Future challenges and opportunities in food allergy

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There have been substantial recent advances in the basic science of food allergies. There has been a broadening of the concepts of food allergy, away from simple focus on IgE and towards a consideration of overall mucosal tolerance. Could a genetic tendency to high IgE responses simply make adverse immunological reactions to foods more noticeable? As many practitioners are uncomfortable without supporting diagnostic tests, non-IgE-mediated allergy may remain a difficult and controversial clinical area. Absence of specific tests can also lead to overdiagnosis of allergies, or inappropriate blaming of non-specific symptoms on food allergy - as can be seen on large numbers of Internet sites.

The advances in basic research, which encompass both gut inflammation and allergy because of shared tolerance mechanisms, may explain some of the recent demographic shifts in allergy. Inappropriate infectious priming of the nascent mucosal immune system may affect the development of normal gut tolerance. Handling of the newborn infant has been shown in one study to affect allergy in young adulthood.168 There is also clear evidence that the early gut colonization of allergic infants differs from those without aller-gies.169 One study which thus demonstrated great promise was the recent placebo-controlled trial by Isolauri's group in which neonatal administration of a probiotic organism (Lactobacillus GG) led to a 50% reduction in the later development of eczema, although without alteration of systemic IgE responses at either 1 year or 4 years.10,11 The use of probiotics at birth may be more effective than later, as it may allow stable long-term colonization, which does not occur if probiotics are administered even at the age of 10 months.170 As interaction between bacterial exposures in early infancy and genetically determined responses in innate immune cells may determine whether an adequate tolerogenic response occurs, probiotics may represent an important new class of immunomodulators, particularly if used in early infancy. However, much work remains to be done to determine the dosage, timing and nature of the probiotics to be used.9 An alternative approach to programming a Th1 or tolerant response is to use bacterial products, such as mycobacterial peptides. A suspension made from killed Mycobacterium vaccae inhibited airway eosinophilia in a murine model of allergy, through the induction of an allergen-specific regulatory T-cell response, dependent on TGF-P and IL-10.171 Such therapy may offer a refined alternative to probiotic therapy, in which regulatory T-cell generation is the therapeutic goal. However, much safety information needs to be accumulated, and placebo-controlled trials completed, before such therapies can become more widely used.

There are other exciting potential therapies for food allergies, some of which have been subject to clinical trials in humans.172 The area of immunotherapy is well established for systemic allergies such as bee-sting allergy, and has depended on increasing the dose of antigen gradually until an allergy-suppressing Th1 response is made. For food allergies, the use of small peptides, foods with altered protein sequences, DNA immunizations and IgE-blocking agents represent future targets for immunotherapy. For small peptide vaccines, an antigenic peptide is sequenced and synthetic 10-20 amino acid portions are then produced, covering the entire protein sequence. While able to block IgE binding sites, they are not long enough to cross-link IgE on mast cells. Food proteins can also be engineered, which are able to bind to T cells but not mast cells. In recent studies, the major peanut proteins Ara h1, ara h2 and ara h3 have been purified, their T-cell and IgE-binding domains elicited, and mutations made in the IgE-binding domain.173

Future challenges and opportunities in food allergy 341

While much of the data outlined above suggests that IL-5 responses may be critical in food allergies, the therapeutic credentials of a highly promising anti-IL-5 monoclonal antibody were dented by a study in asthmatic patients, in which peripheral eosinophilia was reduced, but without any significant modulation of the late broncho-constrictor response in asthma.174 The results of clinical trials in severe food allergy will be extremely interesting, provided that such agents remain in clinical development after such a setback. Similarly, a monoclonal antibody that blocks eotaxin chemoattraction may prevent the migration of eosinophils into the mucosa in response to food allergens.

Relevant therapeutic antibodies that have reached clinical trials include two anti-IgE monoclonals. The humanized monoclonal anti-IgE rhu Mab E-25, which binds to the constant region of IgE, and thus prevents IgE binding to its high- or low-affinity receptors, has shown promising effects in allergic asthma.175 In a potentially very important study, the humanized IgG1 anti-IgE monoclonal TNX-901 showed clear promise in the treatment of established peanut allergy.113 Using a dose of 450mg, given subcutaneously at 4-weekly intervals for 16 weeks, treated patients showed an increase in reaction threshold to peanut from 178 to 2805g, essentially the difference between half a peanut and nine peanuts. A dose-dependent increase in reaction threshold was seen from 150-450mg doses. This represents a clinically worthwhile increase in reaction threshold, and would substantially reduce the chances of inadvertent consumption of sufficient peanut to trigger anaphylaxis.

In addition to such radical advances in therapy, one future challenge in the field of food allergy will be provided by the advent of genetically modified foods, which have so far an unknown propensity for causing allergic reactions. Genes may be introduced into plants either through use of a bacterial vector or by direct physical methods, while alternatively naturally occurring genes may be silenced.176 Important lessons have already been learned. In an attempt to increase the nutritional component of cattle feed, the brazil nut 2S albumen protein was introduced transgenically into soy. Unfortunately, this protein turned out to be a major brazil nut allergen, and indeed the transgenic soy was able to induce hypersensitivity in brazil nut-allergic patients.177 Therefore, avoidance of similar adverse events for the future must be minimized by appropriate predictions. Recognition of potentially allergic molecules can be attempted, on the basis that many are large and heavily glycosylated molecules that are resistant to breakdown by proteolysis or digestion.178 However, some antigens, particularly fruit allergens, do not follow these rules. One suggestion has thus been to test proteins from genes considered for transgenic insertion by immunoassay against sera from a variety of allergic patients.179

Even if genetically modified foods do not reach the market place in large amounts, there still remains the major challenge of ensuring that modern food manufacturing processes do not leave food-allergic patients at risk of anaphylaxis. Taylor et al180 have published an important call for the determination of the minimal doses of antigen required to trigger reactions, and for international legislation to ensure that food manufacturers do not exceed these doses. The dietary exposure of infants and young children have changed out of all recognition within developing countries in the past decades, at a time when their infectious exposures have also been altered in a way that evolution has not prepared them for. The challenge of preventing food-allergic deaths is one in which food manufacturers may have to work together with basic scientists, and in which microbiologists may have as much to offer as immunologists. These are interesting times.

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