# Pollen-Food Allergy Syndrome: Allergens, Clinical Insights, Diagnostic and Therapeutic Challenges
## 8 PFAS Management
### Allergen Immunotherapy (AIT)  
Allergen Immunotherapy (AIT) is a well-established treatment for allergic conditions such as allergic rhinitis, asthma, and insect venom allergies [258; 259]. In recent years, its role in managing PFAS has gained attention, particularly for individuals whose symptoms significantly impact their quality of life. AIT offers the potential to address the underlying sensitization by modulating immune responses, reducing the severity of pollen-induced reactions, and potentially alleviating associated food allergies. AIT involves exposing the patient to gradually increasing doses of the allergen, either subcutaneously (SCIT) or sublingually (SLIT), over time. It works by gradually desensitizing the immune system to specific allergens, altering the underlying immune response and inducing long-term tolerance [260]. The core mechanism involves a controlled exposure to increasing doses of allergens, which modulates the immune system in several stages:  
1. Shift in immune response: during an allergic reaction, the immune system predominantly produces IgE antibodies, which bind to mast cells and basophils, triggering the release of histamine and other inflammatory mediators. AIT induces a class-switch in antibody production from allergen-specific IgE to IgG\({}_{4}\), a blocking antibody that prevents allergen-IgG binding, shifting the balance from a Th2-dominant response, characterized by IgE production, to a Th1-dominant response and Treg activation. This reduces the activation of mast cells and basophils. The production of blocking antibodies, such as IgG\({}_{4}\), plays a key role in neutralizing allergens before they can trigger IgE-mediated reactions [261; 262]. 2. T-cell modulation: AIT promotes the development of regulatory T cells (Tregs), which suppress allergic inflammation by releasing anti-inflammatory cytokines such as IL-10 and TGF-\(\beta\). These cytokines reduce the activity of effector T-helper 2 (Th2) cells, which are responsible for producing IgE and driving allergic inflammation [260]. 3. Dendritic cell modulation: dendritic cells exposed to allergens in the presence of AIT shift their cytokine production profile to favor tolerance rather than sensitization. This further supports the suppression of Th2 responses and enhances the induction of Tregs [262]. 4. Long-term tolerance: over time, AIT leads to the reprogramming of the immune system, resulting in long-lasting tolerance to allergens even after discontinuation of treatment. This effect distinguishes AIT from symptomatic treatments like antihistamines [263]. In PFAS, AIT targeting the primary pollen allergen (e.g., birch or grass pollen) can desensitize the immune system to the cross-reactive proteins in foods, reducing both respiratory and food-related symptoms. Beyond its impact on respiratory symptoms, AIT has also been effective in reducing the severity of oral symptoms caused by cross-reactive food allergens, which is particularly beneficial for patients with significant dietary restrictions or persistent symptoms despite avoidance strategies [264]. Applications of AIT in PFAS primarily focus on addressing the underlying pollen sensitization that drives cross-reactivity with food allergens. Pollen-specific AIT, such as for birch or grass, is the most common approach. By targeting the immune response to pollens, AIT reduces reactivity to related food allergens. For instance, birch pollen AIT can alleviate symptoms triggered by PR-10 proteins found in foods like apples (Mal d 1), hazelnuts (Cor a 1), and carrots (Dau c 1) [265], while grass pollen AIT has been shown to reduce reactions to profiling in melons, tomatoes, and bananas [266]. Another study demonstrated the effectiveness of SCIT with Japanese cedar pollen extract in patients allergic to Japanese cedar pollen and tomatoes. This treatment improved symptoms of both Japanese cedar pollen and tomato allergies. The beneficial effects were associated with a significant reduction in basophil activation [267].