B‐FAHF‐2 plus oral immunotherapy (OIT) is safer and more effective than OIT alone in a murine model of concurrent peanut/tree nut allergy

Abstract

Background Concurrent sensitization to peanut (PN) and tree nuts (TN), the most dangerous food allergies, is common. Current oral immunotherapy (OIT) is not fully satisfactory. Objective To determine if the herbal formula B-FAHF-2 (BF2) ameliorates PN/TN OIT adverse reactions and enhances persistence of a tolerant state. Methods Concurrently sensitized peanut, walnut (WN) and cashew (CSH) allergic mice received 1 day PN/WN/CSH rush OIT plus 3 weeks of maintenance dosing, with or without 3-weeks prior and 3-weeks BF2 co-treatment. Anaphylactic symptom scores, core body temperatures, plasma histamine levels, basophil numbers, antigen-specific IgE, cytokine levels, and IL-4, INF-γ and Foxp3 gene promoter DNA methylation status, and their correlation with final challenge symptom scores were determined. Results BF2+OIT treated mice experienced significantly fewer and less severe adverse reactions than OIT only treated mice (p<0.01) during the one-day rush OIT buildup dose phase. Both OIT only and BF2+OIT mice showed significant desensitization (p<0.01 and 0.001 respectively) at one-week post therapy challenge; being greater in BF2+OIT mice. All sham treated and 91% of OIT treated mice experienced anaphylaxis whereas only 21% of BF2+OIT treated mice exhibited reactions during 5–6 weeks of dose escalation single PN and TN challenges. Greater and more persistent protection in BF2+OIT mice was associated with significantly lower plasma histamine and IgE levels, increased IFN- γ/IL-4 and IL-10/IL-4 ratios, DNA re-methylation at the IL-4 promoter and de-methylation at IFN-γ and Foxp3 promoters. Final challenge symptom scores were inversely correlated with IL-4 DNA methylation levels (p<0.0002), and positively correlated with IFN-γ and Foxp3 gene promoter methylation levels (p<0.0011) (p<0.0165). Conclusions and clinical relevance Combined BF2/OIT therapy was safer and produced longer post treatment protection, and more tolerance-prone immunological and epigenetic modifications than OIT alone. BF2/OIT may provide an additional OIT option for patients with concurrent peanut/ tree nut and other food allergies.

Recent developments and highlights in food allergy

“…By suppressing IL‐4 and IL‐13, which are key for IgE class‐switching, expansion, maintenance, and activation of effector cells, food‐allergic responses may be abolished as suggested by recent case reports . Rare, however significant side effects and the not yet completely understood effects of IL‐4 on innate immune function warrant further investigation …”

“…156 By suppressing IL-4 and IL-13, which are key for IgE class-switching, expansion, maintenance, and activation of effector cells, food-allergic responses may be abolished as suggested by recent case reports. 168,169 Rare, however significant side effects 170 and the not yet completely understood effects of IL-4 on innate immune function warrant further investigation. 171,172 Studies investigating the role of TSLP and IL-25 in the context of food allergy are limited, and recent data on the topic are still derived from rodent in vivo and in vitro models.…”

Oral administration of recombinant Bacillus subtilis spores expressing Helicobacter pylori neutrophil‐activating protein suppresses peanut allergy via up‐regulation of Tregs

“…NAP can elicit high rates of IL‐12, IFN‐γ and IgG2a secretion, while IL‐4, IL‐5, IgE and IgG1 secretion are inhibited, thereby shifting the Th1/Th2 balance to a Th1‐type response . The capability to induce Th1 cytokine secretion by NAP, or other chemical agents such as recombinant IL‐12, Chinese herbal medicines and turmeric, is known to be sufficient to inhibit Th2 responses and ameliorate allergic disorders . Therefore, the Th1‐type immune response caused by NAP and CNAP spores may be a major cause of the weakening of allergic symptoms.…”

“…26,27 The capability to induce Th1 cytokine secretion by NAP, or other chemical agents such as recombinant IL-12, Chinese herbal medicines and turmeric, is known to be sufficient to inhibit Th2 responses and ameliorate allergic disorders. 23,28,29 Therefore, the Th1-type immune response caused by NAP and CNAP spores may be a major cause of the weakening of allergic symptoms.…”

Advances in the approach to the patient with food allergy

“…This same group of investigators combined a Chinese herbal therapy product (B-FAHF-2) with peanut OIT to treat mice with peanut allergy. 78 Findings indicated a significant improvement in clinical and immunologic outcomes in mice treated with both products compared with those treated with peanut OIT alone.…”