Can True Tolerance Be Produced in Food Allergy Patients?

Gary J. Stadtmauer, MD


January 15, 2014

Editor's Note: This is the second of a series of articles dedicated to the memory of my friend and mentor, the renowned mucosal immunologist Dr. Lloyd Mayer.

Can We Produce True Tolerance in Patients With Food Allergy?

Berin MC, Mayer L
J Allergy Clin Immunol. 2013;131:14-22


The means by which the immune system tolerates self antigens and benign non-self antigens include deletion of autoreactive lymphocytes, anergy, and antigen-specific T-regulatory (Treg) cells. This immune tolerance may be central or peripheral.

Central immunologic tolerance involves thymic Treg cells, which in the course of normal development prevent inappropriate immune activity, including autoimmunity, food allergy, and exuberant responses to gut flora. The thymus has a special population of epithelial cells that are under the control of the transcription factor autoimmune regulator (AIRE). Mutations in AIRE lead to an autoimmune variant of an immunodeficiency with which allergist/immunologists are familiar: mucocutaneous candidiasis (autoimmune polyendocrinopathy/candidiasis/ectodermal dystrophy).

Peripheral immune tolerance occurs in multiple organ systems, including the gut, respiratory tract, and skin -- areas that routinely interface with the outside world. In the gut, the Peyer patches and mesenteric lymph nodes possess suppressor cells that may be transferred to naive animals, thus inhibiting immunoglobulin E (IgE) responses in recipient mice.

In food-allergic patients, food-allergen specific T-helper 2 cells (Th2) drive class-switching of B cells to IgE -- which is by definition a failure of the Treg response. Although it has not been easy to study the T cell responses of humans without food allergy, the response appears to be either of the Th0 or Th1 type.

Experimentally, oral tolerance by antigen feeding has successfully decreased IgE production and been shown in the laboratory to prevent asthma and food allergy symptoms, but whether that occurs in humans is unknown. Spontaneous loss of IgE-mediated food sensitivity occurs in the majority of children allergic to milk and egg, and to a lesser degree in children with peanut (20%) and tree nut (10%) allergy. The mechanism of the loss of sensitization in early childhood might be maturation of mucosal immunity, potentially through changes in microbial colonization.

In older children and adults, though, what is the mechanism of acquired clinical tolerance? Is it the same as primary immune tolerance involving Treg cells blocking generation of allergen-specific IgE?


From a clinical standpoint, this is relevant for the management of patients with food allergy who have lost sensitivity and for those who hope to benefit from trials aimed at inducing food allergen tolerance. The question is whether true immunologic tolerance is possible in patients with food allergy.

The only immunologic change in food allergy patients undergoing oral immunotherapy (OIT) that has been consistently demonstrated is blocking of IgG4 antibodies, which is similar to the response to subcutaneous immunotherapy. Not surprisingly, egg OIT trials to date support that clinically, the patients are desensitized to rather than tolerant of the food allergen. The majority of patients in egg OIT trials seem to pass the early double-blind, placebo-controlled food challenge at the end of the study, but then fail the follow-up challenge. Of patients who remained egg-tolerant, it was unclear whether this was a result of OIT or spontaneous resolution of egg allergy.

Either way, the tolerant patients with food allergy have much to teach us. As Dr. Mayer wrote, "The challenge ahead of us is to study these patients to understand how tolerance does occur from an immunologic perspective, so that we can design more rational therapies to facilitate those immune changes in subjects with persistent food allergy."



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