Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.

Background: Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)-mediated inflammation could help in the treatment of related diseases, including atopic dermatitis.

Methods: We performed randomized, double-blind, placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors.

Dupilumab in persistent asthma with elevated eosinophil levels.

Background: Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels.

Methods: We enrolled patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3% who used medium-dose to high-dose inhaled glucocorticoids plus long-acting beta-agonists (LABAs).

Asthma, asthma medications and their effects on maternal/fetal outcomes during pregnancy.

Maternal asthma may increase the risk of adverse fetal and maternal outcomes such as low birth weight, perinatal mortality, preterm birth, preeclampsia, hypertensive disorders, maternal mortality, uterine hemorrhage, and gestational diabetes. Controlling asthma during pregnancy with appropriate medications leads to improved intrauterine growth of the fetus and fewer adverse perinatal outcomes. Prospective population or birth cohort studies have shown that the medications used to treat asthma, such as bronchodilators (short-acting β2-agonists) and controller medications (inhaled corticosteroids, cromones, theophylline, leukotriene inhibitors), have no or minimal effects on fetal growth, and perinatal complications are reduced when maternal asthma is adequately controlled.

A microfabricated fluidic device for performing two-dimensional liquid-phase separations.

A microfabricated fluidic device that combines micellar electrokinetic chromatography and high-speed open-channel electrophoresis on a single structure for the rapid automated two-dimensional analysis of peptides has been devised and demonstrated. The microchip operates by rapidly sampling and analyzing effluent in the second dimension from the first dimension. Second-dimension analyses are performed and completed every few seconds, with total analysis times of less than 10 min for tryptic peptides.

Physiological studies with human leukocyte inhibitory factor.

LIF has been shown to be a potentially important activator of neutrophil function. By means of its dose-dependent dichotomous effects on chemotaxis, LIF can be predicted to both enhance the potency of chemotactic stimuli and promote the passive accumulation of PMN at inflammatory loci. Furthermore, LIF's stimulatory effects on both PMN- and endothelial cell-mediated adherence will promote the migration of neutrophils from the circulation to the inflammatory site.

Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects.

The effect of vitamin E supplementation on the immune response of healthy older adults was studied in a double-blind, placebo-controlled trial. Subjects (n = 32) resided in a metabolic research unit and received placebo or vitamin E (800 mg dl-alpha-tocopheryl acetate) for 30 d. Alpha-tocopherol content of plasma and peripheral blood mononuclear cells (PBMCs), delayed-type hypersensitivity skin test (DTH), mitogen-stimulated lymphocyte proliferation, as well as interleukin (IL)-1, IL-2, prostaglandin (PG) E2, and serum lipid peroxides were evaluated before and after treatment.

Asthmatic patients have neutrophils that exhibit diminished responsiveness to adenosine.

Activation of neutrophils (PMN) within the airways results in the secretion of a number of products such as reduced oxygen metabolites that could contribute to the inflammatory response associated with asthma. However, mediators of allergy, such as histamine, prostaglandin E2 (PGE2), isoproterenol, and adenosine, may serve to mitigate this inflammation through feedback inhibition of neutrophil function. To test the hypothesis that PMN activation and feedback inhibition mechanisms may be abnormal in asthmatics, we compared both superoxide production and adenosine-induced suppression of superoxide production in 12 matched pairs of asthmatics and control subjects.

Immune mechanisms in allergen-specific immunotherapy.

Allergen-specific immunotherapy has been shown to be clinically effective in patients with seasonal allergic rhinitis and/or asthma. Patients who receive this therapy undergo a number of specific immunologic changes in response to the allergen being administered. These include a "blunting" of the seasonal rise of allergen-specific IgE as well as lowering baseline IgE levels, generation of an allergen-specific IgG response, development of auto-anti-idiotypic antibodies, reduced basophil histamine release in response to allergen, decreased lymphocyte proliferation, lymphokine production in response to allergen, and the generation of allergen-specific suppressor T cells that down-regulate lymphoproliferative responses and IgE synthesis.

Nasal eosinophilia in allergic and nonallergic rhinitis: usefulness of the nasal smear in the diagnosis of allergic rhinitis.

Diagnostic nasal cytology has been advocated for use in distinguishing allergic from nonallergic rhinitis. We sought to determine prospectively the frequency of nasal eosinophilia (NE) in 100 patients in whom having allergic rhinitis (AR), nonallergic rhinitis, and other atopic conditions not involving the respiratory tract have been diagnosed. A nasal smear was obtained from consenting adults using the Rhino-Probe curette.

Induction of IgE synthesis in anti-IgM-activated nonatopic human B cells by recombinant interleukin-3.

The signals required to induce purified normal human B cell subpopulations into IgE production were studied. Pokeweed mitogen (PWM)-stimulated T cell supernatant induced IgE synthesis in low-density but not high-density Percoll-gradient-separated resting B cells. The PWM supernatant also enhanced (greater than 2-fold) IgE synthesis by anti-IgM (but not Staphylococcus A Cowan I)-activated high-density B cells (but not low-density B cells) and had affinity for lentil lectin.

T cell responses in allergic rhinitis, asthma and atopic dermatitis.

Although clinical responses to allergens have been shown to primarily involve IgE antibodies, there is often no clear correlation between the amount of allergen-specific IgE present in the serum and the nature and severity of allergic symptoms. This observation raises the question of the possible role of non-IgE mediated types of immune responses in this reaction. It is not known to what extent components of T cell-mediated immunity are involved in IgE-mediated reactions but several observations suggest an association between atopic disease and alterations in cellular immune function.

Dysregulation of arachidonic acid release and metabolism by atopic mononuclear cells.

We studied the ability of monocytes to metabolize [3H]arachidonic acid (AA) provided exogenously by activated T cells, and the extent to which dexamethasone suppressed eicosanoid production by normal and atopic cells. [3H]AA metabolites were identified using a reverse-phase high pressure liquid chromatography system (HPLC). Unstimulated and PHA-stimulated T cells from normal and atopic subjects exhibited a similar uptake and time-dependent release of radiolabel, 90% of which was identified as free AA.

Leukocyte inhibitory factor stimulates neutrophil-endothelial cell adhesion.

We investigated the ability of the human lymphokine leukocyte inhibitory factor (LIF) to modulate neutrophil-endothelial cell (EC) adherence. EC were cultured from collagenase-treated human umbilical cord veins and grown in complete medium supplemented with EC growth factor. Adherence was measured as the percent of 51Cr-labeled neutrophils remaining adherent to the EC after gentle lavage.

Immunologic responses during allergen-specific immunotherapy for respiratory allergy.

At present there is no absolute way to determine which patient will respond to immunotherapy and which will not. Even in treated patients who derive clinical benefit, there is no one "best" immunologic parameter to follow although the generation of allergen-specific IgG seems to correlate better with clinical improvement than the other parameters. Whether or not the measurement of allergen-specific IgG4 will prove to be a useful clinical parameter is still a controversial issue and is an area for active investigation.

T- and B-cell-derived supernatant factors enhance IgE synthesis by a myeloma cell line (U-266).

IgE synthesis by the human myeloma line U-266 was enhanced 3- to 15-fold in the presence of supernatants from cultures of mononuclear cells (MNC). The enhancing activity was concentration-dependent and was derived from cells that were cultured in the absence of serum and received no in vitro stimulation by exogenous mitogens or lymphokines. T- and B-lymphocyte-enriched populations isolated from MNC were found to generate the enhancing activity, but no enhancing activity was produced by monocytes.

Comparison of prostaglandins E2 and D2 as inhibitors of respiratory burst in neutrophils from atopic and nonatopic subjects.

Neutrophils from atopic and nonatopic donors were treated with prostaglandins D2 and E2 before stimulation of the respiratory burst. Both agents inhibited neutrophil response to formyl-methionyl-leucyl-phenylalanine, but superoxide production was inhibited much more profoundly by D2 than by E2. Inhibition was similar in atopics and nonatopics.

Potentiation of neutrophil aggregation by human leukocyte inhibitory factor.

The current studies were designed to extend our investigations on the ability of the lymphokine leukocyte inhibitory factor (LIF) to function as a neutrophil activator. Specifically, we investigated whether LIF could modulate neutrophil (PMN) aggregation. Aggregation was measured as the increase in light transmission using a Payton aggregometer.

Enhancement of the function of neutrophil type-1 and type-3 complement receptors by human leukocyte inhibitory factor (LIF).

The lymphokine leukocyte inhibitory factor (LIF) has previously been documented to enhance several neutrophil (PMN) functions, including stimulated chemotaxis and superoxide generation, phagocytosis and adherence of opsonized targets, and antibody-dependent cellular cytotoxicity. The present studies were designed to investigate the effects of LIF on PMN function mediated by the complement components C3b and C3bi. LIF induced a dose-dependent increase in superoxide production generated by opsonized zymosan (up to 97.

Double-blind comparison of terfenadine, chlorpheniramine, and placebo in the treatment of chronic idiopathic urticaria.

The efficacy of terfenadine, a nonsedating H1 antihistamine, in the management of chronic idiopathic urticaria was compared with chlorpheniramine and placebo in a parallel multicenter trial. Subjects with symptoms of hives for 3 days per week for at least 6 weeks were initially screened and admitted if no identifiable cause for symptoms could be determined. Patients entered a single-blind placebo period, and if hives of moderate severity were present for at least 3 days during the week, they were randomly assigned in a double-blind fashion to take terfenadine, 60 mg twice daily, chlorpheniramine, 4 mg three times a day, or placebo for 6 weeks.

Altered arachidonic acid metabolism and platelet size in atopic subjects.

The release and metabolism of endogenous arachidonic acid (AA) in physiologically activated platelets obtained from 11 atopic patients with allergic rhinitis and/or asthma was compared to that of sex- and age-matched nonatopic controls. Prelabeled [3H]AA platelets were stimulated with thrombin or collagen and the amount of free [3H]AA and radiolabeled metabolites released were measured by high-performance liquid chromatography. The results obtained indicate that although the incorporation of [3H]AA into platelet phospholipids and total release of 3H-radioactivity upon stimulation were comparable in the two groups, the percentage of 3H-radioactivity released from platelets as free AA was significantly lower (P less than 0.

Detection of human auto-anti-idiotypic antibodies (Ab2). II. Generation of Ab2 in atopic patients undergoing allergen immunotherapy.

The present study demonstrates the cross-reactivity of a murine monoclonal antibody (MoAb) directed against purified ragweed antigen E (AgE) with human Ab1. This antiragweed AgE MoAb (clone SC7H.1G, IgM kappa) was used to detect Ab2 in the sera obtained from the three groups of subjects.

Detection of human auto-anti-idiotypic antibodies (Ab2). I. Isolation and characterization of Ab2 in the serum of a ragweed immunotherapy-treated patient.

This study documents, by means of both solid and liquid phase assays, the presence of anti-idiotypic antibodies (Ab2) in the serum of one allergic individual undergoing ragweed immunotherapy. Serum from this individual was collected and F(ab')2 fragments specific for ragweed antigen E (AgE) were prepared (Ab1). These AgE-specific F(ab')2 Ab1, following absorption with normal immunoglobulin, were studied for their capacity to specifically bind autologous Ab2.

Characterization of the neutrophil respiratory burst in atopy.

Activated neutrophils may play a part in atopic disorders. In these studies, neutrophils were obtained from atopic and nonatopic adults for assessment of respiratory-burst activity. Superoxide production was measured in the resting state and after stimulation with phorbol myristate acetate, formyl-methionyl-leucyl-phenylalanine (f-met-leu-phe), or calcium ionophore A23187.