DEVELOPMENT OF TOLERANCE AND TREATMENT OF HYPERSENSITIVITY

VIII. DEVELOPMENT OF TOLERANCE AND TREATMENT OF HYPERSENSITIVITY

A. Development of Tolerance

Immunologic tolerance means immunologic nonreactivity to specific antigens. Normal immune responses fail to develop when antigenic substances come into contact with immu- nocompetent tissues in early fetal life and perhaps also in early childhood. This type of tolerance cannot be transfered to another individual by either serum or cells. The mecha- nism of such ‘‘instant’’ tolerance is, so far, unknown (Miller and Claman, 1976). The development of ‘‘instant’’ tolerance for contact allergens may partly be due to lack of interleukin 2 at the time of challenge (Malkovsky and Medavar, 1984). In contact allergy, tolerance is also mediated by suppressor T cells, which can inhibit either the afferent limb of sensitization or the efferent (elicitation) phase (Claman and Miller, 1980).

Acquired tolerance can be achieved either by giving very large doses of antigen, resulting in high zone tolerance, or by giving small doses of antigen below the immuniza- tion dose, leading to low zone tolerance. Acquired tolerance is induced by intravenous or peroral administration of allergens. The induction of high-dose tolerance can be used in experimental work with laboratory animals, but in clinical work with humans the low- dose method is recommended. Obviously the disappearance of many IgE-mediated food allergies during childhood express low zone tolerance rather than peroral hyposensitiza- tion. Another example of low zone tolerance is the disappearance of nickel allergy in patients with total hip prosthesis.

Pseudotolerance is seen in patients with continuous high allergen administration and, consequently, neutralization of antibodies. Patients allergic to penicillin can be treated with high doses of penicillin without clinical signs of allergy.

Certain factors, called adjuvants, increase the host response to allergens. Many bac- teria may be adjuvants in the development of immediate allergies. Bordetella pertussis vaccine, for example, increases the IgE response and also the sensitivity of the organism to chemical mediators such as serotonin and histamine in laboratory animals (Reed et al., 1972; Pauwels et al., 1983). Freund’s complete adjuvant, containing killed mycobacteria, is used in the induction of contact allergy in guinea pigs (Magnusson and Kligman, 1969).

Other factors also influence the development and grade of allergy. In atopic derma- titis, ultraviolet (UV) light decreases inflammation, erythema, and itch in over 90% of cases (Hannuksela et al., 1985). Ultraviolet B (280–320 nm) seems to be more efficient than longer wavelengths. It is also beneficial in chronic urticaria, especially in dermograph- ism, and cholinergic and cold urticarias (Hannuksela and Kokkonen, 1985).

Ultraviolet radiation is also capable of modifying delayed-type hypersensitivity reac- tions. There are both local and distant alterations, the former resulting as a direct effect

(1985) postulated that UV light causes at least two separate alterations that influence dis- tant immune responses. The first is a reversible ‘‘inflammatory’’ alteration that affects delayed hypersensitivity, and the second is an afferent suppression of contact allergy and the production of antigen-specific suppressor T cells. The most active wavelengths are those below 280 nm, indicating that there must be some soluble substance that acts directly on Langerhans cells or other cells involved in the presentation of haptens. Psoralens and long-wave (320–400 nm) UV light (PUVA) have similar effects on contact allergy (Mori- son et al., 1981).

Cyclophosphamide and other drugs inhibiting cell proliferation may influence the induction of contact allergy and the development of allergic contact dermatitis (Andersen, 1985).

B. Treatment of Hypersensitivity

1. Avoidance Diets Dietary restrictions have been widely used for real food allergy. They have also been used

as a diagnostic and therapeutic tool in chronic and recurrent urticaria. Good or excellent results have been reported in 31–81% of the patients in these experiments (Michaelsson and Juhlin, 1973; Ros et al., 1976; Warin and Smith, 1976; Lindemayr and Schmidt, 1979; Gibson and Clancy, 1980; Rudzki et al., 1980; Kirchhof et al., 1982; Verschave et al., 1983). August (1979) successfully treated 22 urticaria patients with disodium cromogly- cate (DSCG) and an exclusion diet. The studies mentioned above were all uncontrolled, and therefore the results are open to doubt.

In chronic asthma, the avoidance of tartrazine and benzoates was found to be of no use (Tarlo and Broder, 1982). Genton et al. (1985) reported that in an open trial excluding NSAIDs and food additives from the diet resulted in a favorable response in 6 of 9 asthma- tics and in 14 of 15 patients with urticaria. However, only four patients with urticaria noticed a complete disappearance of the symptoms on the diet alone.

The duration of sensitivity to food additives, whether permanent or temporary, has never been evaluated. For aspirin intolerance it is known that once it has developed it lasts for years, and caution for an indefinite period is advocated.

Wolf and Nicklas (1985) recommended that a sulfite-sensitive patient document the sensitivity on a Medic-Alert tag. Ten years ago, a temporary refractory state was found to follow intake of aspirin in aspirin-induced asthma (Zeiss and Lockey, 1976). Since then, this type of induction of tolerance and treatment of asthma with low-dose aspirin regimens has been used with some success (Chiu, 1983; Stevenson et al., 1982), but long-term aspirin treatment seems to be less effective in severe corticosteroid-dependent aspirin-sensitive asthmatics (Dor et al., 1985).

Five of six patients with aspirin urticaria became tolerant to aspirin after a single dose of 30–515 mg of aspirin (Asad et al., 1983). These five patients remained free of symptoms during the following weeks while taking 650 mg of aspirin daily. We have succeeded in desensitizing some asthma patients with aspirin sensitivity, but our experi- ence with urticaria has been disappointing.

Our experience shows that restricted intake of food colorants and benzoates seldom has any effect on symptoms. Many diets are not only unnecessary but may also be harmful. The patients may become neurotic in rejecting foods that they suspect to contain additives.

cies. The assistance of a properly trained dietician is needed if a long-term diet is planned. The dietary protocols are usually difficult and time consuming to follow in everyday life. Nevertheless, a diet that restricts the excessive intake of additives may be worth trying. This is especially important in sulfite-sensitive persons. A diet that totally eliminates food additives is usually not reasonable.

2. Treatment with Drugs Ortolani et al. (1984) showed that premedication with 800 mg of oral DSCG is capable

of protecting against the effects of challenge with aspirin and tartrazine in patients with urticaria. They also reported that 8 weeks treatment with DSCG ameliorates symptoms caused by foods and additives, compared to placebo. Conflicting results have also been published (Harries et al., 1978; Thormann et al., 1980). Oral DSCG has been found to prevent asthmatic reaction from metabisulfite (Schwartz, 1986). Dahl (1981) reported that oral DSCG protected against an asthmatic reaction to foods but neither oral nor inhaled DSCG protected the patient against bronchospasm caused by aspirin. Oral DSCG is poorly absorbed, and it is suggested that the activity occurs within the gastrointestinal mucosa and that DSCG modifies the way in which food allergens are transfered and metabolized in the gut.

The reactivity to additives is linked to the overall balance of the hypersensitivity disease, for example, asthma or urticaria. If the patient’s condition is poor, symptoms are easily provoked by numerous nonspecific irritants. Food additives are in part also nonspe- cific irritants that may cause symptoms at one time and be without effect at another. This emphasizes the primary importance of the treatment as a whole.

Immunologic contact urticaria reactions may sometimes be widespread, and infre- quently systemic reactions are encountered (von Krogh and Maibach, 1982). Peroral anti- histamines are effective, and in very rare cases systemic corticosteroids may be needed.

Oral aspirin and other prostaglandin inhibitors have been found to prevent diarrhea due to food intolerance (Buisseret et al., 1978). Nonimmunologic contact urticaria reactions are mild, and no treatment is needed. Avoidance of causative agent(s) is sufficient. Irritant and allergic contact dermatitis are treated with corticosteroid creams and ointments.