An allergy is a reaction, usually between antibodies, or specific proteins, manufactured by the body of an allergic person and foreign proteins inhaled or ingested by that person. The result is a release of allergic mediators, humoral substances produced by the body that are capable of causing such undesirable effects as itching, redness, runny nose, and wheezing. Sometimes, instead of causing the re­lease of chemical mediators, the foreign substances that are present produce a reaction of lymphocytes and macrophages —a cellular rather than a humoral response. Any attempt to understand allergic reactions raises numerous important questions. What makes someone "allergic," that is, capable of reacting to inhaled or ingested proteins, or both, in a potentially dangerous way, whereas someone else has no reaction at all? How is this allergic potential passed from generation to generation? How is a person’s ability to be allergic modulated? Can this potential be controlled? How does this allergic potential change as people change? Can they "grow into" or "out of" allergies, and can they influence whether they do this by what they eat and breathe? The answers to these questions have much to do with whether a person is allergic. But just as many questions remain about specific allergic conditions. For example, why do some people have rashes while others have hay fever, and still others, asthma? Why do young children often develop eczema first and then rhinitis, finally becom­ing asthmatic? Is medical science capable of halting the progression from one allergic problem to another? What is different about an allergic person who experiences only hay fever, and one who suffers from asthma? Why are an asthmatic’s lungs sensitive to environmental stimuli, while the sensitivity of the sufferer from hay fever is confined to the nose? What about the drugs that are now used for allergic disease? Do we know the optimal doses of drugs for skin rashes, rhinitis, and asthma? How do physicians go about weighing drug risks against benefits? What is the theoretical basis for the many pharmacologic agents used today?

Some scientists specialize in research on the inheritance of allergy characteristics. They study people, examining traits and how these people pass the traits on to their children. They study such char­acteristics as the presence of asthma and allergic rhinitis, or eczema, trying to establish the frequency with which these diseases appear in succeeding generations.

Research in humans takes several different avenues. A major area involves the observation of normal body functions and determination of which ranges are to be considered normal and which are devia­tions. A great many people must be studied under a variety of con­ditions before researchers can determine what is normal and what is not among people subjected to various changes in their environments. Once the definition of what is normal has been established, the next step involves observing and comparing differences between normally functioning people and those who are suffering from specific abnormalities. Another major area concerns the pharmacologic modification of disease states —how drugs affect the way people function, as well as how the drugs can be used to improve people’s health. In short, human investigation is a heterogenous subject encom­passing the definition of normal function, observation comparing normal and abnormal functions, elucidation of the way environmental factors affect people, and investigation of how pharmacologic agents modify physiology.

While much creative energy is being devoted to basic research in the mechanisms that underlie the immune response, other allergic disease entities are being studied. We now shift our focus from the laboratory to an examination of some specific diseases currently being studied. Although asthma is usually defined as a reversible obstruction of the air passages, knowledge of the structural changes that occur in asthma has been gained through examination of the lungs of people who have died of severe, nonreversible asthma. An asthmatic tends to have overly reactive, smooth muscles in the bronchial tree. Muscle constriction, increased mucous secretion, and swelling of the lining of the air passages all contribute to attacks. Secretions occasionally become so thick that obstruction is complete and fatal. The air passages, or airways, are controlled to some extent by nervous innervation, in which the signals for muscle relaxation and those for constriction are unbalanced. The nervous system itself, or the receptors of the signals to the bronchial tree, or both, may be faulty in individuals with asthma. Understanding the possible defect in control mechanisms involves vigorous research. The term nervous, as used in this context, does not imply psychological or psycho­somatic involvement but rather refers to the autonomic nervous system which controls involuntary processes. The effect a person’s psycho­logical makeup has on asthma is a subject for later discussion. During an asthma attack, special chemicals called mediators are released into lung tissue and the circulatory system that promote constriction of the smooth muscles, secretion of mucus, and swelling of tissue. Scientists are expanding the knowledge of these mediators — where they are produced, what effect they have, and how that effect is achieved. Another aspect of this research concerns the mechanisms involved in quelling asthma attacks by inactivating or modifying the mediators. The first step in searching for the optimal therapy is observation of the changes that occur in asthma. Medication that helps relax bronchial muscles or that halts the release of an allergic mediator is discussed in other chapters. Much research effort has been devoted to study of the chemistry of these drugs, with an eye to improving their therapeutic properties while diminishing side effects. Another aspect of research in therapeutics is the leap from the laboratory, where the structure and function of a drug are first observed, to clinical situations, where the reactions of volunteers are evaluated in ascertaining the drug’s safety and effectiveness. Other research focuses on measuring the active drag in the body fluids in an attempt to determine optimal dosages. In summary, asthma research efforts are aimed at delineating the pathological changes that occur during and after an asthma attack and a better understanding of the pharmacologic modification of the problem.

Much of the research today consists of studies of allergies in animals. Because certain species develop allergic sensitivity to specific chemicals, they can be used to study the process of allergic sensitiza­tion. Research in animals can also be used to develop new methods of desensitization. Animals are necessary in tests of new drugs, since all new pharmacologic agents must somehow be proven safe before they can be tested in humans.

Rhinitis is inflammation of the nose. Allergic rhinitis occurs when an individual who is allergic to a foreign antigen, and who has anti­bodies against the antigen (bound to mast cells of the nasal mucosa), inhales the antigen. When antigen and tissue-bound antibody inter-react, mediators are released by the mast cells. These mediators cause dilatation of the blood vessels, leakage of fluid, and swelling of membranes, as well as increased production of mucus. Recent work has led to a clearer understanding of the mechanisms in the nasal pas­sages that control blood vessel constriction and dilatation. Research in recent years has clarified somewhat the mechanism of mucociliary clearance. Propelled by microscopic, hairlike protrusions called cilia, mucus continually cleanses the nasal membranes. Scientists know that many physiologic factors are involved. Methods of measuring changes in nasal airway resistance are being perfected, which means that the way in which foreign antigens affect the nasal passages should soon be better understood. Improved understanding of the allergens responsible for rhinitis is a research priority for the future, and the specific reactive parts of many antigens need to be defined. House dust, for example, is a mixture of poorly characterized components. The molecular identifica- tion of spores, pollen, and animal dander has just begun. Identification techniques must become more chemical-oriented. Which treatment methods cause the number of antigens to decrease? What is the optimal level of environment control? What are the most efficient and effective methods for removing danders, molds, and pollen from the environment? Someday allergy researchers will have to address themselves to these and similar questions. The treatment of allergic rhinitis pharmacologically is in the early stages as well. Medications that compete with the mediator histamine at the histamine receptor sites of the nasal mucosa are known as antihistamines. Decongestants are used systematically and topically to shrink blood vessels and thereby decrease fluid leakage and the swelling of membranes. Although effective only for brief periods, topical agents, if overused, can aggravate the nasal mem­brane swelling already underway. Each of the six families of anti­histamine has a different, fundamental chemical structure. If a drug from one family is ineffective in a particular patient, a drug from another family may be tried and found effective. The best-known side effects of antihistamines are drowsiness, dryness of the mouth, and blurred vision. Sometimes combinations of systemic decongestants and antihistamines are used with good results. Topical corticosteroid sprays are a potent adjunct for more serious cases of rhinitis. They are commonly used for brief periods, however, since some degree of systemic absorption occurs, and adrenal gland suppression, a con­sequence of corticosteroids usage, is a potential adverse effect. The modification of allergic rhinitis by medication is still of un­certain value. Scientists as yet know little of the relationship of dosage to response for either decongestants or antihistamines. Physicians prescribe the drags at dosage levels that appear to relieve distress without adverse effects, but neither they nor scientists have determined the optimal dosage for a given individual. Finally, the development of tolerance to these drugs and how long topical corti­costeroids can be used safely are still a mystery.

The Hymenoptera group of insects consists of yellow jackets, bees, wasps, and hornets. Stings from these insects produce dramatic, sometimes life-threatening, reactions in some people. To prevent these reactions, susceptible patients have for years been instructed to carry Adrenalin or antihistamines for immediate use when they are stung. Susceptible people have for some time also taken allergy immunotherapy injections of whole-body extract to obtain protection from future stings. In recent years, research has demonstrated that venom itself, rather than whole-body extract, is most beneficial for immuno therapy; and venom skin tests can now be given to high-risk individ­uals. Those identified as being at high risk can be treated using venom injection therapy, which appears to confer blocking antibody and probably changes mast-cell sensitivity, so that people are less likely to have an adverse reaction if stung again. Although research has led to improved therapy for stinging insect allergy, important questions remain to be answered. Are some people truly protected after the first sting, so that subsequent stings will be harmless even though the initial sting had serious consequences? What is the optimum period for immunotherapy? Can physicians assess a person’s clinical response in any way besides another sting?

What about treatment in the future? What techniques do scientists use to develop new methods of treatment? How can they be certain of the safety of a treatment for humans? What are the requirements of proper research? What constraints are placed on research, con­straints that sometimes delay the marketing of new drugs? All these questions are relevant to allergy research. Both patients and physicians needs to be better informed about this research, which involves population studies, laboratory studies, experiments using animals, and finally, testing in humans.

The description and pharmacologic modification of disease are of paramount interest to everyone in­volved—clinical practitioners, scientists, and patients alike. We must not, however, allow the fight against disease to lead to abuse of human volunteers or to the development of potentially harmful remedies produced for large-scale consumption. Protecting human volunteers is, or should be, the concern of all researchers. Volunteers deserve a thorough explanation of the risks and possible consequences of research. To ensure that subjects receive proper treatment, most research centers have a "human-subject review committee" composed of physicians and lay individuals who judge prospective research projects to determine whether the projects are safe for humans and whether they are appropriate for human participation. These com­mittees make sure that research is explained to volunteers —both verbally and in writing—and that both written and verbal consent are obtained before a person participates in a scientific study. Most review committees assess projects on a continuing basis. In general, universities and research institutions do not sanction research in humans that does not meet the standards of the committee involved. Similarly, reputable scientific journals have policies of not publishing the results of experimentation in humans unless the research has been reviewed and approved. One aspect of the research review process is that of new drugs. Although new drugs offer the possibility of solving old problems, they also pose serious threats if not adequately evaluated ahead of time. The U.S. Food and Drug Administration (FDA) is charged with investigating and licensing drugs in the United States, which involves the strict regulation of tests of new products and clinical investigators. Usually, the investigators are physicians who wish to use volunteers in clinical trials of new drugs not yet approved. To be approved, a new drug must undergo several phases of in­vestigation. The first phase is that of experiments in animals. In this phase, laboratory animals are studied so that obvious toxicity can be ruled out. If a drug passes this stage successfully, it is cleared for the first phase of human research and is administered to a small number of normal human volunteers. This part of the testing is designed to ascertain a drug’s safety before its use for specific diseases. From this phase the drug moves to phase 2 of the investi­gation, where it is studied in a few human subjects with health problems which, it is believed, the drug under investigation will relieve. The drug is tested for safety and effectiveness af specific dosage levels. Information about the best dosage and frequency of administration is often determined in this phase of research. The next phase, phase 3, involves testing on a greater scale, to gain information about the effectiveness and possible side effects of the drug under study. The final phase, phase 4, is conducted after the drug has been marketed, and involves large-scale, long-term testing of the drug. It is easy to understand why many years may pass before all phases of the testing of a new drug have been completed to everyone’s satisfaction, both the FDA’s and the manufacturer’s. This period is often frustrating for patients and physicians, but it is essential if mistakes with potentially dangerous consequences, are to be avoided.

Allergic skin disease is another research challenge. Atopic derma­titis, or eczema, is an itchy rash which typically starts in early childhood. It is usually, but not always, found in people with other allergic manifestations, such as asthma or rhinitis. Sometimes the disease can be treated successfully by removing or avoiding antigens in the environment, but it is frequently chronic. Although researchers characterize allergic skin disease as an itchy, scaly red eruption, they know little else about its causes. The extent of their knowledge is that many individuals afflicted by it have defects in cellular immunity, for example, abnormal T cell numbers or abnormal white blood cell mobility toward known chemical attractants (chemotaxis), or both. What interests many scientists are the natural history of atopic dermatitis and whether the imposition of environmental controls early in a patient’s life can alter that history. The use of topical corticosteroids (to decrease inflammation), skin softeners, and anti­histamines (to decrease itching) are all being studied. Many individuals, both allergic and nonallergic, suffer from urticaria, commonly known as hives. Urticaria is an itchy skin eruption characterized by wheals, or small welts, on a flared, red base. Angioedema is a disease characterized by, among other things, swelling of the deep skin layers. Researchers now know that hives occur when mast cells in the skin release the mediator histamine. Histamine causes dilatation of blood vessels, leakage of fluid into the skin layers, and itching. The result is engorgement, wheal formation, redness, and itching. Research has confirmed that many different stimuli may contribute to the production of hives. Such immunological reactions as those that provoke allergic asthma and rhinitis can become concentrated in the skin, appearing as urticaria; but nonimmunological factors can also trigger the release of histamine by mast cells. Cold; heat; sunlight; systemic disease (for example, rheumatic disease and thyroid disease); certain viral infections; inherited conditions; and possibly psychological factors —all are physical conditions or factors that can provoke hives at certain times in susceptible individuals. Although histamine has been determined to be the main mediator responsible for hives, other, so-far-undefined mediators probably remain to be discovered. Researchers do not, for example, know how such a variety of nonimmunologic events as physical stimuli, infection, and psychology affect mast cells. What, besides nonimmune events, happens to make mast cells produce histamine, and why are some people and not others stimulated by specific stimuli to develop hives?