The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.

Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma

IgE in the diagnosis and treatment of allergic disease

Traditionally, the concept of allergy implied an abnormal response to an otherwise benign agent (eg, pollen or food), with an easily identifiable relationship between exposure and disease. However, there are syndromes in which the relationship between exposure to the relevant allergen and the “allergic” disease is not clear. In these cases the presence of specific IgE antibodies can play an important role in identifying the relevant allergen and provide a guide to therapy. Good examples include chronic asthma and exposure to perennial indoor allergens and asthma related to fungal infection. Finally, we are increasingly aware of forms of food allergy in which the relationship between exposure and the disease is delayed by 3 to 6 hours or longer. Three forms of food allergy with distinct clinical features are now well recognized. These are (1) anaphylactic sensitivity to peanut, (2) eosinophilic esophagitis related to cow’s milk, and (3) delayed anaphylaxis to red meat. In these syndromes the immunology of the response is dramatically different. Peanut and galactose α-1,3-galactose (alpha-gal) are characterized by high- or very high-titer IgE antibodies for Ara h 2 and alpha-gal, respectively. By contrast, eosinophilic esophagitis is characterized by low levels of IgE specific for milk proteins with high- or very high-titer IgG4 to the same proteins. The recent finding is that patients with alpha-gal syndrome do not have detectable IgG4 to the oligosaccharide. Thus the serum results not only identify relevant antigens but also provide a guide to the nature of the immune response

Immunoglobulin G; structure and functional implications of different subclass modifications in initiation and resolution of allergy.

IgE and not IgG is usually associated with allergy. IgE lodged on mast cells in skin or gut and basophils in the blood allows for the prolonged duration of allergy through the persistent expression of high affinity IgE receptors. However, many allergic reactions are not dependent on IgE and are generated in the absence of allergen specific and even total IgE. Instead, IgG plasma cells are involved in induction of, and for much of the pathogenesis of, allergic diseases. The pattern of IgG producing plasma cells in atopic children and the tendency for direct or further class switching to IgE are the principle factors responsible for long-lasting sensitization of mast cells in allergic children. Indirect class switching from IgG producing plasma cells has been shown to be the predominant pathway for production of IgE while a Th2 microenvironment, genetic predisposition, and the concentration and nature of allergens together act on IgG plasma cells in the atopic tendency to undergo further immunoglobulin gene recombination. The seminal involvement of IgG in allergy is further indicated by the principal role of IgG4 in the natural resolution of allergy and as the favourable immunological response to immunotherapy. This paper will look at allergy through the role of different antibodies than IgE and give current knowledge of the nature and role of IgG antibodies in the start, maintenance and resolution of allergy

USE OF DIMETHYL SULPHOXIDE FOR PRESERVING CORNEAL TISSUE*t

SINCE it was discovered by We have been concerned with retaining the viability of corneal tissue after freezing and in the past Our need to maintain a supply of stored corneae for keratoplasty prompted us to set up an experiment to evaluate the usefulness of dimethyl sulphoxide in preserving the viability of cornea during freezing. Experiment.-Our purpose was to compare the preserving qualities of dimethyl sulphoxide with those of glycerol during the storage of corneal tissue at -64°C. Concentrations of 15 per cent./V glycerol and 15 per cent./V dimethyl sulphoxide, both in Hank's balanced salt solution, were used. Corneal material from rabbits, cats, and dogs was obtained from eyes removed as soon as possible after death, usually within 30 minutes. Pig and ox corneae were obtained from eyes removed approximately 4 hours after death. Method.-The eyes were soaked for 10 minutes in a balanced salt solution containing 200 units penicillin and 75 mg. streptomycin per ml. Then the corneae were removed and washed again in balanced salt solution and antibiotics. Each

Residential exposure to plasticizers and its possible role in the pathogenesis of asthma.

The plasticizer di(2-ethylhexyl) phthalate (DEHP) is widely used in building materials. DEHP is identified as the major plasticizer exposure in dwellings. We provide evidence that inhalation exposure to DEHP as aerosols adsorbed to particulate matter is as important, or more important, than vapor phase exposure. The particulate inhalation exposure to DEHP is considered to be significant due to its low clearance and extensive penetration into the pulmonary region. DEHP is capable of creating high local concentrations in the airways at the deposition site with subsequent local effects. The proposed mechanism of effect states that mono(2-ethylhexyl) phthalate (MEHP), the primary hydrolysis product of DEHP, mimics the inducing prostaglandins (PG) PGD(2), 9alpha,11betaPGF2, and PGF2alpha, and thromboxanes in the lungs, thereby increasing the risk of inducing inflammation in the airways, which is a characteristic of asthma