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The incidence of food allergy has increased dramatically in the last few decades in westernized developed countries. We propose that the Western lifestyle and diet promote innate danger signals and immune responses through production of “alarmins.” Alarmins are endogenous molecules secreted from cells undergoing nonprogrammed cell death that signal tissue and cell damage. High molecular group S (HMGB1) is a major alarmin that binds to the receptor for advanced glycation end-products (RAGE). Advanced glycation end-products (AGEs) are also present in foods. We propose the “false alarm” hypothesis, in which AGEs that are present in or formed from the food in our diet are predisposing to food allergy. The Western diet is high in AGEs, which are derived from cooked meat, oils, and cheese. AGEs are also formed in the presence of a high concentration of sugars. We propose that a diet high in AGEs and AGE-forming sugars results in misinterpretation of a threat from dietary allergens, promoting the development of food allergy. AGEs and other alarmins inadvertently prime innate signaling through multiple mechanisms, resulting in the development of allergic phenotypes. Current hypotheses and models of food allergy do not adequately explain the dramatic increase in food allergy in Western countries. Dietary AGEs and AGE-forming sugars might be the missing link, a hypothesis supported by a number of convincing epidemiologic and experimental observations, as discussed in this article.

Background Food allergy is a serious and sometimes fatal condition for which there is no cure. We previously reported that Food Allergy Herbal Formula (FAHF)–2) protected peanut-allergic mice against anaphylactic reactions as long as 4 weeks posttherapy. This formula is now in clinical trials in the United States. Objective We sought to determine whether FAHF-2–mediated protection could be extended long-term and explored the mechanisms underlying its persistent immunomodulatory effects. Methods Peanut-allergic mice received FAHF-2 daily orally by gavage for 7 weeks, and then received 7 oral peanut challenges at intervals of 4 to 10 weeks over a period of 36 weeks. For mechanistic studies, some mice received CD4 + or CD8 + T-cell–depleting antibodies or IFN-γ–neutralizing antibodies. Anaphylactic symptoms, body temperatures, and plasma histamine levels were recorded after each challenge, and peanut-specific immunoglobulin levels and cytokine profiles of splenocytes, mesenteric lymph node cells, and purified CD4 + and CD8 + T cells were determined. Results Food Allergy Herbal Formula-2 treatment protected mice from anaphylaxis for more than 36 weeks after discontinuing treatment. Peanut-specific IgE levels were reduced as much as 50%, whereas IgG 2a levels were increased as much as 60%, and these effects persisted over time. T H 2 cytokine production by CD4 + T cells from FAHF-2–treated mice was reduced as much as 75%, whereas CD8 + T-cell IFN-γ production was markedly increased by as much as 85% at the final challenge. Neutralization of INF-γ and depletion of CD8 + T cells markedly attenuated FAHF-2 efficacy. Conclusions Food Allergy Herbal Formula-2 provides long-term protection from anaphylaxis by inducing a beneficial shift in allergen-specific immune responses mediated largely by elevated CD8 + T-cell IFN-γ production.

Background Hypersecretion of mucus plays an important role in the pathogenesis and severity of asthma. The primary proteins in mucus are mucin glycoproteins; MUC-5AC is the primary airway mucin gene. The calcium chloride–activated channel gene hCLCA1 (gob-5 in the mouse) has been suggested to increase MUC-5AC gene expression, and both are increased in asthmatic patients and murine models. TNF-α increases the expression of these genes in vitro but has not been investigated in vivo. Objective We sought to determine whether TNF-α increases gene expression of gob-5 and MUC-5AC and induces mucus cell metaplasia in vivo. Methods Naive BALB/c mice received 50 ng of recombinant murine TNF-α (rmTNF-α) intratracheally daily for 1, 2, or 3 weeks; another group received the same dose of intratracheal rmTNF-α daily for 3 weeks and then alternate-day treatment for 3 additional weeks (total of 6 weeks). AKR mice received 50 ng of rmTNF-α intratracheally for 3 or 6 weeks daily. Naive nontreated mice were used as control animals. Airway gene products for gob-5 and MUC-5AC were determined by means of real-time PCR. Lung tissue sections were stained with periodic acid–Schiff/Alcian blue to assess mucus cell metaplasia. Results rmTNF-α significantly increased gene expression of airway gob-5 and MUC-5AC after 2 weeks in the BALB/c mice. There was noticeable mucus staining in all mice treated for at least 3 weeks with TNF-α and in 80% of the mice receiving 2 weeks of treatment. After 3 weeks of treatment, the AKR mice also showed increased gob-5 expression. Conclusions This study demonstrates for the first time that TNF-α alone in vivo is sufficient to increase airway mucus gene expression in 2 murine strains.

Peanut allergy (PNA) is a life-threatening food allergy for which there is no definitive treatment.We investigated the long-term immunomodulatory effect of heat-killed Escherichia coli producing engineered (mutated) Ara h1, 2, and 3 (HKE-MP123) administered rectally (pr) in a murine model of PNA.Peanut-allergic C3H/HeJ mice received 0.9 (low dose), 9 (medium dose), or 90 (high dose) microg HKE-MP123 pr, HKE-containing vector (HKE-V) alone, or vehicle alone (sham) weekly for 3 weeks. Mice were challenged 2 weeks later. A second and third challenge were performed at 4-week intervals.After the first challenge, all 3 HKE-MP123 and HKE-V-treated groups exhibited reduced symptom scores (P.01,.01,.05,.05, respectively) compared with the sham-treated group. Interestingly, only the medium- and high-dose HKE-MP123-treated mice remained protected for up to 10 weeks after treatment accompanied by a significant reduction of plasma histamine levels compared with sham-treated mice (P.05 and.01, respectively). IgE levels were significantly lower in all HKE-MP123-treated groups (P.001), being most reduced in the high-dose HKE-MP123-treated group at the time of each challenge. IL-4, IL-13, IL-5, and IL-10 production by splenocytes of high-dose HKE-MP123-treated mice were significantly decreased (P.01;.001,.001, and.001, respectively), and IFN-gamma and TGF-beta production were significantly increased (P.001 and.01, respectively) compared with sham-treated mice at the time of the last challenge.Treatment with pr HKE-MP123 can induce long-term "downregulation" of peanut hypersensitivity, which might be secondary to decreased antigen-specific T(H)2 and increased T(H)1 and T regulatory cytokine production.

Background: Peanut allergy is a major cause of fatal and near-fatal anaphylactic reactions to foods. There is no curative therapy for this condition. Traditional Chinese medicines have been reported to have antiallergic properties, which might be useful for treating peanut allergy. Objective: The purpose of this study was to investigate the effects of a Chinese herbal formula, FAHF-1, on peanut anaphylactic reactions in a mouse model of peanut allergy. Methods: Mice were sensitized with freshly ground whole peanut in the presence of cholera toxin and boosted 1 and 3 weeks later. FAHF-1 treatment was initiated 1 week later and continued for 7 weeks. After treatment, mice were challenged with peanut, and anaphylactic symptoms, body temperatures, and plasma histamine and IgE levels were measured. T-cell proliferative responses and cytokine production were also determined. Results: FAHF-1 completely blocked peanut-induced anaphylactic symptoms and markedly reduced mast cell degranulation and histamine release. Peanut-specific serum IgE levels were significantly reduced by 2 weeks of treatment at the time of challenge, and they remained lower 4 weeks after discontinuation of treatment. FAHF-1 significantly reduced peanut-induced lymphocyte proliferation as well as IL-4, IL-5, and IL-13 synthesis but not IFN-γ synthesis. No toxic effects on liver or kidney functions were observed, nor was there any overall immune suppression. Conclusion: FAHF-1 protected peanut-sensitized mice from anaphylactic reactions and significantly reversed established IgE-mediated peanut allergy. This suggests that FAHF-1 might prove valuable for the treatment of peanut allergy. (J Allergy Clin Immunol 2001;108:639-46.)

Background Treatments to reverse peanut allergy remain elusive. Current clinical approaches using peanut oral/sublingual immunotherapy are promising, but concerns about safety and long-term benefit remain a barrier to wide use. Improved methods of delivering peanut-specific immunotherapy are needed. Objective We sought to investigate the efficacy and safety of peanut oral immunotherapy using CpG-coated poly(lactic-co-glycolic acid) nanoparticles containing peanut extract (CpG/PN-NPs) in a murine model of peanut allergy. Methods C3H/HeJ mice were rendered peanut allergic by means of oral sensitization with peanut and cholera toxin. Mice were then subjected to 4 weekly gavages with CpG/PN-NPs, vehicle (PBS), nanoparticles alone, peanut alone, CpG nanoparticles, or peanut nanoparticles. Untreated mice served as naive controls. After completing therapy, mice underwent 5 monthly oral peanut challenges. Anaphylaxis was evaluated by means of visual assessment of symptom scores and measurement of body temperature and plasma histamine levels. Peanut-specific serum IgE, IgG 1 , and IgG 2a levels were measured by using ELISA, as were cytokine recall responses in splenocyte cultures. Results Mice with peanut allergy treated with CpG/PN-NPs but not vehicle or other treatment components were significantly protected from anaphylaxis to all 5 oral peanut challenges, as indicated by lower symptom scores, less change in body temperature, and a lower increase of plasma histamine levels. Importantly, CpG/PN-NP treatment did not cause anaphylactic reactions. Treatment was associated with a sustained and significant decrease in peanut-specific IgE/IgG 1 levels and an increase in peanut-specific IgG 2a levels. Compared with vehicle control animals, peanut recall responses in splenocyte cultures from nanoparticle-treated mice showed significantly decreased levels of T H 2 cytokines (IL-4, IL-5, and IL-13) but increased IFN-γ levels in cell supernatants. Conclusions Preclinical findings indicate that peanut oral immunotherapy with CpG/PN-NPs might be a valuable strategy for peanut-specific immunotherapy in human subjects.