Food tolerance and other mysteries

In a timely review and opinion article this month, Berin and Mayer take up the issue of therapeutic induction of food tolerance (J Allergy Clin Immunol 2013;131:14-22). They put to the reader the question of whether we truly understand the mechanisms that restore natural tolerance or induce tolerance in sensitized individuals, noting that without this knowledge it will not be possible to achieve tolerance through therapy in the majority of food allergic patients.

Berin and Mayer begin with a concise review of current understanding about how the human body achieves self and non-self tolerance. They cover central tolerance and peripheral tolerance induction in the thymus and gut, respectively, the development and function of natural and induced regulatory T cells, and anti-specific T-cell deletion and anergy in the context of establishing and maintaining peripheral tolerance. Immunologic profiles of critical immune cells and cytokines is also addressed.

The authors proceed with the question “is food allergy a defective T_reg response?” They review and summarize the current knowledge about T helper cell profiles in food allergic subjects and normal controls, nothing that T_reg frequencies were similar between the controls and the allergic subjects. Mouse models of food allergy are also presented.

Next, the question of whether tolerance can be induced in food allergic patients is discussed. The authors define tolerance as sustained non-responsiveness to a food allergen after therapy is discontinued, distinguishing it from desensitization that is achieved during therapy. Berin and Mayer review the research to date on immunotherapy for food allergy, noting the frequency of spontaneous tolerance. They point out that there has been little in the way of mechanistic findings that would demonstrate what immune regulatory mechanisms were operative between those who achieved desensitization and those who achieved tolerance. It remains unclear if tolerance is achieved by induction of T_reg or by decreased potency of allergic sensitization.

Berin and Mayer conclude by offering considerations for future research, such as novel routes of administration, allergen modification, the addition of adjuvants to enhance the immunotherapy, and manipulation of gut flora. Of particular importance, they press for genetic profiling of immune tolerance that develops naturally or therapeutically in order to design new methods for achieving tolerance in the majority of food allergic patients.