Exploiting Inhibitory Siglecs to Combat Food Allergies

Overview: Food allergies affect 6%-8% of children and 4% of adults in the United States, impacting over 12 million citizens and their families. Food allergies are costing the US healthcare system an estimated $25 billion annually. Importantly, food allergies exclude potential military personnel from enlisting and have been shown to decrease the quality of life for patients and their families. Peanut allergy, in particular, has an estimated prevalence of above 1% of the population, a substantial increase over the past 15 years. Allergic reactions to peanut are often severe and account for the majority of fatal reactions. Food allergies result from B cells producing the allergic antibody IgE. IgE levels to foods are used in the diagnosis of food allergies and cause the reaction during skin prick tests. The IgE antibodies bind to mast cells and basophils, which are allergic cells that contain histamine. Upon ingestion of offending food allergens, IgE antibodies bind the allergen and cause release of histamine and other allergy-causing molecules that result in vomiting, hives, diarrhea, decreased blood pressure, and other allergic symptoms. This research proposal has a two-pronged strategy to develop therapies for food allergy. The overall idea is to target inhibitory immune cell receptors, called Siglecs, to incapacitate the key allergic cells. We will capitalize on technology developed by Dr. Macauley that uses liposomal nanoparticles. These particles are called STALs, which stands for Siglec-engaging Tolerance-inducing Antigenic Liposomes. On the surface of STALs is the antigen of interest -- in this project the primary antigen of interest will be the peanut allergen. Also displayed on the surface of STALs is a high affinity and selective ligand for a Siglec, which effectively shuts down an immune response to immune cells recognizing the peanut allergen. In Aim 1, we will target a Siglec on B cells called CD22 to destroy B cells that are capable of making peanut-specific IgE. The goal is to determine the utility of STALs as a way to delete IgE-producing cells to prevent and treat peanut allergy. In Aim 2, we will target the Siglec on mast cells and basophils called CD33 to turn off these cells such that they do not release histamine in response to peanut allergens. This approach will help to prevent reactions to peanut temporarily, allowing allergens to be tolerated and giving a window of opportunity to administer high doses of peanut as a therapy. Critical Research Problem: There is an urgent need for a treatment of food allergies. Currently, patients are instructed to avoid the allergen and be ready to manage allergic reactions with Epinepherine and antihistamines. Avoidance is very difficult and can cause great anxiety for patients and their families. A therapy would greatly increase the safety for the millions of patients with food allergies and decrease their anxiety. Impact: In this proposal, we will use both mouse models and human cells to perform preclinical evaluation of food allergy treatments. Some therapeutic approaches are in clinical trials aimed to desensitize patients such as oral immunotherapy (OIT), sublingual immunotherapy, and epicutantous immunotherapy. However, these approaches are designed to have a very long treatment phase, need to be taken daily, and likely would need to be taken for a lifetime to retain the desensitized state. Our approach targeting B cells may be effective with just a single injection and could induce long-term tolerance by deleting immune cells where IgE originates. Our approach targeting mast cells and basophils will offer important pre-treatments for other therapies such as OIT, by allowing a high dose to be given quickly, rather than over many months or years. This would help patients interested in enrolling in the military the opportunity to do so, would help military families with young food-allergic children at home, as well as the mill