Immunotherapies in the treatment of immunoglobulin E-mediated allergy: Challenges and scope for innovation

Immunoglobulin E (IgE)-mediated allergy or hypersensitivity reactions are generally defined as an unwanted severe symptomatic immunological reaction that occurs due to shattered or untrained peripheral tolerance of the immune system. Allergen-specific immunotherapy (AIT) is the only therapeutic strategy that can provide a longer-lasting symptomatic and clinical break from medications in IgE-mediated allergy. Immunotherapies against allergic diseases comprise a successive increasing dose of allergen, which helps in developing the immune tolerance against the allergen. AITs exerttheirspecial effectiveness directly or indirectly by modulating the regulator and effector components of the immune system. The number of success stories of AIT is still limited and it canoccasionallyhave a severe treatment-associated adverse effect on patients. Therefore, the formulation used for AIT should be appropriate and effective. The present review describes the chronological evolution of AIT, and provides a comparative account of the merits and demerits of different AITs by keeping in focus the critical guiding factors, such as sustained allergen tolerance, duration of AIT, probability of mild to severe allergic reactions and dose of allergen required to effectuate an effective AIT. The mechanisms by which regulatory T cells suppress allergen-specific effector T cells and how loss of natural tolerance against innocuous proteins induces allergy are reviewed. The present review highlights the major AIT bottlenecks and the importantregulatory requirements for standardized AIT formulations. Furthermore, the present reviewcalls attention to the problem of 'polyallergy', which is still a major challenge for AIT and the emerging concept of 'component-resolved diagnosis' (CRD) to address the issue. Finally, a prospective strategy for upgrading CRD to the next dimension is provided, and a potential technology for delivering thoroughly standardized AIT with minimal risk is discussed.