The prevalence of food allergy has been dramatically increasing for the last few decades. Food Allergy and Anaphylaxis Network (www.foodallergy.org) estimates that up to 15 million Americans have food allergies. Six to eight percent of children under the age of three have food allergies and nearly four percent of adults have them. Signs and symptoms of food allergy range from itching, hives, and diarrhea to life-Âthreatening anaphylaxis. Currently, there is no cure for this disease, although allergen-Âspecifc sublingual and oral immunotherapy (OIT) can successfully treat some patients. However, this therapy is associated with the risk of anaphylaxis and many patients resist the therapy. Thus, novel, innovative therapeutic and preventive measures are urgently needed. Histamine-Âreleasing factor (HRF) is a secreted protein with the ability to activate mast cells and basophil in an IgE-Âdependent manner, while it has multiple intracellular functions. Our recent studies demonstrated that a subset of IgE and IgG molecules bind to HRF, leading to our discovery of specific inhibitors, N19 and H3 peptides, that blocked the HRF-Âimmunoglobulin (Ig) interaction without affecting intracellular functions of HRF. A monomeric mutant of HRF, HRF-Â2CA, also inhibited the HRF-ÂIg interaction. In our unpublished study, prophylactic and therapeutic administration of N19 and HRF-Â2CA strongly reduced diarrhea occurrence and intestinal inflammation in an IgE/FcεRI (high-Âaffinity IgE receptor)-Âdependent mouse model of food allergy. Moreover, egg-Âallergic patients who exhibited high sensitivity to egg at the end of OIT, unlike those who did not, had higher levels of HRF-Âreactive IgE at 12 months than at 1 week after OIT initiation, suggesting the involvement of HRF-Âreactive IgE in human patients with egg allergy. These results collectively indicate that HRF-Âmediated activation of mast cells and basophils is involved in allergen-Âinduced maximal intestinal inflammation. Based on these novel data, we will pursue HRF-Âbased novel preventive and therapeutic modalities for the treatment of food allergy. To this end, we will optimize HRF-Âinhibitory peptides as an anti- fod allergy drug (Specific Aim 1). We will also investigate the mechanisms by which HRF inhibitors suppress food allergy, by identifying the cellular and molecular targets of HRF inhibitors in the murine food allergy model (Specific Aim 2). Therefore, completion of this study will allow us to determine which HRF inhibitor(s), i.e., N19, H3, related peptides (or modified peptides), or a combination thereof can be used to best prevent and/or treat food allergy. Positive results with HRF inhibitor(s) will lay the foundation for clinical studies in humans in the near future. In humans, HRF-Âbased peptides will be used as preventive and/or therapeutic drugs as well as an adjuvant to be used together with OIT. Thus, this study has the potential to drastically change the clinical practice in food allergy.
Public Health Relevance Statement: Public Health Relevance: The prevalence of food allergy has been dramatically increasing for the last few decades. Food Allergy and Anaphylaxis Network (www.foodallergy.org) estimates that up to 15 million Americans have food allergies. Six to eight percent of children under the age of three have food allergies and nearly four percent of adults have them. Signs and symptoms of food allergy range from itching, hives, and diarrhea to life-Âthreatening anaphylaxis. Currently, there is no cure for this disease. Thus, novel, innovative therapeutic and preventive measures are urgently needed. We have accumulated evidence that histamine-Âreleasing factor (HRF)-Â mediated activation of mast cells is required for food allerg. In this study, we will develop optimal HRF-Â inhibitors as an anti-Âfood allergy drug and investigate how HRF inhibitors suppress food allergy. Thus, successful completion of this study will allow us to move on to clinical studies in humans in the future.
Project Terms: Adjuvant; Adult; Affect; Affinity; Age; Allergens; Allergic; Allergic Disease; Allergic Reaction; Allergy to eggs; American; Anaphylaxis; Atopic Dermatitis; base; Basophils; Binding; Bronchoalveolar Lavage Fluid; Bulla; Cell Cycle Progression; cell type; Cells; cellular targeting; Child; clinical practice; Clinical Research; Complex; crosslink; cytokine; Data; Diarrhea; Disease; Drug Hypersensitivity; egg; Embryo; Exhibits; extracellular; Food; Food Hypersensitivity; Foundations; Future; Histamine Release; Human; Hypersensitivity; IgE; IgE Receptors; Immunoglobulin G; Immunoglobulins; improved; in vivo; Inflammatory disease of the intestine; inhibitor/antagonist; innovation; Irrigation; Knockout Mice; Life; Malignant - descriptor; Mediating; Modality; Modeling; Molecular; Molecular Target; mouse model; Mus; mutant; Nature; Nose; novel; oral immunotherapy; Patients; Peptides; Pharmaceutical Preparations; Phase; Prevalence; prevent; Preventive; Preventive measure; Property; prophylactic; protein function; Proteins; Pruritus; public health relevance; receptor; Research; Research Personnel; Risk; Role; Signs and Symptoms; Skin; sublingual immunotherapy; Therape
