**5. Immunotherapy for food allergy in AD**

Presently, there are 3 therapeutic approaches for food allergies. In all cases, the allergen should be avoided until proper treatment is administered [9]. In infants and young children, the allergenic food(s) should be excluded from the diet until the allergy is outgrown unless exclusion results in nutritional deficiency or the allergen cannot be avoided; in such cases, active treatment, such as tolerance induction for food allergy (TIFA), is performed [2]. If exclusion cannot be practiced, patients may experience discomfort caused by non-IgEmediated food allergy and atopic dermatitis or reactions as serious as anaphylaxis from repetitive ingestion of the allergenic food(s). However, with the recent advent of TIFA treatment, management of atopic dermatitis has improved remarkably [7].

Clinical tolerance can develop over time; this process is also called "outgrowing" the allergy. Allergies to milk and eggs are common food allergies that are outgrown: 80% of children with milk and egg allergies show tolerance by the age of 3 to 5 years [8]. In contrast, only about 20% of young children develop tolerance to peanuts, and less than 10% outgrow an allergy to tree nuts. However, the persistence of food allergy is variable and depends on the specific food allergen.

#### **5.1 Specific Immunotherapy for food allergy**

Allergen-specific therapies have been investigated to achieve desensitization and/or tolerance to an allergen [34]. Desensitization is defined as a change in the threshold dose of ingested food allergen necessary to cause allergic symptoms. Tolerance is the induction of long-term immunologic changes associated with the ability to ingest a food without showing symptoms and without ongoing therapy. In a recent pilot study [35], subcutaneous immunotherapy (SCIT) was well tolerated in children with milk allergy. Despite its efficacy in treating food allergy as well as allergic rhinoconjunctivitis and venom hypersensitivity, this traditional approach to allergen immunotherapy is impractical and unsafe for the treatment of food allergies because of an unacceptably high rate of anaphylactic reactions in IgE-mediated food allergy [34]. Sublingual immunotherapy (SLIT) has a broad efficacy for the treatment of inhalant allergies. SLIT has been used to treat hazelnut allergy and a life-threatening kiwi allergy. Currently, trials are in progress to evaluate the efficacy of SLIT in treating other food allergies. Traditional Chinese Medicine represents an innovative approach with the potential to treat food allergies although this approach is not allergen-specific. Food Allergy Herbal Formula (FAHF-2) is reported to promote tolerance and protection from anaphylaxis in mouse models. Further, human clinical trials are just beginning and hold promise for future clinical efficacy. Omalizumab is a recombinant, humanized, monoclonal anti-IgE antibody that was demonstrated to significantly increase the threshold peanut protein dose necessary for allergic response in oral food challenge, thereby providing potential protection from accidental peanut ingestion. Clinical trials are in progress to evaluate both anti-IgE monotherapy for food allergy and the use of omalizumab as an adjunct to oral immunotherapy. While this therapy is suitable for IgE-mediated food allergy, it is not applicable for treatment of non-IgE-mediated food allergy. Protection from peanut allergic response has also been demonstrated in a report where rectal immunization with mutated peanut protein allergens protected mice from

formula feeding during the elimination diet in the infant, as described above. Sequential introduction of solid foods should be performed according to the weaning schedule.

Presently, there are 3 therapeutic approaches for food allergies. In all cases, the allergen should be avoided until proper treatment is administered [9]. In infants and young children, the allergenic food(s) should be excluded from the diet until the allergy is outgrown unless exclusion results in nutritional deficiency or the allergen cannot be avoided; in such cases, active treatment, such as tolerance induction for food allergy (TIFA), is performed [2]. If exclusion cannot be practiced, patients may experience discomfort caused by non-IgEmediated food allergy and atopic dermatitis or reactions as serious as anaphylaxis from repetitive ingestion of the allergenic food(s). However, with the recent advent of TIFA

Clinical tolerance can develop over time; this process is also called "outgrowing" the allergy. Allergies to milk and eggs are common food allergies that are outgrown: 80% of children with milk and egg allergies show tolerance by the age of 3 to 5 years [8]. In contrast, only about 20% of young children develop tolerance to peanuts, and less than 10% outgrow an allergy to tree nuts. However, the persistence of food allergy is variable and depends on

Allergen-specific therapies have been investigated to achieve desensitization and/or tolerance to an allergen [34]. Desensitization is defined as a change in the threshold dose of ingested food allergen necessary to cause allergic symptoms. Tolerance is the induction of long-term immunologic changes associated with the ability to ingest a food without showing symptoms and without ongoing therapy. In a recent pilot study [35], subcutaneous immunotherapy (SCIT) was well tolerated in children with milk allergy. Despite its efficacy in treating food allergy as well as allergic rhinoconjunctivitis and venom hypersensitivity, this traditional approach to allergen immunotherapy is impractical and unsafe for the treatment of food allergies because of an unacceptably high rate of anaphylactic reactions in IgE-mediated food allergy [34]. Sublingual immunotherapy (SLIT) has a broad efficacy for the treatment of inhalant allergies. SLIT has been used to treat hazelnut allergy and a life-threatening kiwi allergy. Currently, trials are in progress to evaluate the efficacy of SLIT in treating other food allergies. Traditional Chinese Medicine represents an innovative approach with the potential to treat food allergies although this approach is not allergen-specific. Food Allergy Herbal Formula (FAHF-2) is reported to promote tolerance and protection from anaphylaxis in mouse models. Further, human clinical trials are just beginning and hold promise for future clinical efficacy. Omalizumab is a recombinant, humanized, monoclonal anti-IgE antibody that was demonstrated to significantly increase the threshold peanut protein dose necessary for allergic response in oral food challenge, thereby providing potential protection from accidental peanut ingestion. Clinical trials are in progress to evaluate both anti-IgE monotherapy for food allergy and the use of omalizumab as an adjunct to oral immunotherapy. While this therapy is suitable for IgE-mediated food allergy, it is not applicable for treatment of non-IgE-mediated food allergy. Protection from peanut allergic response has also been demonstrated in a report where rectal immunization with mutated peanut protein allergens protected mice from

treatment, management of atopic dermatitis has improved remarkably [7].

Nutritional care for the infant is essential.

the specific food allergen.

**5. Immunotherapy for food allergy in AD** 

**5.1 Specific Immunotherapy for food allergy** 

anaphylaxis, Peptide immunotherapy has also been investigated using the immunodominant epitopes of ovalbumin.

#### **5.2 Oral immunotherapy for food allergy: Tolerance induction for food allergies (TIFA) or specific oral tolerance induction (SOTI)**

Oral immunotherapy appears to be effective in inducing desensitization in most patients, as well as oral tolerance in a subset of patients with food allergy [34]. Oral immunotherapy was officially introduced in 1996 in "Monographs in Allergy" [36, 37]. Noh & Lee reported the first successful use of oral immunotherapy for food allergy [38]. They used IFN- as the adjuvant for oral immunotherapy for food allergy and named this therapy "specific oral tolerance induction (SOTI)" in 2003. SOTI was attempted for IgE-mediated food allergy in humans by several investigators [5, 34, 39-43]. The complete SOTI protocol for IgE-mediated food allergy was accomplished by also using IFN- in 2009 by Noh & Lee [6].

Several terms are used to describe oral immunotherapy for food allergy. These terms are based on an escalating dosage of orally ingested foods or food protein to induce immune tolerance for allergenic food(s). Tolerance induction for food allergy (TIFA) was first coined by Noh & Lee in 2003 [38]. Specific oral tolerance induction (SOTI) is currently the more precise term to describe oral tolerance induction for specific allergens in food allergy, and this term, SOTI, was also used first by Noh in 2003 in a report on milk-specific oral tolerance induction for non-IgE-mediated food allergy in atopic dermatitis. Tolerance induction for food allergy (TIFA) is a similar term that has a broader immunologic meaning: to induce immune tolerance for allergenic foods by any method.

### **5.3 IFN- in food allergy and AD**

IFN- was introduced for the correction of Th1/Th2 imbalance, which is the basic immunologic mechanism in allergies, including food allergy [21]. As expected, desensitization for house dust mites was successful when IFN- was used, but was ineffective without IFN- [30]. Moreover, IFN- seemed to show tolerogenic effects in addition to its corrective effects in Th1/Th2 imbalance [7]. Especially, IFN- was absolutely necessary for TIFA for non-IgE-mediated food allergy. Other than SOTI, effective treatment methods for non-IgE-mediated food allergy by using IFN- have not been established. Without IFN-, tolerance is not induced in non-IgE-mediated food allergy.

#### **5.4 Indication for SOTI**

Tolerance induction for food allergy is indicated when (1) nutritional deficiency is expected, (2) the patient is inevitably unable to avoid the allergen (e.g., wheat allergy in a baker), (3) an infant displays allergy to all available formulae, and (4) the patients or parents want an improved quality of life [2].
