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Progress and Future Challenges
in Allergic Disease Research
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Food allergy, asthma and eczema are all atopic diseases that tend to occur in the same families, implying common genetic causes and immune mechanisms. For this reason, four research teams in Children's Division of Allergy/Immunology are especially well positioned to apply and adapt their pioneering research into the basic mechanisms of allergic disease to the study of food allergy in particular. Their discoveries have spawned a host of questions that are ripe for further study and define the hospital's agenda for future allergy research.
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Dale Umetsu, MD, PhD, Rosemary DeKruyff, PhD
Discovery of allergy genes -- Employing a congenic mouse model, Drs. Umetsu (The Prince Turki al Saud Professor of Pediatrics, Harvard Medical School) and Rosemary DeKruyff (Associate Professor of Pediatrics, Harvard Medical School) were the first to identify a four-member family of genes that plays a critical role in the development of allergy and asthma. The TIM family (standing for T-cell Immunoglobulin Mucin) inludes one particular genetic form, or polymorphism, of the TIM-1 gene. This polymorphism has proven in human studies to be a receptor for hepatitis-A (HAV), a virus associated with poor hygiene. One result of this virus-gene interaction is of great interest to investigators: people exposed to HAV have less risk of allergic reactions, including food allergy, suggesting that the virus has a specific protective action.
Questions for further study -- How can TIM-1 protect against food allergy? How can infection with HAV protect against food allergy? Does the HAV vaccine protect against allergy? Can we develop a treatment or vaccine that stimulates TIM-1 thereby replicating the protective effects of HAV? From an epidemiological perspective, does the TIM-1 gene reduce HAV severity?
Bacteria to help treat anaphylaxis -- Using dog studies of anaphylaxis, Dr. Umetsu's group with Dr. Lee Frick at UCSF has demonstrated that the common bacteria Listeria monocytogenes can act as a adjuvant (a catalyst when used in combination with other treatments) to induce antigen-specific protection against food-induced anaphylaxis, as well as allergy and asthma.
Questions for further study -- Can Listeria be used as a catalyst for a food allergy vaccine? What are the components that make Listeria effective? Can we develop a more refined version of Listeria? Are there other ways of induce antigen-specific T-cells (called regulatory T cells) that protect against food allergy?
New type of T-cell prominent in asthma -- In paper recently published in the New England Journal of Medicine (March 2006), Dr. Umetsu's team reported on the discovery of a new type of immune system T-cell (labeled NKT, short for natural killer T-cell) that is required for the development of asthma in mice and is prominent in human asthma as well.
Questions for further study -- Are NKT cells important in food allergy? Does Listeria affect NKT cells? Are there new therapies that can block the function of NKT cells and therefore specifically block the development of food allergy?
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Raif S. Geha, MD
IgE antibody regulation -- Raif S. Geha, MD, Chief of Children's Division of Allergy/Immunology and the James Gamble Professor of Pediatrics, Harvard Medical School, is widely recognized for his studies of the mechanisms of allergic diseases and primary immunodeficiency diseases, two fields that often intersect. Over the past two decades, Dr. Geha's group has made numerous advances in decoding the signals that lead immune system B-cells to switch to the production of IgE antibodies, which cause food allergy. Other important studies in Dr. Geha's laboratory include the development of mouse models of eczema and food allergy that are helping to elucidate the pathways of allergic reactions. Dr. Geha's laboratory has a unique mouse model of atopic dermatitis, which has shed enormous insight into the pathohgenesis of this common allergic disease which is often associated with food allergy. Finally, Dr. Geha was recently asked to participate in an NIH advisory panel to examine future directions in the study of food allergy.
Questions for further study -- What are the precise signaling pathways that lead a person to become sensitized to food? How can these pathways be disrupted or blocked to prevent food allergy? Can mouse models of food allergy demonstrate a relationship between food allergy and eczema?
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Hans Oettgen, MD, PhD
New functions of IgE antibody -- Anaphylactic reactions occur when patients produce IgE antibodies. These bind to receptors on mast cells and, upon interaction with food antigen, trigger the release of potent mediators (such as histamine) of allergic reactions. Dr. Hans Oettgen, MD, PhD, generated a unique line of mice, which completely lacks IgE. By comparing the immune systems of these knock-out animals with those of normal mice Dr. Oettgen has identified a number of previously unknown functions of IgE. These are likely to be relevant to the mechanisms of food allergy and suggest a potential therapeutic benefit of IgE-blockers.
Questions for further study -- Does IgE regulate mast cell numbers and IgE receptor expression in the gut and does this translate into increased food allergy responses in mice? Would IgE blockade make sense?
Using antihistamine drugs to prevent allergic reactions -- Using mouse models of asthma, the Oettgen group has shown that blockade of histamine receptors (using "antihistamine" drugs commonly used to treat established allergic responses) can actually prevent allergy. Recently-completed work using histamine receptor-deficient mice (under review) has shown that histamine regulates the migration of T lymphocytes to sites of inflammation.
Question for further study -- Can the onset of food allergy be prevented in animals by interference with histamine receptor signaling?
Pro-allergic factors in peanuts -- Dr. Oettgen's group has created mouse models of food allergy which, unlike standard models, do not involve unnaturally feeding mice the allergy-promoting factor, cholera toxin. They have identified a minor protein component of peanut that mimics the effects of cholera toxin and that may actually stimulate the induction of allergic responses to the peanut allergens.
Question for further study -- What are the biological mechanisms underlying the action of these allergy-promoting factors, which are called "natural adjuvants"?
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Lynda Schneider, MD
Clinical research -- The Division of Allergy/Immunology's clinical research is directed by Lynda Schneider, MD, one of our nation's leading clinical authorities on food allergy, atopic dermatitis and asthma. Ongoing projects include:
- A study to determine whether IVF conception increases the risk of childhood food allergy.
- A Parental Coping with Food Allergy Program that will assess levels of child and parent adjustment problems related to food allergy and to develop a Child and Parent Group Program to provide support to children and families coping with the challenges associated with the diagnosis of food allergy.
- Evaluation of the demographics, presenting problems, parenting stress index and skin evaluation in patients with atopic dermatitis (eczema). Study includes a review of patients with atopic dermatitis and food allergy who are seen by an allergist, nutritionist and psychologist.
Question for further study -- Can the FDA-approved drug Xolair, an anti-IgE agent used to treat asthma, effectively treat young children with severe food allergy and eczema. Dr. Umetsu is currently studying this possibility in young children with severe food allergy and eczema.
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