Strategies for the prevention and treatment of peanut allergy

Food allergy is a disease driven by an abnormal immune response to food proteins that either involve or do not involve allergen specific immunoglobulin (Ig)E. Peanut allergy is an IgE-mediated type of food allergy that develops in early childhood. Peanut allergy typically involves a life-long burden of disease with outstanding allergenic potential expressed by sensitivity to trace amounts of peanut. Allergic reactions to peanut may include skin itching, tongue swelling, diarrhea or most dramatically anaphylaxis. Strict avoidance of peanut is the main strategy for keeping peanut allergy at bay. However, guaranteeing strict avoidance is troublesome due to the ubiquitous nature of peanut. Thus, unexpected exposures to peanut are common despite efforts to adhere to a peanut avoidance strategy. Prevalence of peanut allergy is on the rise, which further stresses the need for an alternative strategy with improved margin of safety in the case of accidental peanut exposure. Preventive strategies are needed to halt the increasing prevalence of peanut allergy and treatment strategies are needed to improve quality of life of peanut allergic subjects. The concept of induction of oral tolerance has become a prime target for preventive and treatment strategies for peanut allergy. Oral tolerance is antigen-specific meaning that peanut proteins are essential for induction of immune tolerance to peanut. Therefore, peanut-specific immunotherapy (IT), which includes repeated administration of peanut proteins, has emerged as a potential strategy to modify the IgE immune response in peanut allergic subjects towards desensitisation and potentially tolerance. However, the development of IT for peanut allergy has been hampered by an unfavorable balance between safety and efficacy. To circumvent this matter, several IT approaches have been investigated including different routes of administration.

In this PhD project, we aimed to compare the safety and efficacy of IT with peanut protein extract (PPE) administered through the oral, sublingual (SL), intragastric (IG) or subcutaneous (SC) routes in a primary prevention Brown Norway (BN) rat model (manuscript I) and in a desensitisation BN rat model (manuscript III). Indeed, we observed clear differences in the degree of safety and efficacy depending on route of administration. Oral (O)IT, SLIT and IGIT prevented peanut allergy development in naïve BN rats. Contrary, SCIT promoted peanut allergy development (manuscript I). All ITs with PPE (OIT, SLIT, IGIT and SCIT) exerted a densensitising capacity in peanut allergic BN rats. However, IGIT demonstrated a persistent desensitising effect with a potential to induce sustained unresponsiveness (manuscript III). Peanut allergy development was originally thought to occur mainly through the oral route. However, increasing evidence suggests that the skin is likely to play a role in peanut allergy development. Understanding how the route-of-sensitisation influences the acquired peanut allergy could pave the way for better or personalised allergen-specific ITs. Thus, this PhD project aimed to compare the immunological features of allergic sensitisation induced via the oral and skin routes in BN rat models of peanut allergy (manuscript II). Distinct allergen-specific IgE patterns were observed between orally and skin sensitised BN rats, however conformational epitopes dominated both routes of sensitisation. On the cellular level, the skin, but not oral, route influenced the immune cell composition in the skin and the intestine. Additionally, orally and skin sensitised BN rats were presented with distinct cytokine profiles in the intestine (manuscript II).

Collectively, the studies included in this PhD project highlighted the application of different routes of administration for both prevention and treatment of peanut allergy. Furthermore, this PhD project highlighted differences in the underlying immunological features of oral and skin sensitisation to peanut. Such differences may need to be accounted for in the development of ITs for peanut allergy.