The worldwide number of people suffering from some form of allergy - allergic rhinitis, skin, asthma, insect, drug or food - is extremely high. Each year in the U.S. alone, more than 50 million people suffer from allergies, making allergies the sixth leading cause of chronic illness (1). Individuals resort to medications and sensitization techniques to provide temporary relief, but currently the cures are very limited. Hence, it is necessary to rely on medications for a long time to relieve allergic symptoms.

For some of these allergy sufferers, allergen specific immunotherapy (allergen-SIT) has provided more than temporary relief. The immunological mechanism of allergen-SIT is essentially the induction of persistent specific allergen tolerance. The allergen-specific memory T and B cell responses are altered, leading to immune tolerance (2).

In normal, healthy individuals, allergens interact with antigen presenting cells (APCs), which enter the lymphatic system. The APCs interact and activate CD4+ naïve T helper cells (Th0), which transform into T helper1 (Th1) cells. The Th1 cells interact with B cells that release cytokines like IL-2 and IFN-γ and are stimulated to produce IgG antibodies. The IgG antibody plays a protective role and does not elicit an allergic reaction.

The scenario in allergic individuals follows a different pathway. The APCs exposed to allergens enter the lymphatic system where they interact with naïve T helper cells, which then transform into Th2 cells instead of Th1. The Th2 cells interact with B cells, which release different cytokines like IL-4, IL-5, IL-9, IL-13, IL-25, IL-31 and IL-33 and IgE antibodies (3). This outcome is abnormal and results in an allergic reaction. The excessive Th2 activity suppresses Th1 cells, and allergen-specific IgE interacts with high affinity receptor FcεRI on mast cells, basophils and APCs. The two phases: sensitization and development of memory responses (early phase), and tissue inflammation and injury mediated by the effector cell function (late phase), underlie the pathogenesis of an allergy (2).   

Allergen immunotherapy follows a model similar to vaccination, whereby encounters with previously exposed allergens provoke mild to no allergic reactions. The composition of the vaccine is based on allergens that cause patient symptoms. Over a hundred years ago Leonard Noon attempted to treat hay fever allergies by injecting patients with small amounts of grass pollen (4). Modern allergen immunotherapy still uses the same principle and has become more sophisticated with allergen-SIT provided subcutaneously, orally and sublingually.

Significant work over the years has provided information to standardize treatment and make it more effective. The molecular and cellular basis of allergen-SIT is modulation of peripheral T cell tolerance, activation of mast cell and basophils, and IgE- mediated histamine release (5). Allergens in the vaccine interact with APCs, which enter the lymphatic system and activate T cells, yielding regulatory T cells (Treg)(6). These Tregs suppress Th2 cells while simultaneously stimulating growth of Th1 cells. Interaction between Treg and B cells leads to release of suppressive cytokines IL10 and TGFβ. As a result, B cells are stimulated to produce IgG4 and IgA antibody subtypes. The IgG4 antibodies are non-inflammatory isotypes with the ability to block allergic reactions by preventing allergen interaction with the IgE found on the surface of mast cells (5).

After a period of time, Th1 cells significantly outnumber Th2 cells, and the allergic symptoms decrease gradually with a long-lasting effect. The below image by Akdis and Akdis (3) nicely illustrates the roles of B and T cells in suppression of an allergic reaction. A better understanding of the molecular processes will help gain more insight in the regulation of the complex immune system. New markers or molecules can thus aid in providing effective allergen-SIT. 

The roles of B and T cells in the suppression of an allergic reaction

 

Fig. 1 - The roles of B and T cells in suppression of an allergic reaction


Check out how Lonza can support your immunotherapy research with hematopoietic and immune cells as well as immune cell Nucleofector™ Kits to aid in your allergen-SIT research. Our scientific support experts are looking forward to helping answer both scientific and product-related questions you may have. 


References:

(1) Allergies: Gateway to Health Communication & Social Marketing Practice (CDC)
(2) Larche M, Akdis CA, Valenta R. Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunology 2006;  6: 761-771
(3)  Akdis CA and Akdis M. Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens. World Allergy Organization Journal 2015; 8:17

(4)

Durham SR and Nelson H. Allergen Immunotherapy: A Centenary Celebration World Allergy Organ J 2011; 4(6) 104-106.
(5) Akdis CA and Akdis M: Mechanisms of allergen-specific immunotherapy. J allergy Clin Immunol 2011; 127(1); 18-27
(6)  Palomares O, et al. Role of Treg in immune regulation of allergic diseases. Eur J. Immunol 2010: 40 (5) 1232-1240