Food Allergen Immunotherapy: Current Status and Prospects for the Future

Food allergies are a growing problem, with one in twelve children having at least one allergy, commonly peanut, eggs, milk, wheat, soy, and shellfish. Despite the enormity of this problem, allergists have so far been unable to provide any pro-active treatments, apart from advising patients to avoid those foods and to keep an epi-pen nearby in case of anaphylaxis.  But there’s now some hope.  In this month’s issue of JACI, Dr. Wood surveys a slew of new therapies that aim to modify the immune system so that children can be desensitized to the foods they are allergic to (J Allergy Clin Immunol 2016; 137(4): 973-982). 

The classic approach of desensitizing patients to environmental allergens – like pollens or dander - through shots, has been tried before with food allergies. Although this approach was somewhat successful for a few children, the risks were far too high and it has largely been avoided.  Recently, oral immunotherapy – that is, ingesting really small amounts of the food, and increasing that dose of food, over the course of weeks – is coming into fashion.  Early research results suggest that this approach is effective but it is still far from coming to the clinic.

More recently, sublingual immunotherapy has been tried: small amounts of the food is allowed to sit under the tongue for two minutes and then swallowed.  This amount is slowly increased to help children become less sensitive.  Compared to oral immunotherapy, it’s safer, but it also seems to be less effective.

This has led people to think of other ways to desensitize allergic children to their foods. One way is percutaneous immunotherapy, in which a patch with the food allergen is applied to the skin.  While research is still early, it looks promising – although a lot of side effects like local redness or eczema at the site of the patch have been reported.

A lot of unknowns remain– how long should children be on immunotherapy?  What are the long term benefits … and risks?  How do we measure success? And should we also be using ‘adjunct therapies’ like the anti-IgE antibody omalizumab while trying this immunotherapy?  Currently, we don’t have many answers but, much to the relief of the 8% of children with food allergies, cutting edge research should hopefully change that very soon.

Prevention of Food Allergy

Children are afraid of a lot of things: the dark, strangers, and even the bogeyman.  But for more and more kids, ordinary foods, like peanuts, eggs, and milk, are becoming sources of fear.  Food allergies are becoming increasingly common in the developed world, and we don’t have a good explanation of why.  In this month’s issue of JACI, du Toit and his colleagues talk about the factors that lead to food allergies, and what can be done to prevent children from developing food allergies (J Allergy Clin Immunol 2016; 137(4): 998-1010). It’s clear that there are some risk factors that we just can’t change: male gender, a family history of food allergies, and even race can put children at a higher risk for developing food allergies.  But there are other things that we can possibly change.  Since children with eczema (atopic dermatitis) tend to have food allergies, there have been some discussion about whether preventing and controlling eczema by regularly applying moisturizers could help prevent food allergies.  Attendant to the link between high levels of aerosolized peanut dust and the development of peanut allergies, it has been suggested that, at least for peanuts, children may become sensitized through the skin and not the gut. Thus, it is possible that by keeping the skin barrier intact, we may be able to prevent peanut allergy.  Studies are still ongoing; if successful, these would be simple ways to stop food allergies in their tracks.

Another big hope has been that we can mitigate the development of food allergy by modifying the types of food that the mother takes while pregnant or lactating.  To date, these studies have been inconclusive.  Likewise, there is not much data on the efficacy, or even safety of, dietary interventions such as fatty acids, antioxidants, pre- and probiotics and vitamin supplementation.

The one glimmer of hope is that early introduction of common food allergens during infancy may be a pro-active approach.  Two major trials, LEAP (Learning Early About Peanut Allergy), and EAT (Enquiring About Tolerance) have suggested that introducing children to peanuts during infancy does not lead to food allergy, and may actually help to prevent them.

Food allergy is an enormous problem but new research on prevention may help to bring it under control, and make sure that children can have at least one less thing to be afraid of. 

Molecular and Cellular Mechanisms of Food Allergy and Food Tolerance

One may not believe it, but there is an entire universe in one's belly.  One's guts, in and of themselves, are over 300 square meters in surface area, and are home to thousands of different species of bacteria, as well as an immune system that is exquisitely tailored towards sensing, which of the 300 kilograms of food ingredients  that we ingest each year are safe, and which are unsafe.  So in this veritable universe of bowel, it is incredibly difficult to figure out what decides whether one becomes allergic or tolerant to food.

Chintharajah et al tackle this problem in this month’s issue of JACI (J Allergy Clin Immunol 2016; 137(4): 984-997).  They begin by surveying the types of immune cells that service our gut.  They highlight the central role of a specific type of immune cell called the dendritic cell, which lives in the walls of the small intestine (among other areas), in capturing the proteins in food particles, processing them, and then presenting them to other types of immune cells.  In certain circumstances, particular food proteins, chemical messengers from the gut, and the genetic makeup of immune cells can move the immune system into a pro-allergic state.  Perhaps just as important is the role of another type of immune cell, the regulatory T-cell, which ensures the proper balance of immune responses.  When these regulatory T-cells don’t work properly, the immune system can go into overdrive and become less likely to see food proteins as safe and tolerable.

Interestingly, a lot of other surprising factors that may lead to food allergies.  The microbiome is not limited to the gut. The skin has its own microbial ecology and skin breakdown and inflammation can alter the skin microbiome and allow sensitization to aerosolized food antigens such as peanut dust.  in addition,  the gut bacteria in children with food allergies are less diverse and have different levels of different types of bacteria compared to children without food allergies. 

All of these factors need to be taken into consideration when one tries to   modify the immune system to nudge it away from producing an allergic response.  There are ongoing studies trying to figure out how to desensitize allergic individuals to certain foods.  Knowing how these approaches alter the immune system will help take those techniques out of research centers and into the allergist’s office.

The Contributions of Allergic Sensitization and Respiratory Pathogens to Asthma Inception

Childhood asthma is the most common chronic disease among grade school children, and is responsible for the greatest number of school days missed.  Fortunately, there are now efficient management strategies to minimize the effect of asthma for many children, but what are the factors that lead to its development in the first place?  In this month’s issue of JACI, Jackson and colleagues discuss the risk factors that contribute to the development of asthma (J Allergy Clin Immunol 2016; 137(3): 659-665) .

As the authors explain, asthma starts long before the first wheeze.  In the first few years of life, as young immune systems encounter the environment around them, children who are more likely to eventually develop asthma tend to develop sensitization to aeroallergens and have recurrent lower respiratory infections.  This can happen alone, but new evidence suggests that they feed off each other, leading to a mix where asthma becomes a likely outcome.

Nearly all wheezing illnesses in the first few years of life are due to respiratory viruses.  New molecular techniques have shown that there is a wide variety of viruses that can cause upper and lower respiratory tract infections.  Among these, respiratory syncytial virus (RSV) and rhinoviruses (RV) are the most common pathogens.  Indeed, one third of children who have had RSV bronchiolitis develop recurring wheezing episodes, and one study showed that passively immunization against RSV led to an 80% reduction in the risk of recurrent wheezing in nonatopic children.  Rhinovirus, which was previously thought to only cause upper respiratory tract infections, is now known to cause lower respiratory tract infections too.  And, at least in one Finnish study, 60% of children with RV who wheezed in the first two years of life continued on to develop asthma five years later.  Bacteria may also play a role, but the evidence is preliminary and mixed: some bacterial infections are associated with wheezing and asthma, but exposure to other bacteria may actually be protective.

Additionally, it’s been known for some time that environmental allergies are major contributors to asthma.  In addition, they increase the chance that children will get wheezing respiratory infections.  Part of it is because allergic sensitization leads to enhanced airway responsiveness due to respiratory viral infections.  Another important factor is that allergen exposure impairs antiviral responses, such as production of Interferons I & III.  Interestingly, the use of omalizumab, a medication targeting IgE, the type of antibody responsible for allergens, also leads to a decrease in virus-induced asthma exacerbations.

Of course, there is so much more to the story.  What makes certain children more susceptible to viral infections and allergies is still unknown.  17q21, CDHR3 and IL-33 polymorphisms offer possible answers, but they are only pieces of the puzzle.  The biggest question on the horizon is can we ward off asthma by preventing allergen sensitization or avoiding  severe respiratory infections.  More research is needed, but there’s at least some glimmer of hope that we can finally stop asthma before it actually sets in.

Leveraging Gene-Environment Interactions and Endotypes for Asthma Gene Discovery

Asthma is a pressing public health problem in many developed countries.  But we don’t really know what causes asthma.  In this month’s issue of JACI, Drs. Bønnelykke and Ober talk about the genes and the gene-environment interactions that are thought to underlie susceptibility to developing asthma (J Allergy Clin Immunol 2016; 137(3): 667-679).

So far, there have been about 15 genes strongly linked to asthma, based on large genome-wide association studies (GWAS).  But each of these individual gene variants confers only a very modest increase in asthma risk.  Clearly, there remains a lot of missing information.  Although a significant portion of the risk for asthma may be attributed to environmental exposures, genetic variants may play a stronger role among subgroups of asthmatics who share similar clinical characteristics or similar exposures, as the article discusses.

To tease this apart, genome-wide interaction studies (GWIS) have been conducted to associate specific gene variants to asthma in the presence of specific environmental exposures.  Additionally, previous studies have already shown interactions between genes, early life viral wheezing illnesses, and asthma onset in childhood.  In particular, genetic variants at the 17q locus are associated with asthma among children with significant rhinovirus infections (common colds) during early childhood, but not among children who do not get very sick with rhinovirus infection.  Interestingly, these same variants at the 17q locus are associated with protection from developing asthma among children exposed to farm animals in early life.  Similarly, a variant of the CDHR3 gene, which encodes for a receptor for one type of rhinovirus, is associated with risk of severe childhood asthma.

There are several challenges to performing GWIS studies. For example, environmental exposures can be difficult to measure precisely and it is often impossible to dissect effects of a specific exposure from other related factors. An alternative approach is to study gene-environment interactions in cell models where single exposures can be studied in isolation and effects can be directly attributed to the exposure. Drs. Bønnelykke and Ober suggest that future studies using this approach will complement and guide human studies and thereby help understanding the complex mechanisms of asthma. 

    

Regardless, the roots of asthma seem to lurk at the intersections between genetic susceptibility and environmental exposures.  As Drs. Bønnelykke and Ober explain, future studies will require targeted, thoughtful research linking particular exposures in combination with genetic variants to asthma risk.

The microbial environment and its influence on asthma prevention in early life

It’s a tale of two farming communities: one run by the Amish, who retain very traditional farming practices with horses for field work, and other run by Hutterites, who have embraced modern farming technologies.  Despite coming from the same genetic background and having otherwise similar lifestyles, the Hutterites have a greater than 40% rate of allergen sensitization, while the Amish have a rate lower than 7.5%.  What can account for such a difference?  As Dr. von Mutius outlines in this month’s issue of JACI, it’s likely in the billions of bacteria that colonize the skin, gut, and respiratory passages as well as those that live all over your house, workplace, and everywhere in between (J Allergy Clin Immunol 2016; 137(3): 680-689).

Believe it or not, it’s only been within the past few years that we’ve even found out about all these bacteria.  New technology has enabled scientists to take a closer look at the microbiome, the collection of microbes that colonize virtually everything around and within us.  These microbiomes are diverse and dynamic; and can provide fingerprints about the world around us.  Cat and dog ownership can be predicted by the presence of certain bacteria.  More significantly, the presence of certain bacteria, like H. influenzae, M. catarrhalis, and S. pneumoniae in the throats of 1 month old infants, and somewhat predict the development of persistent wheeze and asthma by age 6.

This is seen in larger epidemiologic studies.  Children who enter daycare before their first birthday are at much lower risk of developing allergen sensitization compared to those who enter after their second birthday.  And, as mentioned above, upbringing on a farm with animal husbandry, especially around dairy animals, confers significant protection.  This is extended to urban environments as well, where exposure to high levels of cockroach, mouse, and cat allergens in the presence of Firmicutes and Bacteroidetes bacteria actually conferred some protection against asthma.

This field is evolving tremendously, and there are still a lot of unanswered questions.  We still don’t know which particular microbes are protective and whether increased diversity really does help to prevent sensitization to allergens.  Nevertheless, with newer, more sensitive technologies that can scan and identify bacterial and other microbial DNA, we’re on the path towards better understanding how our microbial environment shapes our susceptibility to asthma, allergies, and other immune disorders.

International consensus on allergen immunotherapy-II: Mechanisms, standardization, and pharmacoeconomics

This month, JACI presents the second portion of the comprehensive international consensus (ICON) statement on allergen immunotherapy. The ICON statement is an effort of the International Collaboration in Asthma, Allergy and Immunology (iCALL) that includes the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI) and the World Allergy Organization (WAO). Jutel et al. review the evidence on how allergen immunotherapy (AIT) works and summarize what lies on the horizon (J Allergy Clin Immunol 2016; 137(2): 358-368).

A number of mechanisms underlie an allergic response to a substance such as grass pollen, house dust mites, or bee venom. Allergen immunotherapy involves slowly increasing exposure to an allergen over time, ideally resulting in a patient’s increased tolerance and clinical improvement. The literature indicates that administration of AIT leads to early decreases in the susceptibility of mast cells and basophils to respond to environmental proteins, even in the presence of elevated allergen-specific immunoglobulin (Ig)E. Desensitization is followed by allergen-specific T-regulatory (Treg) and B-regulatory (Breg) cell generation and regulation of allergen-specific IgE and IgG₄. In the longer term, changes in memory T- and B-cell compartments and shift in the balance of type 1 T-helper (Th1) and type 2 T-helper (Th2) cells result in sustained improvement.

There are a number of barriers to the use of AIT worldwide. One such barrier is a low awareness of its potential, in the context of patient welfare and improved pharmaco-economics. AIT is currently the only therapy with the capacity to alter the course of allergic disease. Further, standardization of the potency, consistency, and stability of allergen extracts used in AIT is essential, as is the standardization of the practices of regulatory agencies from different parts of the world. Potential facilitators for acceptance and increased use of AIT include validation and consensus on outcome measures for clinical trials; validated methods of assessing AIT’s impact; and post-marketing studies demonstrating the positive impact of AIT on the quality of life of its recipients.