Concurrent Blockade of Platelet Activating Factor and Histamine Prevents Life-threatening Peanut-induced Anaphylactic Reactions

Abstract

RATIONALE: Food anaphylaxis is a life-threatening systemic allergic reaction. Fatality registries place peanut as the most common culprit of fatal reactions in North America. Since prophylaxis and treatment have advanced little in recent years, it is imperative to evaluate novel therapies. Here, we have investigated the impact of blocking mediators of anaphylaxis in a mouse model of peanut-induced anaphylaxis (PIA).METHODS: Mice were sensitized with peanut protein and cholera toxin orally for four weeks. One week following the last sensitization, separate groups of mice were treated with either a 5-lypoxygenase inhibitor, a platelet activating factor receptor (PAF-R) antagonist, histamine receptor antagonists, or a PAF-R antagonist along with histamine receptor antagonists (combination therapy) prior to peanut challenge.RESULTS: Peanut challenge resulted in severe (clinical score ∼3.5/5 and ∼7 °C-drop in core body temperature) and prolonged (up to 24 h) anaphylaxis which is largely mediated by mast cells via both IgE and IgG1. Interestingly, treatment targeting either leukotrienes or histamine alone had no beneficial effects. Conversely, PAF antagonism prevented life-threatening reactions (clinical score ∼2 and ∼4°C-drop in body temperature) and allowed faster recovery (83% PAF-treated vs. 43% untreated mice recovered within 120 min after challenge) from PIA; even greater benefit was achieved with combination therapy which, in addition, led to a substantial decrease in vascular leakage and release of vasoactive mediators.CONCLUSIONS: Concomitant blockade of PAF and histamine markedly lessens the severity and duration of peanut-induced anaphylactic reactions and, thus, may represent a life-saving therapy for peanut and, likely, other food-induced anaphylaxis. RATIONALE: Food anaphylaxis is a life-threatening systemic allergic reaction. Fatality registries place peanut as the most common culprit of fatal reactions in North America. Since prophylaxis and treatment have advanced little in recent years, it is imperative to evaluate novel therapies. Here, we have investigated the impact of blocking mediators of anaphylaxis in a mouse model of peanut-induced anaphylaxis (PIA). METHODS: Mice were sensitized with peanut protein and cholera toxin orally for four weeks. One week following the last sensitization, separate groups of mice were treated with either a 5-lypoxygenase inhibitor, a platelet activating factor receptor (PAF-R) antagonist, histamine receptor antagonists, or a PAF-R antagonist along with histamine receptor antagonists (combination therapy) prior to peanut challenge. RESULTS: Peanut challenge resulted in severe (clinical score ∼3.5/5 and ∼7 °C-drop in core body temperature) and prolonged (up to 24 h) anaphylaxis which is largely mediated by mast cells via both IgE and IgG1. Interestingly, treatment targeting either leukotrienes or histamine alone had no beneficial effects. Conversely, PAF antagonism prevented life-threatening reactions (clinical score ∼2 and ∼4°C-drop in body temperature) and allowed faster recovery (83% PAF-treated vs. 43% untreated mice recovered within 120 min after challenge) from PIA; even greater benefit was achieved with combination therapy which, in addition, led to a substantial decrease in vascular leakage and release of vasoactive mediators. CONCLUSIONS: Concomitant blockade of PAF and histamine markedly lessens the severity and duration of peanut-induced anaphylactic reactions and, thus, may represent a life-saving therapy for peanut and, likely, other food-induced anaphylaxis.