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.

 

Re-equilibrating human health

Susan Prescott, PhD, MD makes a compelling case for broadly focused, interdisciplinary approaches to inflammatory non-communicable chronic diseases (iNCD) in her Current Perspectives contribution this month (JAllergy Clin Immunol 2013;131:23-30). She points to the global rise in allergies, obesity, cardiovascular disease and autoimmune diseases and their common characteristic of low grade chronic inflammation while discussing the radical and health-hostile environmental conditions that are known to influence these disease processes. Prescott states that the rise in allergic diseases specifically implicates vulnerability of the human immune system to micro- and global environmental shifts.

The author briefly discusses evidence that supports early immune dysfunction in infants and notes that environmental influences begin in utero. Thus, maternal health is a critical starting point to any preventive measures, such as dietary and nutritional support. She comments further on the need to create and sustain optimal immune development as a prerequisite to minimizing future causes of low grade chronic inflammation, which increases the risk associated with iNCD.

Prescott covers current research on important nutritional supplements known to impact immune function, such as fish oil, probiotics, and dietary soluble fiber, as well as the critical role of exposure to sunlight. She goes on to briefly discuss the roles of genetics, epigenetic modification and genetic plasticity in the context of adaptive and maladaptive evolutionary shifts.

Prescott concludes by urging interdisciplinary approaches to modifying the environment and a return to more traditional dietary and lifestyle patterns known to achieve and/or restore human health.

 

Standardizing research food challenges

A pressing need for standards of conduct for research-related double-blind, placebo-controlled, oral food challenges (OFC) provided the impetus for a consensus report by Sampson et al in this month’s issue (J Allergy Clin Immunol 2012;130:1260-1274).

After a brief review of the historical literature on diagnosing food allergy, Sampson et al present topical discussion summaries for major issues in the conduct of research OFC, noting that the guidance and recommendations apply equally to clinically performed challenges. The authors emphasize that patient/subject safety was the pre-eminent consideration. The following are highlights from their discussions:

·      Pre-challenge assessments. The authors cover important evaluations and practices prior to conducting OFC. These include case history, current food avoidance, comorbid conditions that impact safety such as atopic dermatitis and chronic disease, the utility of surrogate test results and their intrinsic problems, and the requirement for an optimal challenge setting. They also discuss the issue of differential severity of allergens as an important safety consideration prior to OFC.

·      Challenge procedures and assessments. Sampson et al discuss dosing schedules and their necessary variability tied to outcomes. General recommendations for dosing include low starting doses, separate active and placebo challenge days, dosing intervals no less than 20 minutes and appropriate, low fat matrices. Recording important, objective clinical parameters, such as respiratory symptoms and other physical reactivity symptoms, is covered. Sampson et al emphasize that scoring and stopping criteria must be pre-specified in light of the critical role of clinical judgment in OFC conduct. Delayed reaction considerations and subjective symptom issues are also reported. Tables of their recommendations are provided for reference.

·      OFC analysis and reporting. To ensure a reliable evidence base, Sampson et al provide guidance and recommendations for statistical analysis and reporting results, particularly from randomized trials. 

Revisiting LABAs with the help of Macbeth

Szefler and Busse provide an entertaining and thoughtful editorial this month on the predicament of LABA step-down by invoking Macbeth’s notorious witches’ ominous chant (J Allergy Clin Immunol 2012;130:1256-1259). Likening the clinician’s dilemma at the FDA recommendation to withdraw LABAs for safety reasons from treatment of well-controlled asthma to the troubling brew of the witches, the authors review the history of long-acting beta 2 agonists’ use and the evidence that supports the safety concerns that prompted the FDA’s action. Szefler and Busse note that a recent evidence review does not concur that LABAs are unsafe when used in combination with ICS and, in fact, concludes that withdrawal of LABAs in that treatment context results in asthma worsening.

At the heart of the controversy are several “Catch-22s”: how and when to step down and, critically, with what to replace LABAs if control is lost. Clinicians and researchers are concerned that the delay in safety reporting will also delay the development of new asthma drugs in the LABA category. Further, the FDA safety trial does not address how to step-down LABAs in the event of a poor safety profile. This would require yet another set of trials, which implies further delays.

Results from the current FDA-mandated safety study are expected to be reported in 2016. Until then, the authors provide approaches for possible step-down in patients on ICS and LABA combination products. Among these, they suggest that clinicians consider the asthma natural history, especially over the previous year, the possibility of adjusting either the ICS or the LABA, and alternative supportive treatments, such as omalizumab or tiotropium, if they decide to step-down the LABA. Szefler and Busse emphasize that there is no current evidence that supports changing the current EPR-3 guidelines, which already advise against LABA monotherapy.