Blockade of histamine-releasing factor as a new prophylactic and therapeutic strategy for food allergy

DESCRIPTION provided by applicant 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 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 threatening anaphylaxis Currently there is no cure for this disease although allergen specifc 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 releasing factor HRF is a secreted protein with the ability to activate mast cells and basophil in an IgE dependent 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 N and H peptides that blocked the HRF immunoglobulin Ig interaction without affecting intracellular functions of HRF A monomeric mutant of HRF HRF CA also inhibited the HRF Ig interaction In our unpublished study prophylactic and therapeutic administration of N and HRF CA strongly reduced diarrhea occurrence and intestinal inflammation in an IgE Fc RI high affinity IgE receptor dependent mouse model of food allergy Moreover egg allergic patients who exhibited high sensitivity to egg at the end of OIT
unlike those who did not had higher levels of HRF reactive IgE at months than at week after OIT initiation suggesting the involvement of HRF reactive IgE in human patients with egg allergy These results collectively indicate that HRF mediated activation of mast cells and basophils is involved in allergen induced maximal intestinal inflammation Based on these novel data we will pursue HRF based novel preventive and therapeutic modalities for the treatment of food allergy To this end we will optimize HRF inhibitory peptides as an anti fod allergy drug Specific Aim 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 Therefore completion of this study will allow us to determine which HRF inhibitor s i e N H 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 based 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 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 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 threatening 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 releasing factor HRF mediated activation of mast cells is required for food allerg In this study we will develop optimal HRF inhibitors as an anti food 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