challenges.

Blockade of CTLA-4 promotes airway inflammation in naive mice exposed to aerosolized allergen but fails to prevent inhalation tolerance.

In subjects not developing allergy, inhalation of nonpathogenic protein antigens causes no harm and is associated with tolerance induction. Repeated exposure to aerosolized ovalbumin (OVA) likewise does not evoke airway inflammation and induces inhalation tolerance in experimental animals. The present study explored the role of the inhibitory T-cell receptor CTLA-4, in preventing inflammation and in establishing inhalation tolerance in response to a protein antigen.

Genomic and functional delineation of dendritic cells and memory T cells derived from grass pollen-allergic patients and healthy individuals.

Dendritic cells (DCIs) possess a potent ability to modulate and activate specific T-cell responses to allergens, which play a pivotal role in allergic inflammation by secreting cytokines and other mediators. However, the molecular mechanisms by which allergen-challenged DCs regulate specific T-cell responses are still not well characterized. This study aims at elucidating the molecular mechanisms underlying the DC-T-cell interaction during an allergic immune response to grass pollen, using a genomic and functional approach.

Secretoneurin is released into human airways by topical histamine but not capsaicin.

Background: The neuropeptide secretoneurin, with potential relevance to leukocyte trafficking, is present in nerves of the nasal mucosa in allergic rhinitis and may be released in response to allergen and histamine exposure. There is no information on the occurrence and mechanisms of release of secretoneurin in healthy human airways.

Methods: The presence of secretoneurin in nasal biopsies and its release in response to nasal capsaicin and histamine challenges were examined.

Acute allergic responses induce a prompt luminal entry of airway tissue eosinophils.

Traditionally, traffic and activation of eosinophils in asthmatic airways are thought to take place during the late-phase allergic reaction. The present study tests the hypothesis that when eosinophils are present in the tissue before allergen exposure, as in chronically inflamed asthmatic airways, acute anaphylactic reactions initiate an eosinophil response. Using a guinea-pig allergic model, where eosinophilia is present at baseline conditions, the traffic of resident eosinophils was examined in vivo immediately after allergen challenge.

Neural expression and increased lavage fluid levels of secretoneurin in seasonal allergic rhinitis.

Secretoneurin is a neuropeptide potentially involved in migration of eosinophils, monocytes, and dendritic cells. Whether secretoneurin is present in the human airway mucosa and whether it is released at ongoing allergic airway inflammation is currently unknown. In patients with allergic rhinitis, we have explored the occurrence of secretoneurin in nasal mucosal biopsies and lavage fluids before and during natural allergen exposure.

NK cells and asthma.

NK cells have been associated with immune surveillance of tumor cells and defense mechanisms against various pathogens. However, by their capacity for immunoregulation NK cells may also play a role in determining the response to allergens. The novel possibility that NK cell activity may in part decide development of allergic airway inflammation and thus potentially be involved in the inception of asthma is discussed in this review article.

Eosinophil infiltration and activation at the gastric ulcer margin in rats.

Background: Recruitment and activation of eosinophils have been studied intensely in asthma and other allergic diseases. Less is known about the infiltration and behaviour of eosinophils during gastric ulcer healing.

Aim: To examine the tissue infiltration and activation of eosinophils in the ulcer margin at different time points after ulcer induction (days 1-15).

Role of macrophage migration inhibitory factor (MIF) in allergic and endotoxin-induced airway inflammation in mice.

Macrophage migration inhibitory factor (MIF) has recently been forwarded as a critical regulator of inflammatory conditions, and it has been hypothesized that MIF may have a role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Hence, we examined effects of MIF immunoneutralization on the development of allergen-induced eosinophilic inflammation as well as on lipopolysaccharide (LPS)-induced neutrophilic inflammation in lungs of mice. Anti-MIF serum validated with respect to MIF neutralizing capacity or normal rabbit serum (NRS) was administered i.

Evidence that neuroepithelial endocrine cells control the spontaneous tone in guinea pig tracheal preparations.

The hypothesis that neuroepithelial endocrine (NEE) cells control spontaneous tone in isolated guinea pig tracheal preparations was examined. Epithelium-denuded preparations were unable to develop a normal oscillating tone in 12% oxygen (corresponding to systemic arterial oxygen levels) and, instead, developed a strong, smooth tone, similar to the "classic" tone in 94% oxygen. Inhibition of the hydrogen peroxide-producing NADPH oxidase in the NEE cells by 20 microM diphenyleneiodonium chloride transformed, in intact preparations in 94% oxygen, the tone from a strong, smooth type to an oscillating tone of considerably less force.

Natural killer cells determine development of allergen-induced eosinophilic airway inflammation in mice.

The earliest contact between antigen and the innate immune system is thought to direct the subsequent antigen-specific T cell response. We hypothesized that cells of the innate immune system, such as natural killer (NK) cells, NK1.1(+) T cells (NKT cells), and gamma/delta T cells, may regulate the development of allergic airway disease.

Lack of systemic anaphylaxis and aeroallergen-induced airway plasma extravasation in allergic immunoglobulin-deficient mice.

Background: In Ig-deficient mice allergen challenge-induced pulmonary late phase inflammation is at least as pronounced as in wild-type animals. This study investigates immediate hypersensitivity responses in these mice.

Methods: To examine the acute plasma extravasation response in airway tissue, immunized Ig-deficient and wild-type mice and sham-immunized wild-type controls were subjected to 15 min ovalbumin aerosol challenge.

Allergen challenge-induced extravasation of plasma in mouse airways.

Background: Mouse models are extensively used to study genetic and immunological mechanisms of potential importance to inflammatory airway diseases, e.g. asthma.