This is the first double-blind, placebo-controlled study of peanut OIT as a treatment for peanut allergy. By establishing the safety and efficacy of allergen-specific desensitization, these data support the feasibility of using peanut OIT as an interventional therapy. Sixteen of 19 subjects (84%) completed one year of peanut OIT treatment; three (16%) were unable to complete the protocol. All 16 reaching OFC completed the 5000 mg peanut protein challenge, ingesting approximately 20 peanuts; only one subject required antihistamine therapy. Subjects receiving placebo ingested a median cumulative dose of 280 mg, or approximately 1 peanut, before stopping the OFC due to allergic symptoms. Desensitization represents an important advance in the treatment of food allergy by increasing the threshold of food antigen causing allergic symptoms. This degree of protection would likely prevent accidental peanut anaphylaxis, offering great benefit to affected patients and their families. Studies addressing the impact of peanut OIT on health-related quality of life are currently underway.20, 21
The immunologic changes during peanut OIT in antigen-specific immunoglobulins, mast cells, and T cells mirror those seen with traditional allergen immunotherapy and are similar to the natural development of tolerance to food allergens.22
In active subjects but not controls, peanut-specific IgE increased during the first year of OIT treatment but was not significantly different from baseline levels at OFC, whereas peanut-specific IgG and IgG4
increased as early as 2 months into treatment and continued to rise throughout the first year. Titrated skin prick test size decreased by the time of OFC. Peanut OIT induced a shift in allergen-specific cytokine production away from a Th2
-type profile, with decreased IL-5 and IL-13 production. Peanut OIT subjects had an increased ratio of FoxP3 hi
: FoxP3 intermediate
CD4+CD25+ T cells at OFC, which may represent the induction of Treg cells important in suppressing the allergic response. Allergen-specific Treg cells may play a role in the natural resolution of milk allergy;23
it is possible that the same immunosuppressive functions play a role in OIT. The exact mechanism of Treg-induced immunosuppression remains unknown. It is interesting that there was only a transient increase in blood TGF-beta levels and no change in IL-10 levels; it is possible that blood cytokine levels do not reflect mucosal production or that mucosal Treg function differs from that seen in the periphery.
This study utilizes a rigorous study design to confirm and extend the findings seen in our open-label study16
and adds to the small body of literature of controlled interventional food allergy trials.10, 24
It is unlikely that all subjects in the intervention group naturally outgrew their allergy given their history and baseline immunologic parameters. Furthermore, all placebo subjects reacted at low doses of peanut protein after approximately one year in the study; none demonstrated natural tolerance acquisition. The only other placebo-controlled study of OIT for food allergy found an increased amount of milk protein ingested at challenge as well as increased milk-specific IgG4
levels in subjects receiving active treatment but not placebo.25
Although a number of subjects receiving active treatment had changes in the end-point titration SPT threshold, the median change did not reach statistical significance, and there was no change in milk-specific IgE, possibly due to methodologic differences (sample size, shorter study duration) or differing immune responses to different allergens.
This regimen was well-tolerated, with peanut OIT subjects experiencing clinically-relevant symptoms after only 1.2% of build-up doses. Importantly, no peanut OIT subjects required epinephrine treatment with dose escalation visits or home doses. During the open-label study, we observed certain patterns of allergic reactions with home dosing and were able to implement changes in this blinded study.18
The strengths of this study include its placebo-controlled design, favorable safety profile, and convincing clinical desensitization, which occurs in parallel with biologically-relevant immune modulation. However, there are also several important limitations to note. We use the term desensitization to signify a change in the amount of food antigen needed to cause allergic symptoms; this state is dependent on regular antigen exposure. In contrast, tolerance refers to long-term immunologic changes associated with the ability to ingest a food without symptoms and without ongoing therapy. Desensitization is a worthwhile therapeutic goal in that it offers individuals freedom from the risk of accidental ingestion in everyday settings; achieving long-term clinical tolerance would allow safe food ingestion without ongoing therapy by inducing lasting immunologic changes. This report does not address the induction of tolerance, which requires longer-term follow-up; the subjects in this study continue to receive peanut protein, and these longer-term outcomes will be followed. Additionally, baseline entry challenges are necessary to definitively evaluate the change in threshold dose with OIT treatment; future protocols will utilize challenges at study entry to define baseline allergen thresholds. The study's sample size is small, limiting the ability to generalize the results. Moreover, this protocol included only pediatric subjects, and further study is needed to evaluate the efficacy of OIT in adults with long-standing peanut allergy.
Peanut OIT is relatively safe under strict supervision; however, with current forms of OIT, as with other forms of immunotherapy, certain individuals are unable to endure associated side effects.15, 26
In this cohort, three subjects were unable to complete the initial day escalation or build-up dosing due to side effects. Further study may help identify the clinical and/or immunologic profiles of patients who are the best candidates for this therapy. Although many of our subjects had experienced systemic reactions to peanut prior to enrollment, we excluded patients with a history of severe anaphylaxis. This is an important limitation, as these severely affected patients may be more likely to seek treatment. Moreover, there remain numerous unanswered questions that must be addressed before OIT can be applied in widespread clinical use, including risks of OIT compared to avoidance, dosing regimen issues, patient selection, post-desensitization strategy, allocation of clinical resources, and reimbursement.27
When performed by experienced investigators in an appropriate setting, peanut OIT is a safe, allergen-specific therapy effective in inducing desensitization and providing protection against accidental exposure with ongoing therapy. Immunologic changes suggest downregulation of the allergic response. Further investigation of this promising intervention will address outstanding issues and continue to refine therapeutic protocols in hopes of offering an allergen-specific treatment option for food allergy.