**6. Allergen-specific Immunotherapy**

Two stages have been defined in AR immune pathophysiology. The first stage is named sensitization phase reaction, and is initiated by preferential activation and polarization of the immune response to environmental antigens, that culminates with a generation of a predominant Th2 immune response and production of IgE antibodies; the second stage, named effector phase reaction, is initiated with a second encounter with antigen (Ag) leading to activation of effector mechanisms, such as degranulation of granulocytes and release of histamine (Robles-Contreras et al, 2011). Allergen-induced cell degranulation is the key event in allergic inflammation and leads to early-phase symptoms. Early phase reaction (EPR) has been studied extensively in both humans and animals; EPR is initiated with a second encounter with the antigen by IgE previously attached to IgE receptors (FcεRI, FcεRII or CD23). Cross-linking of IgE receptors induces: a) release of preformed mediators such as histamine, proteases and chemotactic factors; b) activation of transcription factors and cytokine gene expression, and c) production of prostaglandins and leukotrienes by phospholipase A2 pathway (Figure 1).

Treatment of Allergic Rhinitis: Anticholinergics, Glucocorticotherapy,

Fig. 2. Mechanisms of action of allergen-specific immunotherapy (SIT).

Heterogeneity: Low = *I2* 25%; Moderate = *I2* 50%; High = *I2* 75%;

Participant numbers

Symptom scores SMD

Medication scores SMD

1988; Cirla et al, 2003).

Subcutaneous IT for seasonal AR (Calderon et al, 2007)

(active/placebo) 597/466 2333/2256

random (95% CI) -0.73 (-0.97, -0.50) -0.49 (-0.64, -0.34) *P*-value <0.00001 <0.00001 Heterogeneity (*I2*) 63% 81%

random (95% CI) -0.57 (-0.82, -0.33) -0.32 (-0.43, -0.21) *P*-value <0.00001 <0.00001 Heterogeneity (*I2*) 64% 50%

Table 2. Efficacy of immunotherapy (IT) in AR (summary of Cochrane meta-analyses)

e. Increased in vitro IL-10 production by peripheral blood mononuclear cells (PBMC) following stimulation with allergen (Nouri-Aria et al, 2004; Francis et al, 2008). f. Reduction in allergen-induced in vitro PBMC proliferative responses (Fanta et al, 1999). g. Reduction in bronchial responses to allergen and methacholine challenge (Rak et al,

Sublingual IT for seasonal and perennial AR (Olaguibel & Álvarez-Puebla, 2005)

Leukotriene Antagonists, Omalizumab and Specific-Allergen Immunotherapy 99

Fig. 1. Mechanism of allergic reaction.

The mechanisms of action of allergen-specific immunotherapy (SIT) include the very early desensitization effects, modulation of T-and B-cell responses and related antibody isotypes, and migration of eosinophils, basophils, and mast cells to tissues, as well as release of their mediators (Figure 2). Regulatory T (Treg) cells have been identified as key regulators of immunologic processes in peripheral tolerance to allergens. Skewing of allergen-specific effector T cells to a regulatory phenotype appears as a key event in the development of healthy immune response to allergens and successful outcome in patients undergoing allergen-specific immunotherapy (Akdis & Akdis, 2011).

Have been reported biomarkers of clinical response to IT:

	- Inhibition of basophil histamine release (Niederberger et al, 2004).
	- Inhibition of IgE-facilitated allergen binding (IgE-FAB) (Shamji et al, 2006).

The mechanisms of action of allergen-specific immunotherapy (SIT) include the very early desensitization effects, modulation of T-and B-cell responses and related antibody isotypes, and migration of eosinophils, basophils, and mast cells to tissues, as well as release of their mediators (Figure 2). Regulatory T (Treg) cells have been identified as key regulators of immunologic processes in peripheral tolerance to allergens. Skewing of allergen-specific effector T cells to a regulatory phenotype appears as a key event in the development of healthy immune response to allergens and successful outcome in patients undergoing

a. Increase in allergen-specific serum IgG4 (Tari et al, 1990; Tari et al, 1994; Durham et al, 1999; La Rosa et al, 1999; Bufe et al, 2004; Lima et al, 2002; Smith et al, 2004; Til et al,

Inhibition of basophil histamine release (Niederberger et al, 2004).

et al, 2003) concentrations in nasal lavage during the pollen season

Durham et al, 1999; La Rosa et al, 1999; Tonnel et al, 2004).

 Inhibition of IgE-facilitated allergen binding (IgE-FAB) (Shamji et al, 2006). c. Reduction in immediate and late-phase skin test responses to allergen (Tari et al, 1994;

d. Suppression of rise in Eosinophil Cationic Protein (ECP) (Gozalo et al, 1997; Passalacqua et al, 1998; Vourdas et al, 1998; Ippoliti et al, 2003) and tryptase (Marcucci

Fig. 1. Mechanism of allergic reaction.

2004; Tonnel et al, 2004).

allergen-specific immunotherapy (Akdis & Akdis, 2011). Have been reported biomarkers of clinical response to IT:

b. Increase in serum functional IgG responses:

Fig. 2. Mechanisms of action of allergen-specific immunotherapy (SIT).


Heterogeneity: Low = *I2* 25%; Moderate = *I2* 50%; High = *I2* 75%;

Table 2. Efficacy of immunotherapy (IT) in AR (summary of Cochrane meta-analyses)


Treatment of Allergic Rhinitis: Anticholinergics, Glucocorticotherapy,

immunostimulatory DNA sequences, with encouraging results.

treatment of AR, we provide the following guidelines:

rhinitis in patients 6 months of age and older

product chosen for treatment.

Electronic ISSN 1097-6825.

1879-114X.

**9. References** 

undergoing specific immunotherapy simultaneously.


Print ISSN 0091-6749, Electronic ISSN 1097-6825.

**8. Conclusions** 

Leukotriene Antagonists, Omalizumab and Specific-Allergen Immunotherapy 101

*Monoclonal antibodies anti-IL-5* seem to be an effective treatment that reduces the number of eosinophils locally in the airway and in peripheral blood in asthmatic patients. Two monoclonal antibodies have been designed to neutralize IL-5 (mepolizumab and reslizumab). Mepolizumab is a fully humanized anti-IL-5 monoclonal IgG1 antibody that binds to free IL-5 with high affinity and specificity to prevent IL-5 from associating with the

There are clinical trials with recombinant soluble IL-4 receptor, and recombinant IL-12. Immunomodulatory treatments for IL-9, IL-l0, IL-12 and IL-13 are being studied, as well as

Considering the reviewed data, and unifying the above-mentioned opinions on the





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Akdis CA, Akdis M. Mechanisms of allergen-specific immunotherapy. (2011) *J Allergy Clin* 

Allen A, Down G, Newland A, Reynard K, Rousell V, Salmon E, et al. Absolute

humanized mAb-E25, an anti-IgE mAb, in birch pollen induced seasonal allergic rhinitis. (2000) *J Allergy Clin Immunol*, Vol.106, No.2 (August 2000), pp. 253-259,

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Bioavailability of Intranasal Fluticasone Furoate in Healthy Subjects. (2007) *Clin Ther*, Vol.29, No.7 (July 2007), pp. 1415–1420, Print ISSN 0149-2918, Electronic ISSN

systemic corticosteroids unless there is another associated pathology.

IL-5 receptor complex alpha-chain on the surface of eosinophils (Leckie et al, 2000).

The ARIA document clearly states that immunotherapy (IT) is considered effective in AR, and that it is the only treatment that can change the natural course of the disease and prevent its evolution into asthma (Bousquet et al, 2008).

IT, both subcutaneous and sublingual, is an effective treatment for adults and children with severe AR that does not respond to conventional pharmacotherapy and allergen avoidance measures. The efficacy of IT depends on correct patient selection, the type of allergen and the product chosen for treatment. Each vaccine requires individual assessment before recommendation for routine use. In support of the conclusions of recent meta-analyses, data have provided further evidence for the efficacy of Sublingual immunotherapy (SLIT) at least for grass pollen-induced (Table 2).
