**3. Approaches for allergy treatment**

#### **3.1. Antihistaminic treatment**

Researchers have devoted their efforts for many years to the development of effective and safe strategies for the treatment of allergy to alleviate the symptoms triggered by the body's responses to allergens [1, 13, 14]. Antihistamines are currently the most commonly used treat‐ ment. These drugs are used to alleviate allergic symptoms, that is, they are based on the con‐ sequences of the allergy [5]. First‐generation antihistamines, or H1‐receptor antagonists, may have undesirable side effects on the central nervous system, even at therapeutic doses, due to their ability to cross the blood‐brain barrier rather than to their lack of selectivity. Side effects include sleepiness, sedation, and fatigue that may lead to reduced cognitive, memory, and psy‐ chomotor performance [7, 15]. First‐generation antihistamines include doxepin, diphenhydr‐ amine, pyrilamine, chlorpheniramine, hydroxyzine, promethazine, and cyproheptadine [6].

A new class of antihistamine has been developed. Second‐generation H1 antagonists cannot cross the blood‐brain barrier as easily and have a greater affinity to H1 receptors, decreasing their sedative effects compared to the first‐generation drugs [7]. These antihistaminic agents include cetirizine, ebastine, epinastine, fexofenadine, loratadine, desloratadine, levocetiri‐ zine, and rupatadine. The second‐generation antihistamines cause fewer adverse effects, but some drugs, for example, levocetirizine, may cause drowsiness, and fexofenadine has a brief effect and may require more than one daily dose. Treatment with antihistaminic drugs does not address the cause of allergic responses but only alleviates their symptoms [7, 14, 16].

#### **3.2. Allergen‐specific immunotherapy (ASIT)**

Immunotherapy was first conceived in 1911, from which a type of therapy was developed that used allergens as a tool for the development of immunological tolerance in sensitized individuals [17]. The term "desensitization" was replaced with "hypo‐sensitization." The term "immunotherapy" became popular only in the 1980s and "specific immunotherapy" is a commonly used term. When immunotherapy involves the direct use of allergens as immuno‐ therapeutics, the appropriate term is ASIT [12]. ASIT has been used for more than a century and remains one of the few antigen‐specific treatments for inflammatory diseases.

ASIT consists of the gradual administration of doses of a specific allergen or part of that aller‐ gen to reduce the sensitivity and consequently to decrease the symptomatic reactions to a future exposure of the allergic individual to the causative natural agent [1, 18]. ASIT is a widely used therapeutic strategy for treating allergic rhinitis, venom‐induced hypersensitivity, some drug allergies, and mild bronchial asthma [13]. The mechanisms of ASIT are not yet clear but include modulating both T and B cell responses, thereby reducing the incidence and severity of IgE‐mediated adverse reactions [19]. Some of the immunological changes that occur dur‐ ing ASIT have been elucidated [1]. ASIT increases the level of allergen‐specific IgA and IgG4 antibodies and decreases the level of allergen‐specific IgE antibodies. Oral, sublingual, and subcutaneous immunotherapies are used the most in the treatment of hypo‐sensitization in various types of allergies. These three mechanisms of immunotherapies, however, are specific to particular allergens, so the therapy is effective only for the particular allergen.

Approaches to improving ASIT include the use of modified recombinant allergens, novel adjuvants, and alternative routes of administration. Recombinant allergens are similar to wild‐type allergens, generally equivalent in structure and properties, but with alterations in their epitopes that do not guarantee their ability to trigger an allergic response [20].

## *3.2.1. Recombinant hypoallergenic peptides for immunotherapy*

Valenta et al. using purified recombinant allergens and derivatives of recombinant hypoal‐ lergenic allergens has identified the induction of the production of IgG‐specific allergen‐ blocking antibodies as one of the main mechanisms of ASIT [21]. Blocking IgG, however, may also inhibit the presentation of antigen in APCs to antigen T cells and therefore suppress the activation of T cells induced [22]. ASIT can also alter the balance of specific helper T cells from a Th2 profile to an allergen‐specific Th1 immunity profile and can induce the secretion of immunoregulatory cytokines such as interleukin (IL)‐10, and regulatory T cells [23]. The induction of allergen‐specific tolerance is thus the essential immune mechanism of ASIT.

Recombinant hypoallergenic from variants have been produced. Linhart constructed, puri‐ fied, and characterized two hybrid hypoallergenic recombinant proteins from *Brassica rapa* allergens, Der p 2 (rder p 2)/1 C and rder p 2/1S [19]. Mutations in aspartic acid residues in these allergens decreased the cross‐linking of IgE in the membrane of sensitized mast cells by decreasing the allergenic potential of the protein [24].

Patients immunized in 2016 with a variant Bet v1 (birch allergen) hypoallergen did not develop a local allergic response, as observed by histopathological tests of skin contact. Rats immunized with the same recombinant hypoallergen demonstrated that a profile of tolero‐ genic responses with proinflammatory cytokine production was possible [25].

#### *3.2.2. Synthetic peptides*

In this chapter, we will describe the most common allergy treatments using antihistamines and emphasize the new methodologies of allergen‐specific immunotherapy (ASIT) as a pro‐

Treg Secretors of TGF‐β and IL‐10; induce Foxp3 expression,

Eosinophils Decrease the activity of inflammatory mediator secretion

Th2 suppression; direct, and indirect suppression of mast cells, basophils, and eosinophils; stimulate B lymphocytes in IgG4 production and IgE suppression

(histamine and leukotrienes) by the action of IL‐10 and

Researchers have devoted their efforts for many years to the development of effective and safe strategies for the treatment of allergy to alleviate the symptoms triggered by the body's responses to allergens [1, 13, 14]. Antihistamines are currently the most commonly used treat‐ ment. These drugs are used to alleviate allergic symptoms, that is, they are based on the con‐ sequences of the allergy [5]. First‐generation antihistamines, or H1‐receptor antagonists, may have undesirable side effects on the central nervous system, even at therapeutic doses, due to their ability to cross the blood‐brain barrier rather than to their lack of selectivity. Side effects include sleepiness, sedation, and fatigue that may lead to reduced cognitive, memory, and psy‐ chomotor performance [7, 15]. First‐generation antihistamines include doxepin, diphenhydr‐ amine, pyrilamine, chlorpheniramine, hydroxyzine, promethazine, and cyproheptadine [6]. A new class of antihistamine has been developed. Second‐generation H1 antagonists cannot cross the blood‐brain barrier as easily and have a greater affinity to H1 receptors, decreasing their sedative effects compared to the first‐generation drugs [7]. These antihistaminic agents include cetirizine, ebastine, epinastine, fexofenadine, loratadine, desloratadine, levocetiri‐ zine, and rupatadine. The second‐generation antihistamines cause fewer adverse effects, but some drugs, for example, levocetirizine, may cause drowsiness, and fexofenadine has a brief effect and may require more than one daily dose. Treatment with antihistaminic drugs does not address the cause of allergic responses but only alleviates their symptoms [7, 14, 16].

Immunotherapy was first conceived in 1911, from which a type of therapy was developed that used allergens as a tool for the development of immunological tolerance in sensitized individuals [17]. The term "desensitization" was replaced with "hypo‐sensitization." The term "immunotherapy" became popular only in the 1980s and "specific immunotherapy" is a

phylactic treatment and IgE blockade as a therapeutic treatment.

Breg Expression of IL‐10 and IgG4

TGF secreted by regulatory cells Basophils

**3. Approaches for allergy treatment**

**3.2. Allergen‐specific immunotherapy (ASIT)**

**3.1. Antihistaminic treatment**

**Table 2.** Roles of cells in allergen tolerance.

Mast cells

70 Allergen

Immunotherapy using peptides has some advantages over immunotherapies fusing recom‐ binant allergens. Vaccines using peptides with T cell epitopes can induce regulatory T cells. The use of synthetic peptides derived from allergens containing T cell epitopes is an alterna‐ tive to the production of allergen‐specific T cells in ASIT. These peptides are formed from linear sequences representing fragments of small allergens that bind to the allergen‐specific T cell receptor and do not react with IgE antibodies, which give them an advantage because they do not trigger the classic allergic symptoms measured by IgE. The treatment may induce T cell tolerance by the secretion of the immune cytokine regulator IL‐10 from regu‐ latory T cells. The diversity of T cell epitopes is a possible disadvantage of vaccines based on T cell epitopes, making treatment with only one or a few peptides difficult. This treatment can cause secondary systemic symptoms and lacks the ability to induce IgG blocking [2].

Vaccines for allergies based on B cell epitopes of approximately 20–40 amino acids use pep‐ tides that lack the ability to bind IgE. The peptides must be covalently linked to a protein transporter that is unrelated to the T allergens in order to render these peptides immuno‐ genic, capable of inducing the production of IgG, which blocks the binding of IgE to the cor‐ responding allergen. Valenta et al. demonstrated the use of carrier‐linked allergenic peptides to induce IgG antibodies to the main pollen allergen of thyme grasses, Phl p 1, and to the main birch pollen allergen, Bet v 1. These conjugates decreased allergenic activity even more than the recombinant hypoallergens, because the non‐IgE‐reactive peptides were selected from the IgE‐binding sites [21].

#### **3.3. Allergen‐nonspecific therapy**

#### *3.3.1. Anti‐IgE antibodies*

The new approaches for the treatment of allergic diseases have two main strategies using nonspecific allergens [26]. The first strategy is to bind IgE to high‐affinity receptors (FcϵRI) in mast cells and basophils, and the second strategy is to interfere with the signaling generated by receptor binding (FcϵRI) [26, 27]. Knowledge of the pathophysiological role of IgE antibod‐ ies has allowed the development of new drugs against many allergic diseases.

#### *3.3.2. Anti‐IgE receptor antibodies*

A currently promising therapeutic approach has been the use of antibodies against the region of the IgE molecule that interacts with specific IgE receptors. The interaction of IgE molecules with high‐ and low‐affinity receptors may be inhibited by the use of anti‐IgE for reducing the induced allergic responses, preventing the activation of mast cells and consequently the release of allergic mediators [2, 26]. Omalizumab is a murine anti‐human IgE monoclonal antibody that binds to the same receptor site (Cε3) to which IgE binds, thereby inhibiting the binding of IgE‐to‐IgE receptors [2, 8]. Omalizumab does not bind to fixed IgE in cells, because the IgE epitope (specific fragment) against which omalizumab is targeted is already fixed to the receptors and is therefore hidden. Anti‐IgE therapy is most commonly used to treat bron‐ chial asthma but is also effective for treating allergic rhinoconjunctivitis, but therapy must begin before the pollen season [26]. The anti‐IgE therapy is currently being studied for use in food allergies, but the cost has limited its use for this purpose [1].

### *3.3.3. IgE blocker*

The use of synthetic peptides derived from allergens containing T cell epitopes is an alterna‐ tive to the production of allergen‐specific T cells in ASIT. These peptides are formed from linear sequences representing fragments of small allergens that bind to the allergen‐specific T cell receptor and do not react with IgE antibodies, which give them an advantage because they do not trigger the classic allergic symptoms measured by IgE. The treatment may induce T cell tolerance by the secretion of the immune cytokine regulator IL‐10 from regu‐ latory T cells. The diversity of T cell epitopes is a possible disadvantage of vaccines based on T cell epitopes, making treatment with only one or a few peptides difficult. This treatment can cause secondary systemic symptoms and lacks the ability to induce IgG blocking [2].

Vaccines for allergies based on B cell epitopes of approximately 20–40 amino acids use pep‐ tides that lack the ability to bind IgE. The peptides must be covalently linked to a protein transporter that is unrelated to the T allergens in order to render these peptides immuno‐ genic, capable of inducing the production of IgG, which blocks the binding of IgE to the cor‐ responding allergen. Valenta et al. demonstrated the use of carrier‐linked allergenic peptides to induce IgG antibodies to the main pollen allergen of thyme grasses, Phl p 1, and to the main birch pollen allergen, Bet v 1. These conjugates decreased allergenic activity even more than the recombinant hypoallergens, because the non‐IgE‐reactive peptides were selected from the

The new approaches for the treatment of allergic diseases have two main strategies using nonspecific allergens [26]. The first strategy is to bind IgE to high‐affinity receptors (FcϵRI) in mast cells and basophils, and the second strategy is to interfere with the signaling generated by receptor binding (FcϵRI) [26, 27]. Knowledge of the pathophysiological role of IgE antibod‐

A currently promising therapeutic approach has been the use of antibodies against the region of the IgE molecule that interacts with specific IgE receptors. The interaction of IgE molecules with high‐ and low‐affinity receptors may be inhibited by the use of anti‐IgE for reducing the induced allergic responses, preventing the activation of mast cells and consequently the release of allergic mediators [2, 26]. Omalizumab is a murine anti‐human IgE monoclonal antibody that binds to the same receptor site (Cε3) to which IgE binds, thereby inhibiting the binding of IgE‐to‐IgE receptors [2, 8]. Omalizumab does not bind to fixed IgE in cells, because the IgE epitope (specific fragment) against which omalizumab is targeted is already fixed to the receptors and is therefore hidden. Anti‐IgE therapy is most commonly used to treat bron‐ chial asthma but is also effective for treating allergic rhinoconjunctivitis, but therapy must begin before the pollen season [26]. The anti‐IgE therapy is currently being studied for use in

ies has allowed the development of new drugs against many allergic diseases.

food allergies, but the cost has limited its use for this purpose [1].

IgE‐binding sites [21].

72 Allergen

*3.3.1. Anti‐IgE antibodies*

**3.3. Allergen‐nonspecific therapy**

*3.3.2. Anti‐IgE receptor antibodies*

A new proposal has been studied by Deus‐de‐Oliveira et al. for blocking IgE‐allergen binding. The identification of the IgE‐binding epitopes and the amino acids involved in these interactions are fundamental steps. Deus‐de‐Oliveira et al. found that two glutamic acid residues in the main allergens of *Ricinus communis*, Ric c1 and Ric c 3, are involved in IgE binding, triggering an allergic response. They also found that the *Ricinus* allergens cross‐reacted with aeroallergens and food allergens from several sources. Free glutamic acid can bind to castor‐allergen‐specific IgE, occupying the epitope‐interaction site and preventing the binding of the allergens in a second exposure to the IgEs fixed in the mast cells. IgE blockade may be a safe approach for the treatment of allergy but will depend on determining the structures of allergens and on identifying epitopes and cross‐allergen responses.


A summary of strategies for treating allergies is presented in **Table 3**.

**Table 3.** Summary of strategies for treating allergies.
