Concurrent blockade of platelet-activating factor and histamine prevents life-threatening peanut-induced anaphylactic reactions.
BACKGROUND
Food anaphylaxis is an acute and life-threatening systemic allergic reaction. Fatality registries place peanut as the most common culprit of fatal and near-fatal reactions in North America. Because prophylaxis and treatment have advanced little in recent years, it is imperative to evaluate novel therapies.


OBJECTIVE
To investigate the impact of blocking mast cell mediators in a mouse model of peanut-induced anaphylaxis.


METHODS
Mice were sensitized with peanut protein and cholera toxin via oral gavage weekly for 4 weeks. One week after the last sensitization, separate groups of mice were treated with either a (1) 5-lypoxygenase inhibitor, (2) a platelet-activating factor (PAF) receptor antagonist, (3) histamine receptor antagonists, or (4) a PAF receptor antagonist along with histamine receptor antagonists before peanut challenge.


RESULTS
Treatment targeting either leukotrienes or histamine alone had no beneficial effects. In contrast, PAF antagonism significantly attenuated the magnitude and duration of the anaphylactic reactions. Particularly, it prevented severe reactions. Moreover, 83% of PAF-treated versus 43% of untreated mice reached recovery within 120 minutes after peanut challenge. Notably, combined blockade of PAF and histamine had a clearly greater beneficial effect. In fact, all but 1 mouse developed mild, if any, anaphylactic reactions. In addition, combination therapy was associated with a significant decrease in vascular leakage and release of vasoactive mediators after peanut challenge.


CONCLUSIONS
Combination therapy blocking both PAF and histamine markedly reduces the severity of peanut-induced anaphylaxis, and thus it may be a potential life-saving therapeutic approach in peanut and, likely, other food-induced anaphylaxis.
Arias
Katherine
K
Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
Baig
Moiz
M
Colangelo
Marc
M
Chu
Derek
D
Walker
Tina
T
Goncharova
Susanna
S
Coyle
Anthony
A
Vadas
Peter
P
Waserman
Susan
S
Jordana
Manel
M
D000485:Allergens / Q000276:immunology; D000707:Anaphylaxis / Q000276:immunology / Q000517:prevention & control*; D000818:Animals; D010367:Arachis / Q000276:immunology*; D002772:Cholera Toxin / Q000276:immunology; D002927:Cimetidine / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006632:Histamine / Q000276:immunology / Q000378:metabolism*; D006633:Histamine Antagonists / Q000627:therapeutic use*; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D006918:Hydroxyurea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D021183:Peanut Hypersensitivity / Q000150:complications*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011738:Pyrilamine / Q000008:administration & dosage / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D011968:Receptors, Histamine / Q000276:immunology / Q000378:metabolism
D000485:Allergens; D004791:Enzyme Inhibitors; D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D007074:Immunoglobulin G; D016859:Lipoxygenase Inhibitors; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; C039351:platelet activating factor receptor; D007073:Immunoglobulin E; D002927:Cimetidine; D006632:Histamine; D002772:Cholera Toxin; D011738:Pyrilamine; C063449:zileuton; D006918:Hydroxyurea