Allergy is when the body's immune system overreacts when exposed to substances such as dust, pollen, animal hair or metals. Millions of people across Europe are affected. The pharmaceutical industry is researching the complex nature of allergy in order to develop medicines to relieve the misery it causes.
Allergy is a hypersensitivity of the body’s immune system in response to exposure to specific substances or antigens, such as varied as dust, pollen, saliva, skin particles, feathers, hair or urine of pets, insect stings and bites, certain types of food, ingredients in medicines, contact with metals such as nickel, or exposure to plants like poison ivy. The reaction occurs on second contact with an antigen and can result immediately - generally called Type I hypersensitivity and is immunoglobulin E (IgE) mediated - or may be delayed – generally called Type IV or cell-mediated hypersensitivity.
In most cases, the cause of the allergy is otherwise harmless to the body. The term allergy (from the Greek nouns “allos”, meaning altered state, and “ergon”, meaning reaction or reactivity) was first coined in 1906 by the Viennese paediatrician Clemens von Pirquet. He had observed altered reactions in his patients which he put down to the influence of external factors on the immune system. The most severe form of allergy is anaphylactic shock, which is a medical emergency.
The primary causes of allergies related to dust are the excretions of dust mites. Tree and grass pollens are the most common cause of hay fever (seasonal allergic rhinitis). They may also cause asthma and bronchitis. Allergies to pets often cause inflammation of the lining of the eyes (conjunctivitis) and reactions of the nose (rhinitis). Skin contact with pet-derived allergens may lead to itching and hives. Medicines like analgesics and antibiotics can occasionally cause an allergy. Allergic reactions to insect stings can be very severe, including dizziness, massive swelling of the joints, inability to breathe or speak, fainting and, in rare cases, death. While allergies to food can be worrisome, it is worthy to note that deaths are extremely rare. Fewer lives are lost in this way than from insect stings and lightning strikes combined.
Eczema, or atopic dermatitis as it is sometimes called, occurs in individuals who are sensitive to allergens in the environment which are harmless to others. In mild forms, the skin is dry, hot and itchy, whilst in more severe forms the skin can become broken, raw and bleeding. Although it can sometimes look unpleasant, eczema is not contagious. In atopy, which is thought to be a hereditary condition, there is an excessive reaction by the immune system producing inflamed, irritated and sore skin.
In Europe, disorders associated with allergy affect more than 25 million people, with a steady increase in prevalence. Up to 15 per cent of all children of school age have a type of eczema, along with about eight per cent of the adult population. In identical twins, if one twin suffers from atopic eczema, the likelihood of the other twin also developing the disease is around 75 per cent. In non-identical twins, the likelihood is 30 per cent. It must be stressed, however, that eczema is a highly individual condition, which is why it is so difficult to find a “cure-all”.
Administering increasing quantities of allergens in sensitised patients was established in the first half of the 20th century. “Vaccination” – also termed “allergenspecific desensitisation” or immunotherapy - with different antigens has been subsequently used to desensitise patients with allergic rhinitis, conjunctivitis, asthma or insect sting allergy. In the past 20 years, recombinant DNA technology has provided the tools for large-scale production of well-defined purified allergens. Until very recently, there was no clear understanding of the underlying mechanisms of action after “vaccination”. It is now widely held that the changes which lead to such clinical improvement as are seen are mediated by changes in T-lymphocyte function. However, while promising for the future, this kind of treatment is not yet at a stage of maturity.
Common medicines used to treat allergic reactions are analgesics to reduce the pain, anticholinergic medicines and adrenaline as decongestants, and antihistamines to alleviate or stop histamine-induced inflammatory responses. Beta-agonists are widely used as bronchodilators in the treatment of asthma. In more severe cases of skin or airways allergy and inflammation, corticosteroids are used either topically or systemically.
The shift to inhaled corticosteroids has dramatically improved their safety profile, as scientists have come to understand more about how they work. Furthermore, patients may be treated with mast-cell stabilising agents. Treatment with theophylline plays a role in extrinsic asthma. While all of these medicines are effective in providing symptomatic relief, they do not address the underlying disorder.
In atopic eczema, apart from ways of minimising environmental allergens commonly found in the home, treatments include wet-wrap dressings in acute cases, emollients to maintain skin hydration, as well as oral histamines and topical steroids to reduce inflammation. In severe cases, oral steroids are also prescribed. If a baby’s parents, brothers or sisters have atopic allergies, it is recommended that highly allergenic foods be avoided in the first months of life. Breast feeding has been shown to protect from or delay the development of the condition. In 2004, the introduction of topical immuno-modulators applied as ointments or creams represented the first new treatment options for childhood eczema in 40 years.
Recently, a new type of therapy which reduces circulating IgE has been launched for the treatment of severe allergic asthma.
The specific receptor responsible for the physiological role of histamine was identified in the 1960s. The discovery of the H1 receptor was followed by the discoveries of the H2 and H3 receptor in the two subsequent decades. In 2000, researchers were able to demonstrate the existence of a fourth member of this receptor family. One possible role for the H4 receptor is in the histamine-induced reaction of mast cells. A series of histamine H4 receptors are being investigated for potential application in the treatment of allergic disorders, including asthma.
New data on the role of the cytokines (molecules released in an immune response) interleukin-4 and interleukin-5, which either sustain inflammation in the tissue or are required for the generation of immunoglobulin E, have led to the development of soluble interleukin-4 receptor and monoclonal antibodies against interleukin-5 and an antibody toward immunoglobulin E (IgE). Research has also lead to an appreciation of the crucial role played by the Th2 subset of T-cells and their corresponding cytokines in allergic diseases.
For some 20 years, it has been thought that cytokines have a critical role in the onset and development of clinical asthma, but evidence to confirm this has been lacking. In 2007, researchers reported that targeted treatment with a compound that is considered to be an inhibitor of interleukins-4 and -13 in the lung could substantially diminish the symptoms of asthma. These findings will breathe new life into the debate about the role of the Th2-cytokine cascade in asthma pathogenesis and how best to design medicines to attenuate their effects.
The introduction of leukotriene inhibitors represents the first new class of medicines for the treatment of asthma in twenty years. Another strategy is to prevent the migration of effector cells, such as mast cells, eosinophilic white blood cells and Th2 cells, via chemokine receptor antagonism with suitable small molecules. Chemokines mobilise and activate white blood cells and so help the body tackle an allergic reaction. The chemokine receptors CCR3, CCR4, and CCR8 are preferentially expressed by these cells and therefore represent promising therapeutic targets. Antagonists can be antibodies, antisense, and protein-based inhibitors.
To reduce the symptoms of perennial allergic rhinitis, research is also focusing on antihistamines and other new approaches such as purine receptor P2Y2 agonists, which are administered intranasally. In childhood eczema (atopic dermatitis) and asthma, mycobacterium vaccae-derived products are being tested in Phase 3. They are given as intradermal injections which should stimulate the immune system.
In allergy, the processes that lead to excessive allergen-specific IgE production and the activation of effector cells are highly complex and diverse. An optimal treatment strategy would permanently modify the underlying inflammatory process with long-term alleviation of symptoms. The principal challenge for approaches to block IgE is to inhibit its activity without inducing mast cell degranulation. Meanwhile, monoclonal antibodies with a lower incidence of anaphylactic shock have been developed.
New strategies for immunotherapeutic “vaccination” include methods of modifying allergen recognition by the patient’s own immune system. Such techniques will include allergen modification, immunisation against allergen genes, controlled immunostimulation, and peptide immunotherapy. Non-allergen specific targets including receptor, cytokine and IgE targets will most probably complement specific immunotherapy. Additionally, vaccines against IgE itself are expected to complement the therapeutic range of anti-allergic treatments in the future.