Project Grant P01AI179273

THE ROLE OF NEUROIMMUNE PATHWAYS IN FOOD ALLERGIES - SUMMARY FOOD ALLERGY AFFECTS MILLIONS OF PEOPLE WORLDWIDE AND THE PREVALENCE IS INCREASING RAPIDLY. UNFORTUNATELY, MANY ASPECTS OF THE MECHANISMS BEHIND FOOD ALLERGY ARE POORLY UNDERSTOOD, AND THUS TREATMENT OPTIONS ARE LIMITED. TO ENHANCE OUR UNDERSTANDING OF FOOD ALLERGY, THE FOOD ALLERGY SCIENCE INITIATIVE (FASI) WAS FOUNDED IN 2016 WITH THE GOAL OR UNDERSTANDING THE MECHANISM OF DISEASE IN FOOD ALLERGIES AND BRING THOSE INSIGHTS INTO THERAPEUTICS. FOOD ALLERGY IS TRADITIONALLY THOUGHT OF AS A MALFUNCTION OF THE IMMUNE SYSTEM. HOWEVER, IT HAS BECOME CLEAR THAT THE NERVOUS SYSTEM AND INTESTINAL EPITHELIUM ALSO PLAY AN IMPORTANT ROLE IN ALLERGIC DISEASE; THIS PROGRAM WILL USE AN INTEGRATIVE APPROACH TO INVESTIGATE THESE UNDERLYING PATHWAYS. OUR TEAM WILL EXPLORE THE HYPOTHESIS THAT FOOD ALLERGY IS AN EXAGGERATED OR MIS-TARGETED REACTION THAT NORMALLY AIMS TO PROTECT FROM HARMFUL SUBSTANCES PRESENT IN FOOD, INCLUDING NOXIOUS PHYTOCHEMICALS AND TOXINS. THIS IS BASED ON GROWING EVIDENCE INDICATING THAT NEURO-IMMUNE INTERACTIONS PLAY A FUNDAMENTAL ROLE IN FOOD ALLERGIES. FOR EXAMPLE, MANY MANIFESTATIONS OF FOOD ALLERGIES (VOMITING, DIARRHEA, ABDOMINAL PAIN, NAUSEA) INVOLVE COMBINED EFFECTS OF INFLAMMATORY MEDIATORS AND PARASYMPATHETIC REFLEXES. IN ADDITION, SENSORY INPUTS THROUGH THE VAGAL AFFERENTS AND DORSAL ROOT GANGLIA NEURONS DEDICATED TO MONITORING NOXIOUS INPUTS APPEAR TO BE RESPONSIVE TO ALLERGENS DETECTED BY THE IMMUNE SYSTEM. MULTIPLE RECIPROCAL INTERACTIONS BETWEEN THE TWO SYSTEMS COMPLEMENT EACH OTHER'S CAPACITIES SUCH THAT ANTIGEN-SPECIFIC ANTIBODIES PROVIDE INPUTS TO THE SENSORY NEURONS, LEADING TO THEIR PROCESSING IN THE CNS, AND NEURONAL CONTROL CIRCUITS COORDINATE OPTIMAL DEFENSE MODALITIES OF THE IMMUNE SYSTEM. CONVERSELY, THE NERVOUS SYSTEM HAS GREATER CAPACITY FOR EVALUATION OF ENVIRONMENTAL CUES AND THE INTERNAL STATE OF THE ORGANISM AND CAN USE ITS SUPERIOR INFORMATION PROCESSING CAPACITIES TO DICTATE THE OUTCOME OF IMMUNE RECOGNITION (TOLERANCE VERSUS SENSITIZATION) AND IMMUNE EFFECTOR FUNCTIONS. NEURO-IMMUNE COMMUNICATIONS IS A NASCENT FIELD AND THE PROGRAM WILL ADDRESS SOME OF THE FOUNDATIONAL QUESTIONS THAT WILL ILLUMINATE THE LOGIC OF THESE MECHANISMS AND HELP UNCOVER NEW TARGETS FOR THERAPEUTIC INTERVENTIONS. WE WILL FOCUS ON KEY QUESTIONS IN NEURO-IMMUNE INTERACTIONS THAT ARE RELEVANT FOR UNDERSTANDING FOOD ALLERGY. THIS WILL INCLUDE INVESTIGATION OF HOW MAST CELLS ORCHESTRATE EPITHELIAL AND NEURONAL RESPONSES (PROJECT 1), NEURONAL CIRCUITS ENGAGED ININ FOOD ALLERGY (PROJECT 2), AND MAPPING PHYSICAL INTERACTIONS BETWEEN EPITHELIAL, IMMUNE, AND NEURONAL CELLS INVOLVED IN DEVELOPMENT OF FOOD ALLERGY (PROJECT 3). ALL THREE PROJECTS WILL BE SUPPORTED BY BOTH THE TRANSGENIC CORE (CORE B) AND BIOINFORMATICS CORE (CORE C). THE POWER OF THIS PROGRAM TEAM IS THAT INVESTIGATORS WITH EXPERTISE IN MUCOSAL IMMUNOLOGY, NEUROBIOLOGY, AND ALLERGIC INFLAMMATION ARE COMING TOGETHER TO STUDY FOOD ALLERGEN RESPONSES, AND THE TEAM IS MUCH STRONGER THAN THE SUM OF ITS INDIVIDUAL PARTS. THE PROJECTS PROPOSED HERE WILL INCORPORATE INSIGHTS AND EXPERTISE FROM DIVERSE AND COMPLEMENTARY PERSPECTIVES FROM OUR INVESTIGATORS TO PROVIDE A COMPREHENSIVE ASSESSMENT OF HOW THE ENTERIC NERVOUS SYSTEM, THE CENTRAL NERVOUS SYSTEM, THE IMMUNE SYSTEM, AND INTESTINAL EPITHELIAL CELLS INTERACT TO REGULATE THE RESPONSES TO FOOD ALLERGY.