Category: Allergies

Categories : Allergies PaediatricsTags :

Eliminating the Risk of Anaphylaxis from Children’s Peanut Allergy Desensitisation

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Oral immunotherapy helps many children with peanut allergy – but for some, it can also trigger severe allergic reactions. In the journal Allergy, a team led by Young-Ae Lee explains what might be behind these differences and how treatment could become more personalised.

Peanut allergy is one of the most common – and most dangerous – food allergies. Tiny amounts of the protein-rich legumes can be enough to cause allergic reactions like itching and swelling, or even life-threatening anaphylaxis. For a long time, the only solution was to avoid peanuts as vigilantly as possible. Since many foods may contain traces of peanuts, that’s still a major challenge, especially for parents of affected children. Emergency medication must always be close at hand.

Recently, oral desensitisation has become available for children with peanut allergies. “Some children respond well to this treatment, but others don’t benefit at all,” says Professor Young-Ae Lee, Group Leader of the Molecular Genetics of Allergic Diseases lab at the Max Delbrück Center. “In some cases, the therapy – based on gradually increasing doses of peanut allergens – can even trigger anaphylactic reactions.”

A team led by Lee and Professor Kirsten Beyer, Head of the Pediatric Allergy Clinical Research Center at Charité – Universitätsmedizin Berlin, has now investigated why children respond so differently to the therapy and how to make it safer and more effective. Their study, published in “Allergy,” was led by first author Dr Aleix Arnau-Soler, a scientist in Lee’s lab. “We looked for molecular changes in the immune systems of children undergoing oral immunotherapy ¬– and we found them,” explains Arnau-Soler.

Gut immune cells play a key role

For their study, the researchers analyzed blood samples from 38 children, with an average age of seven, who were undergoing oral desensitization for peanut allergy at Charité. The team measured levels of immunoglobulins, which are allergy-related antibodies, and cytokines, which are inflammatory messengers, before and after therapy. 

Our results open the door to personalised approaches to treating peanut allergy – which affects three per cent of all children in industrialised countries – more effectively and safely in the future.

Young-Ae LeeHead of the “Molecular Genetics of Chronic Inflammation and Allergic Disease” lab

They also assessed how much peanut protein each child could tolerate before and after treatment – essentially, how successful the desensitization was. To delve deeper, they used modern omics technologies to identify which genes in the children’s immune cells were activated when they were exposed to peanut proteins in the lab.

“Children who responded well to the therapy already had a less reactive immune system before treatment began. Their blood showed lower levels of immunoglobulins and cytokines,” explains Arnau-Soler. These findings could help identify in advance which children are most likely to benefit from desensitization – and those who are at higher risk of side effects.

The team also found consistent differences in gene expression and DNA methylation patterns between children who responded well and those who didn’t. Methylation plays a key role in regulating gene activity. “These differences were particularly pronounced in certain immune cells that are rarely found in the blood, but more common in the gut, where they perform important functions,” says Arnau-Soler. These included both specialized T cells, part of the adaptive immune system, and cells involved in the body’s innate defenses.

New biomarkers pave the way for personalized therapy

“Our results open the door to personalized approaches to treating peanut allergy – which affects three percent of all children in industrialized countries – more effectively and safely in the future,” says Lee. “We now have potential biomarkers to find out how well a child will respond to the therapy and what risks are associated with it in each individual case, even before the therapy begins.” It may soon be possible to tailor the length of treatment and the amount of peanut allergen given to each child’s unique immune profile.

The team is currently working to validate their findings in a follow-up study. They also plan to further investigate the gut-associated immune cells found in blood. “At the same time, we’re developing a predictive model so that in the future we can use a simple blood test to better tailor oral desensitization to the individual child,” adds Arnau-Soler. That could make peanut allergy far less frightening for families.

Source: Max Delbrück Center for Molecular Medicine

Categories : AllergiesTags :

Nasal ‘Molecular Shield’ May Soon Treat a Common Pollen Allergy

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Approximately 40% of the European population are allergic to pollen, and their symptoms cause an estimated loss of 100 million school- and workdays every year. The prevalence of hay fever has been surging for decades and this is likely to continue – a change so fast that genetic and health changes can’t be solely responsible. Improved hygiene, the widespread use of antibiotics and antiseptics, lifestyle changes, diet, pollution, and the climate crisis are also thought to play a major role in this increase.

But now there is new hope for sufferers. As proof-of-principle, researchers have engineered an antibody from mice, which when applied to the inside of the nose stops mice from developing hay fever and asthma symptoms in response to mugwort pollen. Mugwort is the most common cause of pollen allergies in central Asia and parts of Europe, where between 10% and 15% of people with hay fever are allergic to it. The article was published in Frontiers in Immunology.

“This is the first time a monoclonal antibody designed to block a specific pollen allergen has been delivered directly into the nose, and been shown to protect against allergy symptoms in the upper and lower airways,” said Prof Kaissar Tabynov, the director of the International Center for Vaccinology at the Kazakh National Agrarian Research University (KazNARU) in Almaty, and the study’s senior author.

“In the future, similar antibodies could be developed for other major pollen allergens, such as ragweed or grass. This opens the door to a new generation of precision allergy treatments that are fast-acting, needle-free, and tailored to individual allergen sensitivities.”

‘Molecular shield’

Traditional treatment is allergen-specific immunotherapy: patients are exposed to gradually increasing doses of the allergen, until they become desensitised. However, this doesn’t work for all patients, and in recent decades, so-called ‘allergen-specific monoclonal antibody therapy’ has increasingly come to the fore as an alternative.

In allergen-specific monoclonal antibody therapy, researchers engineer antibodies of the IgG class, which either specifically recognise the allergen itself and block it, or bind to IgE antibodies in general. In either case, this prevents the allergen from triggering an allergic reaction. A disadvantage is that typically, these antibodies needed to be injected into the bloodstream – until now.

“Our method acts immediately and locally at the lining of the nose, by neutralising the allergen on contact. This ‘molecular shield’ not only prevents IgE antibodies from being activated, but may also reduce inflammation through other mechanisms, such as calming immune cell responses and promoting regulatory pathways,” explained Tabynov.

The researchers injected mice with a dose of mugwort pollen, stimulating them to produce antibodies against it. The mice were then humanely euthanised and their spleens harvested to isolate white blood cells. The use of mice was approved by the local Institutional Animal Care and Use Committee, under the Ministry of Health of the Republic of Kazakhstan.

The white blood cells were then fused with laboratory-grown cancer cells from mice with multiple myeloma. This yielded five immortal ‘hybridoma’ cell lines which each secreted a single type (hence ‘monoclonal’) of antibody against mugwort pollen. A suite of diagnostic tests showed that the most powerful was produced by hybridoma cell line XA19, which was selected for further development.

Reduction in allergy symptoms

To test their efficacy, purified antibodies from XA19 were administered to the interior of the nose of five mice, which had been stimulated to become allergic to mugwort pollen through injections of pollen extract. Five additional mice served as positive control: they had been similarly sensitized but received a placebo. A further five mice were the negative control, neither sensitized to the pollen nor given monoclonal antibodies. Three weeks later, all mice were exposed three times under anaesthesia to an aerosol of mugwort pollen, as well as to pollen extract delivered directly inside the nose.

The results showed that the sensitized mice given the XA19 antibody displayed a major reduction in allergy symptoms compared to controls: for example, they showed a weaker ear swelling response to the pollen (a common allergic reaction in rodents); they rubbed their nose less frequently, indicating less irritation of the upper airways; their full lung capacity was preserved upon exposure to the pollen; and they showed less inflammation inside the nostrils. Inside the lungs, levels of two inflammation-promoting molecules called cytokines were likewise reduced.

The researchers concluded that the monoclonal antibody from XA19 is effective in blocking allergic reactions against mugwort pollen triggered by IgE, at least in mice.

“Before this treatment can be tested in people, we need to adapt the antibody to make it suitable for humans – a process called ‘humanisation’ – and conduct additional preclinical safety and efficacy studies,” said Tabynov.

“If these are successful and provided we have adequate support, we could begin clinical trials in two to three years, though bringing it to market would likely take five to seven years. We are already planning for this transition and working on scaling up production.”

Source: Frontiers

Categories : Allergies Respiratory DiseasesTags :

Inflammatory Cells Remain in the Blood After Treatment of Severe Asthma with Biologics

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Biological drugs have improved the lives of many people with severe asthma. However, a new study from Karolinska Institutet shows that some immune cells with high inflammatory potential are not completely eradicated after treatment.

Biological drugs have become an important tool in the treatment of severe asthma. 

“They help most patients to keep their symptoms under control, but exactly how these drugs affect the immune system has so far remained unknown,” says Valentyna Yasinska, consultant in pulmonary medicine at Karolinska University Hospital and doctoral student at Karolinska Institutet’s Department of Medicine in Huddinge.

Increased in blood

In a new study published in the scientific journal Allergy, researchers at Karolinska Institutet have explored what happens to the immune cells of patients being treated with biologics. By analysing blood samples from 40 patients before and during treatment, they found that instead of disappearing during treatment, certain types of immune cell – which play a key part in asthma inflammation – actually increased.

“This suggests that biologics might not attack the root of the problem, no matter how much they help asthma patients during treatment,” says Jenny Mjösberg, professor of tissue immunology at Karolinska Institutet’s Department of Medicine in Huddinge. “Continued treatment might be necessary to keep the disease under control.”

Surprising finding

The study is based on data from patients with severe asthma sourced from the BIOCROSS study. The researchers used advanced methods such as flow cytometry and single-cell sequencing to determine the properties and function of the immune cells.

“We were surprised to find that blood levels of inflammatory cells increased rather than decreased,” says Lorenz Wirth, doctoral student at the same department at Karolinska Institutet. “This could explain why inflammation of the airways often returns when the treatment is tapered or discontinued. It is important that we understand the long-term immunological effects of these drugs.”

Relatively new drugs

Little is still known about the long-term effects of biologics like mepolizumab and dupilumab since they are relatively new, having been prescribed to asthmatics for less than ten years. 

The next stage of the study will be to analyse samples from patients with a long treatment history and to study lung tissue to see how the immune cells are affected in the airways.

Source: Karolinska Instutet

Categories : Allergies DermatologyTags :

Can Early Exposure to Dogs Lessen Genetic Susceptibility to Eczema?

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New research published in Allergy indicates that certain environmental exposures may affect a child’s risk of developing atopic eczema, a condition characterised by dry, itchy, and inflamed skin. In other words, although some people may be genetically predisposed to eczema, certain environmental factors may increase or decrease that risk.

For the study, investigators analysed data from 16 European studies to test for interactions between the 24 most significant eczema-associated genetic variants and 18 early-life environmental factors. They applied their findings to an additional 10 studies and used lab modelling tests to assess their results.

The first analysis (including 25 339 individuals) showed suggestive evidence for interaction between 7 environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking, and washing practices) and at least one established genetic variant for eczema, with 14 interactions in total.

In the additional analysis (254 532 individuals), dog exposure interacted with a particular genetic risk variant on chromosome 5, near the gene that codes for the interleukin-7 receptor, a protein involved in immune cell function. Lab modelling tests showed that this variant affects expression of interleukin-7 receptor in human skin cells and that dog exposure modifies the genetic effect of this variant on the development of eczema, essentially providing a protective effect by suppressing skin inflammation.

Additional studies are needed to explore these lab findings and the other potential interactions identified in the first analysis.

“Our research aims to answer some of the most difficult questions that I am asked in clinic: ‘Why does my child have eczema?’ and ‘What can I do to help protect my baby?’ We know that genetic make-up affects a child’s risk of developing eczema and previous studies have shown that owning a pet dog may be protective, but this is the first study to show how this may occur at a molecular level,” said corresponding author Sara J. Brown, MD, PhD, FRCPE, of the University of Edinburgh. “More work is needed, but our findings mean we have a chance to intervene in the rise of allergic disease, to protect future generations.”

Source: Wiley

Categories : AllergiesTags :

Key Player in Childhood Food Allergies Identified: Thetis Cells

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A decade ago, a clinical trial in the UK famously showed that children who were exposed to peanuts in the early months of life had reduced risk of developing a peanut allergy compared with children who avoided peanuts.

Now, researchers at Memorial Sloan Kettering Cancer Center (MSK) have a likely answer as to why that’s the case: Thetis cells.

This recently discovered class of immune cells, which were first described by MSK researchers in 2022, plays an essential and previously unknown role in suppressing inflammatory responses to food, according to findings published in Science, one of the world’s premier scientific journals.

Moreover, the study, which was conducted in mouse models, points to a critical window in the early months of life for training the immune system not to overreact to food allergens, termed “oral tolerance.”

The study also opens the door to new therapeutic possibilities, the researchers say.

“This is a great example of how clinical studies can reveal clues to fundamental mechanisms in biology,” says physician-scientist Chrysothemis Brown, MBBS, PhD, the study’s senior author. “These new understandings can pave the way for new treatment strategies for food allergies, which are desperately needed.”

The research was led by co-first authors from the Brown Lab: paediatric hematologist-oncologist Vanja Cabric, MD, and research assistant Yollanda Franco Parisotto, PhD.

Thetis Cells Train the Immune System To Tolerate Helpful Outsiders

Thetis cells are a type of antigen-presenting cell, whose job is to present foreign substances (antigens) to other immune cells. Antigen-presenting cells must educate the immune system. These cells provide signals that tell the immune system to attack foreign bacteria and viruses – or instruct it to tolerate harmless proteins in the foods we eat.

Previous research led by Dr Brown and immunologist Alexander Rudensky, PhD, Chair of the Immunology Program at MSK’s Sloan Kettering Institute, identified a window in early life where a “developmental wave” of Thetis cells within the gut creates an opportunity for developing immune tolerance.

“We previously showed that Thetis cells train the immune system not to attack the helpful bacteria in the digestive system. So we wondered whether these cells might also be important for preventing inflammatory responses to food, and whether the increased abundance of the cells during early life would result in increased protection against food allergy,” says Dr. Brown, whose lab is in MSK’s Human Oncology and Pathogenesis Program (HOPP).

The new study found that Thetis cells not only help to broker peace accords with “good” bacteria, but also with proteins in foods that can act as allergens, such the Ara h proteins found in peanuts (though they weren’t specifically tested in the study) or the ovalbumin found in eggs.

Thetis cells got their name because they share traits with two different types of antigen-presenting cells: medullary thymic epithelial cells and dendritic cells, just as Thetis in Greek mythology had shape-shifting attributes.

A Key Role for Gut-Draining Lymph Nodes

The research team used a variety of genetically engineered mouse models to investigate oral tolerance. They attached a fluorescent dye to ovalbumin in order to visualise which cells in the gut interacted with it.

And this showed that a subset of Thetis cells, the same ones that regulated tolerance to healthy gut bacteria, took up the protein. This allowed Thetis cells to program another type of immune cell called regulatory T cells to suppress the immune response to the egg protein, essentially telling the body it was safe.

“This process is often studied in adult models, but by examining what happens when mice first encounter food proteins at the time of weaning, we could see which specific cells were critical to generating tolerance to food during early life,” Dr. Cabric says.

Although Thetis cells could also induce tolerance throughout life, there was a significant difference in the immune response when the egg protein was introduced later.

Source: Memorial Sloan Kettering Cancer Center

Categories : AllergiesTags :

Why Are Urban Children More Prone to Allergies?

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Study finds unique immune cell linked to risk

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A previously uncharacterised subset of immune cells may play a critical role in the development of allergic diseases and explain differences between urban and rural populations. The finding, published in the journal Allergy, provides new insight into how the immune system is shaped in early life – and why urban children are more prone to allergies than children from rural areas.

Led by researchers from the University of Rochester Medical Center (URMC) Department of Pediatrics, including MD/PhD student Catherine Pizzarello and senior author Kirsi Järvinen-Seppo, MD, PhD, the study uncovered a unique subpopulation of T cells known as helper 2 (Th2) cells with distinct molecular characteristics.

T-cells are the foundational immune cells that fight off infections, but there is evidence that this specific subtype is recognizing certain foods as allergenic and attacking them, according to Jarvinen-Seppo.

“These pro-allergic T cells are more inflammatory than anything previously described in this context,” said Järvinen-Seppo, chief of Pediatric Allergy and Immunology at UR Medicine Golisano Children’s Hospital. “They were found more frequently in urban infants who later developed allergies, suggesting they may be a predictive biomarker or even a mechanistic driver of allergic disease.”

The study compared blood samples from urban infants with those from infants in a farming community, specifically the Old Order Mennonites (OOM) of New York’s Finger Lakes region – known for their low rates of allergies. Researchers found that while urban infants had higher levels of the aggressive Th2 cells, OOM infants had more regulatory T cells that help keep the immune system in balance and reduce the likelihood of allergic responses.

While additional research is needed to identify a possible cause, Jarvinen-Seppo speculates that differences in the development of the gut microbiome between the two populations, and more exposure to “healthy” bacteria in rural children, may be a factor.

“The farming environment, which is rich in microbial exposure, appears to support the development of a more tolerant immune system. Meanwhile, the urban environment may promote the emergence of immune cells that are primed for allergic inflammation,” said Jarvinen-Seppo.

The work is part of a broader, NIH-funded investigation into how early-life exposures influence long-term immune outcomes. In 2023, Järvinen-Seppo’s team received a $7 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) to study environmental, microbiome, and immune differences between OOM and urban infants. The goal is to continue this foundational work to uncover protective factors that could be translated into preventive therapies, including probiotics or microbiome-supporting interventions.

“If we can identify the conditions for this disparity between the different T cell subpopulations, we can potentially find solutions in allergic disease development,” Järvinen-Seppo said.

Source: University of Rochester Medical Center

Categories : Allergies Environmental EffectsTags :

How is Climate Change Affecting Seasonal Allergies?

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A review published in The Laryngoscope indicates that climate change’s effects on pollen seasons and concentrations are contributing to increasing rates of allergic rhinitis.

When investigators assessed research published between 2000 and 2023, they identified 30 studies that reported on the current epidemiological state of allergic rhinitis, described factors related to climate change, and observed how global warming is affecting pollen seasons and allergy symptoms.

Sixteen studies reported longer pollen seasons and/or higher pollen concentrations related to climate change. As an example, total pollen emissions in the U.S. are projected to increase by 16–40% by the end of the century and pollen season length to increase by 19 days. Four studies reported an increase in allergic rhinitis–related health care usage, particularly among low-income residents. Two studies reported that health care professionals want more education on climate change. 

“Physicians are uniquely positioned to witness the impact of allergic rhinitis on patient outcomes and can adapt their practice as climate change intensifies,” said corresponding author Alisha R. Pershad, BS, a third-year medical student at the George Washington University School of Medicine and Health Sciences. “As trusted voices in the community, they should leverage their frontline experience to advocate for meaningful change in addressing the climate crisis.”

Source: Wiley

Categories : Allergies PaediatricsTags :

Review Supports Introducing Small Amounts of Food Allergens During Early Childhood

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A review in Clinical & Experimental Allergy concludes that exposing young children to small amounts of foods that they’re allergic to is safer than avoiding the foods altogether, which could be very dangerous if accidental exposure occurs.

The review notes that exposing preschool-aged children to small amounts of food allergens—called oral immunotherapy—can lessen the severity of a reaction following an accidental exposure. Also, delaying exposure until a later age misses the window of opportunity when oral immunotherapy is safest, and it prolongs unnecessary dietary restrictions. Also, after early childhood avoidance, some people who outgrow their allergy will not reincorporate the food into their diet due to fear and anxiety, thus potentially increasing their chance of redeveloping the allergy.

A growing body of evidence indicates that oral immunotherapy is safe and effective in preschoolers, but additional research is needed to clarify its impact on children’s health and quality of life.

“This research highlights a critical shift in how we approach food allergies—moving from strict avoidance to controlled exposure in early childhood, which not only reduces the risk of severe reactions but also helps prevent long-term negative consequences of living with food allergies,” said corresponding author Lianne Soller, PhD, of the University of British Columbia, in Canada.

Source: Wiley

Categories : AllergiesTags :

Immunotherapy Lets Children with High-threshold Allergy Safely Eat Peanut Butter

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Children with high-threshold peanut allergy who ate gradually larger doses of store-bought peanut butter achieved significantly higher and long-lasting rates of desensitisation compared to those who avoided peanuts, according to a new study led by researchers at the Icahn School of Medicine at Mount Sinai.  

Results of the trial appear in NEJM Evidence. 

“Our study results suggest a safe, inexpensive and effective pathway for allergists to treat children with peanut allergy who can already tolerate the equivalent of at least half a peanut, considered a high-threshold peanut allergy,” said Scott Sicherer, MD, director of a food allergy institute at Mount Sinai and lead author of the paper. “Our findings open the gateway to personalised threshold-based treatments of food allergy and will encourage additional studies that delve deeper into peanut and other foods for this approach that might be a game-changer for the majority of people with food allergies.”   

The most common approach to a food allergy is to avoid the food, but in recent years peanut oral immunotherapy – medically supervised, very gradual daily feeding of increasing amounts of pharmaceutical-grade peanut protein – has become an option for individuals with peanut allergies.. However, studies that led to Food and Drug Administration approval of an injected biologic and oral peanut immunotherapy have specifically focused on people who react to very small amounts of food allergens, such as half a peanut or less (considered a low-threshold peanut allergy).

“Years ago, when people with milk and egg allergies were advised to undertake strict avoidance, our team initiated studies that found most people with milk and egg allergies could tolerate these foods in baked goods, which changed the global approach to these allergies,” said Julie Wang, MD, Professor of Pediatrics at the Icahn School of Medicine, clinical researcher at the Jaffe Food Allergy Institute, and co-senior author of the paper. “The research team recognised that more than half of people with peanut allergy can tolerate half a peanut or more, and thought that this group of people might be treatable if we took a different approach to peanut oral immunotherapy. We were thrilled to find that this treatment strategy was even more successful than we had anticipated.”  

To test this hypothesis, the study team recruited 73 children ages 4 to 14 years old. Study participants were assigned, at random, to either test the new treatment strategy or continue avoiding peanuts. The children in the peanut-ingestion group began with a minimum daily dose of 1/8 teaspoon of peanut butter and gradually increased their dose every eight weeks over the course of 18 months, ending at one tablespoon of peanut butter or an equivalent amount of a different peanut product. All dose increases took place under medical supervision. None of the study participants in the peanut-ingestion group had severe reactions or needed epinephrine during home dosing  and only one received epinephrine during a supervised dosing visit.  

Following the treatment regimen, children from the peanut-consuming cohort participated in a feeding test, carefully supervised by the study team, to evaluate how much peanut they could eat without an allergic reaction. All 32 children from the peanut-consuming group who participated in the feeding test could tolerate the maximum amount of 9 grams of peanut protein, or three tablespoons of peanut butter. By contrast, only three of the 30 children from the avoidance group who underwent the feeding test after avoiding peanuts for the duration of the study could tolerate this amount.  

Because the trial took place during the COVID-19 pandemic and some families preferred avoiding close encounters indoors, some did not return to the study site for the feeding test. Using a common statistical technique to account for the children who missed the feeding test, the team reported that 100 percent of the ingestion group and 21 percent of the avoidance group tolerated an oral food challenge that was at least two doses more than they could tolerate at the beginning of the study.  

To test if the response to treatment was durable, children in the peanut-ingestion group who could tolerate nine grams of protein during the feeding test went on to consume at least two tablespoons of peanut butter weekly for 16 weeks and then avoided peanuts entirely for eight weeks. Twenty-six of the 30 treated children who participated in a final feeding test after the eight-week abstinence period continued to tolerate nine grams of peanut protein, indicating that they had achieved sustained unresponsiveness to peanuts. The three participants from the avoidance group who could eat nine grams of peanut protein without reaction at the earlier food test were considered to have developed natural tolerance to peanuts. A comprehensive analysis of data collected from all 73 study participants revealed that 68.4 percent of the peanut-ingestion group achieved sustained unresponsiveness, while only 8.6 percent of the avoidance group developed a natural tolerance.   

“These study results are very exciting and a huge step forward in personalizing food allergy treatment,” concluded Dr. Sicherer, the Elliot and Roslyn Jaffe Professor in Pediatric Allergy and Immunology at Mount Sinai. “My hope is that this study will eventually change practice to help these children and encourage additional research that includes this approach for more foods.”  

In addition to expanding the work to more foods and validation studies of their approach, the Mount Sinai study team aims to determine a better way of identifying individuals with higher thresholds, because the best way to do so currently requires a feeding test that is bound to cause an allergic reaction.  

Source: The Mount Sinai Hospital / Mount Sinai School of Medicine

Categories : AllergiesTags :

New Clues to the Mechanism Behind Food Tolerance and Allergies

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How the gut decides which food to tolerate and which food to respond to as an allergen has long puzzled scientists. Now, new research identifies specific gut cell types that communicate with T cells – prompting them to tolerate, attack, or simply ignore – and explains how these opposing responses are triggered.

The findings, published in Science, give scientists a new understanding of how the intestinal immune system keeps the gut in balance, and may ultimately shed light on the root causes and mechanisms of food allergies and intestinal diseases.

“The big question is, how do we survive eating?” says lead author Maria C.C. Canesso, a postdoctoral fellow in the laboratories of Daniel Mucida and Gabriel D. Victora. “Why do our bodies normally tolerate food, and what goes wrong when we develop food allergies?”

Gut decisions

The intestinal immune system is complicated machinery. Tolerance to food begins with antigen presenting cells, or APCs, instructing T cells to stand down. This signal gives rise to pTregs, a special type of T cell that calms the immune response to food particles, and kicks off a cascade of activity involving additional immune cells that reinforce the message. But without knowing which specific APCs run the show, it’s difficult to tease out the ins and outs of the body’s eventual tolerance to food and intolerance to pathogens.

“There are so many types of antigen-presenting cells,” Canesso says. “Pinpointing which ones are doing what is a longstanding technical challenge.”

She began exploring this conundrum as a PhD student in the Mucida lab, which focuses on how the intestine balances defense with tolerance. During her postdoc, Canesso also joined the Victora lab, which developed a technology known as LIPSTIC that helps scientists catalogue cell-to-cell interactions, particularly among immune cells.

“The technological advances made by the Victora lab allowed us to understand immune cell dynamics that would not have been possible using existing tools,” says Mucida, head of the Laboratory of Mucosal Immunology.

After optimising LIPSTIC for the task, Canesso and colleagues succeeded in pinpointing those APCs that promote tolerance – a process primarily handled by two types: cDC1s and Rorγt+ APCs. These cells capture dietary antigens from ingested food and present them to T cells, giving rise to the pTregs that ensure food tolerance.

“When we first developed LIPSTIC, we were aiming to specifically measure the interactions between B and T cells that promote antibody responses to vaccines,” says Victora, head of the Laboratory of Lymphocyte Dynamics. “It was to Maria’s credit that she was able to adapt this to settings so different from those it was originally intended for.”

They also uncovered how infections of the intestines can cause interference, demonstrating in mice that the parasitic worm Strongyloides venezuelensis shifts the balance away from tolerance promoting APCs and toward those that promote inflammation. Indeed, mice infected with this worm during a first exposure to a dietary protein display reduced tolerance towards this protein, and signs of allergy when challenged.

Finally, the team characterised the molecular signals underpinning these immune shifts, identifying key cytokines and pathways that influence how APCs present antigens and modulate immune responses. For example, the infection induced a surge in pro-inflammatory cytokines such as IL-6 and IL-12, which have been shown to nudge APC activity toward inflammatory outcomes. This inflammatory environment appears to override the immune system’s tolerance mechanisms. “The worm infection induces this an expansion of non-tolerogenic APCs that help deal with the infection, outnumbering the tolerance-related APCs,” Canesso says.

From food to food allergies

Together, the findings illuminate how the immune system maintains food tolerance and, in the case of parasitic infections, highlights the specific immune mechanisms that can go awry. “It’s important to note that our findings do not suggest that worm infections trigger food allergies,” clarifies Mucida, head of the Laboratory of Mucosal Immunology. “They reduce tolerance mechanisms while the immune response focuses on dealing with the worms.”

While these findings aren’t directly relevant to food allergies, they do lay some groundwork for further investigation into food intolerance. “If food allergies are derived from dysregulation on intestinal APCs inducing tolerance and protective responses to infections, perhaps we could one day modulate those APCs specifically to prevent food allergies,” Canesso says.

Next up, Canesso plans to shift her focus toward early life, exploring how maternal-neonatal interactions shape food intolerance. “Most allergies develop early in life,” she says. “I want to focus on how breast milk and maternal exposure to dietary antigens may influence a baby’s immune system, potentially shaping their risk of developing food allergies.”

Source: Rockefeller University