Purpose of review
This review summarizes recent reports on non-allergen specific therapies for food allergy. These therapies are especially appealing for food allergy, because unlike allergen-specific immunotherapy, they would allow for the treatment of multiple food allergies in a single patient with one therapy.
Chinese herbal therapy, anti-IgE, probiotics, engineered lactic acid bacteria, and helminth therapy are all examples of allergen non-specific therapies that have been investigated in recent years. While some have only been studied in animal models of food allergy, some are undergoing rigorous, human clinical trials.
Increasing amounts of research are examining the efficacy and safety of non-allergen specific therapies for food allergy. There is hope that clinicians will have effective treatments either as an alternative or as an adjunct to immunotherapy.
Food allergy; Chinese herbal therapy; omalizumab; probiotics; treatment
Purpose of review
To describe the potential effect that avoidance diets for food allergy may have on nutrition and growth in children.
We report here findings from previous studies suggesting impairment of growth and nutritional deficiencies due to elimination diets for food allergy. Feeding difficulties have also been reported, particularly in children with eosinophilic esophagitis that may further impact nutrient intake.
Food allergies are becoming more prevalent and better recognized. Treatment options typically include strict dietary elimination of major food allergens such as milk, eggs, wheat, soy, peanut, tree nuts, fish and shellfish. Monitoring growth and guiding food allergic patients in choosing appropriate alternatives to supply necessary nutrients becomes crucial to avoid deficiencies and retardation in growth.
Food Allergy; Growth; Nutrition; Vitamin Deficiencies
food allergy; prevalence; urban; minority; peanut; shellfish; tree nut; milk; asthma
Traditional Chinese medicine (TCM) has been widely used in China to treat various diseases for thousands of years. Given its reputed effectiveness, low cost, and favorable safety profile, TCM is attracting great interest in Western societies as a source of therapy for an array of illnesses, including allergies and asthma. Although food allergy has not been described in the TCM literature, a novel treatment for food allergy, named the food allergy herbal formula-2 (FAHF-2), was developed using TCM principles. Using a well-characterized murine model of peanut allergy, FAHF-2 has been shown to be highly effective in providing long-term protection against peanut-induced anaphylaxis, with a high safety margin. Phase 1 human trials have demonstrated the safety of FAHF-2 in food allergic individuals. Currently, a phase 2 trial examining efficacy of FAHF-2 is on-going. Other TCMs also show a potential for treating food allergies in preclinical studies.
Food; Allergy; Treatment; Chinese herbal medicine; Therapy; FAHF-2; Food allergy herbal formula-2
Purpose of review
To describe the development of a novel treatment for food allergy, named the food allergy herbal formula-2 (FAHF-2), that is based on Traditional Chinese Medicine.
FAHF-2 has proven to be safe and effective for the treatment of food allergies in murine models of peanut and multiple food allergies. These results are accompanied by evidence of favorable immune modulation, and the effects are persistent after discontinuation of treatment. Early clinical trials demonstrate the safety and tolerability of this formula in subjects with food allergies. An on-going Phase II clinical trial will evaluate the efficacy of FAHF-2 in protecting individuals from allergen-induced allergic reactions during oral food challenges.
FAHF-2 is an herbal formula that has a high safety profile and has shown to prevent anaphylaxis in murine models of food allergy. Similar findings in clinical trials could bring a novel treatment for food allergies.
food allergy; anaphylaxis; treatment; Traditional Chinese Medicine; herbs
Food allergies can cause life-threatening reactions and greatly influence quality of life. Accurate diagnosis of food allergies is important to avoid serious allergic reactions and prevent unnecessary dietary restrictions, but can be difficult. Skin prick testing (SPT) and serum food-specific IgE (sIgE) levels are extremely sensitive testing options, but positive test results to tolerated foods are not uncommon. Allergen component-resolved diagnostics (CRD) have the potential to provide a more accurate assessment in diagnosing food allergies. Recently, a number of studies have demonstrated that CRD may improve the specificity of allergy testing to a variety of foods including peanut, milk, and egg. While it may be a helpful adjunct to current diagnostic testing, CRD is not ready to replace existing methods of allergy testing, as it not as sensitive, is not widely available, and evaluations of component testing for a number of major food allergens are lacking.
Food allergy; Diagnosis; Skin prick testing; Food-specific IgE; Sensitivity; Specificity; Oral food challenge; Component-resolved diagnostics; Microarray; Milk allergy; Hazelnut allergy; Egg allergy; Peanut allergy; Shrimp allergy
Food allergy continues to be a challenging health problem, with prevalence continuing to increase and anaphylaxis still an unpredictable possibility. While improvements in diagnosis are more accurately identifying affected individuals, treatment options remain limited. The cornerstone of treatment relies on strict avoidance of the offending allergens and education regarding management of allergic reactions. Despite vigilance in avoidance, accidental ingestions and reactions continue to occur. With recent advances in the understanding of humoral and cellular immune responses in food allergy and mechanisms of tolerance, several therapeutic strategies for food allergies are currently being investigated with the hopes of providing a cure or long-term remission from food allergy.
Food; Allergy; Anaphylaxis; Treatment; Tolerance
Despite strict avoidance, severely food-allergic children experience frequent and potentially severe food-induced anaphylaxis (FSFA). There are no accepted preventive interventions for FSFA. A Traditional Chinese Medicine (TCM) formula prevents anaphylaxis in murine food allergy models, and has immunomodulatory effects in humans. We analyzed the effects of TCM treatment on three pediatric patients with FSFA.
Three FSFA patients (P) ages 9–16 years (P1 allergic to milk; P2 and P3 to tree nuts) qualified for case analysis. All experienced numerous reactions requiring administration of rescue medications and emergency room (ER) visits during the 2 years prior to starting TCM. P1 experienced approximately 100 reactions, 50 epinephrine administrations, 40 ER visits, and 3 admissions to intensive care units. P2 experienced 30 reactions, all requiring epinephrine administration, as well as 10 emergency hospitalizations. P3 experienced 400 reactions, five of which required epinephrine administration and ER visits. TCM treatment markedly reduced or eliminated reactions in all. P1 experienced no reactions after 2.5 years of TCM. P2 experienced no reactions after 1 year of TCM treatment, at which time she passed an oral almond food challenge. She continues to be reaction-free 6 months off TCM while consuming nuts. P3 has achieved a 94% reduction in reaction frequency following 7 months of TCM, has discontinued daily antihistamine use, and has required no epinephrine administrations or ER visits.
Three children treated with TCM experienced dramatic reductions or elimination of FSFA. This regimen appears to present a potential option for FSFA, and warrants further investigation in controlled clinical studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s13223-014-0066-5) contains supplementary material, which is available to authorized users.
Traditional Chinese medicine; Food allergy; Food induced anaphylaxis
During the acute liver injury, immune responses are provoked into eliciting inflammation in the acute phase. In the healing phase, the inflammation is terminated for wound healing and restoration of immune homeostasis. In this study, we sought to address how regulatory T cells (Tregs) are involved in the progression of liver injury and repair. In the acute phase, intrahepatic Tregs (CD4+FoxP3+Helios+) diminished promptly through apoptosis, which was followed by inflammation and tissue injury. In the healing phase, a new subset of Tregs (CD4+Foxp3+Helios−) was generated in correlation with the matrix metalloproteinase (MMP) cascade and transforming growth factor-beta (TGF-β) activation that were manifested mainly by hepatic stellate cells. Moreover, the induction of induced Tregs and wound healing were both impaired in mice lacking TGF-β signaling or MMPs. The depletion of induced Tregs also impeded wound healing for tissue repair. Together, this study demonstrates the mechanism that the loss of nTregs through apoptosis in the acute phase may facilitate inflammation, while regenerated Tregs through MMP9/13-dependent activation of TGF-β in the healing phase are critical to terminate inflammation and allow for wound healing.
liver injury; wound healing; regulatory T cells; TGF-β; IL-1; hepatic stellate cells; matrix metalloproteinase
We report that polyclonal CD8regs generated in one week ex-vivo with anti-CD3/28 beads and cytokines rapidly developed suppressive activity in vitro sustained by TGF-β. In immunodeficient mice, these CD8regs demonstrated a markedly protective, IL-10 dependent activity against a xeno-GVHD. They expressed IL-2Rα/β, Foxp3, TNFR2, and the negative co-stimulatory receptors CTLA-4, PD-1, PD-L1 and Tim-3. Suppressive activity in vitro correlated better with TNFR2 and PD-L1 than Foxp3. Blocking studies suggested that TNF enhanced PD-L1 expression and the suppressive activity of the CD8regs generated. Unlike other polyclonal CD4 and CD8 Tregs, these CD8regs preferentially targeted allogeneic T cells, but they lacked cytotoxic activity against them even after sensitization. Unlike CD4regs, these CD8regs could produce IL-2 and proliferate while inhibiting target cells. If these CD8regs can persist in foreign hosts without impairing immune surveillance, they could serve as a practical remission-inducing product for the treatment of autoimmune diseases, graft-versus-host disease, and allograft rejection.
Much is known about the short-term risks of stroke following cardiac surgery. We examined the rate and predictors of long-term stroke in a cohort of patients who underwent cardiac surgery.
We obtained linked data for patients who underwent cardiac surgery in the province of Ontario between 1996 and 2006. We analyzed the incidence of stroke and death up to 2 years postoperatively.
Of 108 711 patients, 1.8% (95% confidence interval [CI] 1.7%–1.9%) had a stroke perioperatively, and 3.6% (95% CI 3.5%–3.7%) had a stroke within the ensuing 2 years. The strongest predictors of both early and late stroke were advanced age (≥ 65 year; adjusted hazard ratio [HR] for all stroke 1.9, 95% CI 1.8–2.0), a history of stroke or transient ischemic attack (adjusted HR 2.1, 95% CI 1.9–2.3), peripheral vascular disease (adjusted HR 1.6, 95% CI 1.5–1.7), combined coronary bypass grafting and valve surgery (adjusted HR 1.7, 95% CI 1.5–1.8) and valve surgery alone (adjusted HR 1.4, 95% CI 1.2–1.5). Preoperative need for dialysis (adjusted odds ratio [OR] 2.1, 95% CI 1.6–2.8) and new-onset postoperative atrial fibrillation (adjusted OR 1.5, 95% CI 1.3–1.6) were predictors of only early stroke. A CHADS2 score of 2 or higher was associated with an increased risk of stroke or death compared with a score of 0 or 1 (19.9% v. 9.3% among patients with a history of atrial fibrillation, 16.8% v. 7.8% among those with new-onset postoperative atrial fibrillation and 14.8% v. 5.8% among those without this condition).
Patients who had cardiac surgery were at highest risk of stroke in the early postoperative period and had continued risk over the ensuing 2 years, with similar risk factors over these periods. New-onset postoperative atrial fibrillation was a predictor of only early stroke. The CHADS2 score predicted stroke risk among patients with and without atrial fibrillation.
Osteoclasts are responsible for bone destruction in rheumatoid arthritis (RA) and natural CD4+Foxp3+regulatory T cells (nTregs) can inhibit osteoclastogenesis. This study aims to determine whether TGF-β-induced CD4+Foxp3+regulatory T cells (iTregs) also suppress osteolastogenesis and bone erosion in collagen induced arthritis (CIA).
Osteoclasts were induced from bone-marrow CD11b+ cells with RANKL and macrophage colony-stimulating factor (M-CSF), and assessed with tartrate-resistant acid phosphatase (TRAP) staining. CD4+ iTregs were generated with TGF-β and added to cultures with different ratios with CD11b+ cells. Transwell and antibody blockade experiments were performed to define the mechanism of action. NF-kB activation was determined by western blot. 3×106 CD4+ iTregs, nTregs or control cells were adoptively transferred to DBA1/J mice on day 14 after immunization with CII/CFA. CIA onset and severity were monitored and bone erosion was examined by CT scan.
Both CD4+ Tregs almost completely suppressed osteoclastogenesis but only iTregs sustained the effect in the presence of IL-6 in vitro. CD4+ iTregs but not nTregs and control cells injected after immunization and before of onset of CIA significantly suppressed disease development. Of note, CT scan showed that the joints in CD4+ iTregs but not nTregs or control cells infused CIA had less bone erosion. Treatment with CD4+ iTregs but not other cells dramatically decreased the levels of NF-kB p65/p50 in osteoclasts in vitro and P65/50 and RANKL expression by synovial tissues in vivo.
Manipulation of CD4+ iTregs may have therapeutic effects on rheumatoid arthritis and other bone erosion related diseases.
The purpose of this study was to examine utilization and growth in echocardiography among the general population of Ontario between 2001 and 2009. The age- and sex-adjusted rates of echocardiography grew from 39.1 per 1,000 persons in 2001 to 59.9 per 1,000 persons in 2009, for an annual rate of increase of 5.5%. Repeat echocardiograms increased at a rate of 10.6% per year and accounted for 25.3% of all procedures in 2009 as compared to 18.5% in 2002. While significant increases in echocardiography utilization were observed, opportunities may exist to improve the clinical utility of the echocardiograms performed in Ontario.
echocardiography; resource utilization; cardiovascular imaging
Prior studies showed that Toll-like receptor (TLR) signaling pathway genes were up regulated in the liver of rats fed ethanol, but not in rats fed ethanol plus S-adenosylmethionine (SAMe). These results were obtained using a PCR microplate array analysis for TLRs and associated proteins such as proinflammatory cytokines and chemokine mRNA levels. A large number of genes were up regulated by the ethanol diet, but not the ethanol plus SAMe diet. In the present study, using the same experimental rat livers, DNA methylation analysis was done by using an Epitect Methyl DNA Restriction Kit (Qiagen, 335451) (24 genes). The results of all the genes combined shows a highly significant increase in methylation in the ethanol-fed group of rats, but not in the dextrose-fed, SAMe-fed or ethanol plus SAMe-fed groups of rats. There was also an increase in DNA methylation in rats with high blood alcohol levels compared to a rat with a low blood alcohol level. The individual genes that were up regulated as indicated by the increased mRNA measured by qPCR correlated positively with the increased methylation of the DNA of the corresponding gene as follows: Cd14, Hspa1a, Irf1, Irak1, Irak2, Map3k7, Myd88, Pparα, Ripk2, Tollip and Traf6.
TLR (Toll-like receptor); SAMe (S-adenosyl methionine); BAL/blood alcohol levels; 5-methylcytosine
We have previously demonstrated that quercetin, a bioflavonoid, blocks hepatitis C virus (HCV) proliferation by inhibiting NS5A-driven internal ribosomal entry site (IRES)-mediated translation of the viral genome. Here, we investigate the mechanisms of antiviral activity of quercetin and six additional bioflavonoids. We demonstrate that catechin, naringenin, and quercetin possess significant antiviral activity, with no associated cytotoxicity. Infectious virion secretion was not significantly altered by these bioflavonoids. Catechin and naringenin demonstrated stronger inhibition of infectious virion assembly compared to quercetin. Quercetin markedly blocked viral translation whereas catechin and naringenin demonstrated mild activity. Similarly quercetin completely blocked NS5A-augmented IRES-mediated translation in an IRES reporter assay, whereas catechin and naringenin had only a mild effect. Moreover, quercetin differentially inhibited HSP70 induction compared to catechin and naringenin. Thus, the antiviral activity of these bioflavonoids is mediated through different mechanisms. Therefore combination of these bioflavonoids may act synergistically against HCV.
HSP70; NS5A; IRES; HCV; Bioflavonoid
Lung cancer remains the top cause of cancer morbidity and mortality in the world. Although the identification of epidermal growth factor receptor (EGFR) gene mutations could predict efficacy of tyrosine kinase inhibitor (TKI), testing for predictive biomarkers are not always possible due to tissue availability. The overall therapeutic decision remains a clinical one for a significant proportion of elderly patients with advanced stage lung cancer but no known EGFR mutation status. The purpose of this study was to compare the outcome of drug treatment modalities in progression-free survival (PFS) and overall survival (OS) for elderly with advanced-stage non-small cell lung cancer (NSCLC) and to identify clinical parameters that could predict treatment outcome.
Clinical records of patients aged 70 years or older with advanced-stage NSCLC who have received treatment were reviewed. A group of gender- and histology-matched subjects younger than age 70 years were identified as controls.
Fifty-six elderly patients were included. The median age at diagnosis was 73 years; 60.7 % received only one line of treatment. Baseline performance status (PS) was the only predictor of improved PFS (p = 0.042) and OS (p = 0.002). There was no difference in survival between the upfront chemotherapy and the TKI groups
In elderly with advanced-stage NSCLC without known EGFR mutation status, use of EGFR–TKI and chemotherapy resulted in comparable survival benefits. Age was not predictive of worse treatment outcome. The baseline PS should be taken into consideration in the therapeutic decision in elderly with NSCLC where the EGFR mutation status is not known.
Lung cancer; Elderly; Treatment; Outcome
Peyronie’s disease (PD) is a condition of the penis, characterized by the presence of localized fibrotic plaque in the tunica albuginea. PD is not an uncommon disorder, with recent epidemiologic studies documenting a prevalence of 3–9% of adult men affected. The actual prevalence of PD may be even higher. It is often associated with penile pain, anatomical deformities in the erect penis, and difficulty with intromission. As the definitive pathophysiology of PD has not been completely elucidated, further basic research is required to make progress in the understanding of this enigmatic condition. Similarly, research on effective therapies is limited. Currently, nonsurgical treatments are used for those men who are in the acute stage of PD, whereas surgical options are reserved for men with established PD who cannot successfully penetrate. Intralesional treatments are growing in clinical popularity as a minimally invasive approach in the initial treatment of PD. A surgical approach should be considered when men with PD do not respond to conservative, medical, or minimally invasive therapies for approximately 1 year and cannot have satisfactory sexual intercourse. As scientific breakthroughs in the understanding of the mechanisms of this disease process evolve, novel treatments for the many men suffering with PD are anticipated.
oral therapy; intralesional treatment; topical therapy; extracorporeal shockwave therapy; traction devices; plication; incision and grafting; penile prosthesis
Interplay between Foxp3+ regulatory T cells (Treg) and dendritic cells (DCs) maintains immunologic tolerance, but the effects of each cell on the other are not well understood. We report that polyclonal CD4+Foxp3+ Treg cells induced ex vivo with transforming growth factor beta (TGFβ) (iTreg) suppress a lupus-like chronic graft-versus-host disease by preventing the expansion of immunogenic DCs and inducing protective DCs that generate additional recipient CD4+Foxp3+ cells. The protective effects of the transferred iTreg cells required both interleukin (IL)-10 and TGFβ, but the tolerogenic effects of the iTreg on DCs, and the immunosuppressive effects of these DCs were exclusively TGFβ-dependent. The iTreg were unable to tolerize Tgfbr2-deficient DCs. These results support the essential role of DCs in ‘infectious tolerance’ and emphasize the central role of TGFβ in protective iTreg/DC interactions in vivo.
regulatory T cells; dendritic cells; TGFβ; graft-versus-host disease
antihistamines; diphenhydramine; cetirizine; acute food allergic reactions; oral food challenges
Studies have demonstrated that IgE-binding cross-reactive epitopes between shrimp, cockroach and house dust mite tropomyosins can account for the presence of detectable IgE to shrimp in people who have cockroach and dust mite allergies.
We investigated the correlation between IgE-mediated sensitization to shrimp, cockroach, and dust mite in relation to allergen exposure in inner-city children.
Five hundred and four serum samples from the National Cooperative Inner City Asthma Study (NCICAS) were evaluated for specific IgE to shrimp and the results were compared to specific IgE to cockroach (Blattella germanica) and dust mite (Dermatophagoides farinae). Associations between IgE sensitization to these allergens and environmental exposures were determined.
There was a strong positive correlation between shrimp, cockroach, and dust mite IgE levels. High exposure to cockroach (Bla g) in the home, particularly in the bedroom and television room, was significantly correlated with higher shrimp and cockroach IgE levels. In contrast, high exposure to dust mite in the home was highly correlated with IgE to D.farinae, but not with shrimp IgE levels. There is a synergistic relationship between cockroach IgE and exposure in predicting shrimp IgE levels.
For children with evidence of IgE-mediated sensitization to cockroach and shrimp, having high exposure to cockroach in the home can contribute to higher shrimp IgE levels, which may not correlate with clinical reactivity. Further patient evaluations with clinical histories of shrimp exposure and reactions as well as oral food challenges would have to be performed to confirm these findings.
cockroach; dust mite; shrimp; tropomyosin; cross-reactivity
Both nature and induced regulatory T (Treg) lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic inflammation, exogenously induced Treg cells were infused into ovalbumin-sensitized mice prior to or during intranasal ovalbumin challenge. The results showed that adoptive transfer of induced Treg cells prior to allergen challenge markedly reduced airway hyperresponsiveness, eosinophil recruitment, mucus hyper-production, airway remodeling, and IgE levels. This effect was associated with increase of Treg cells (CD4+FoxP3+) and decrease of dendritic cells in the draining lymph nodes, and with reduction of Th1, Th2, and Th17 cell response as compared to the controls. Moreover, adoptive transfer of induced Treg cells during allergen challenge also effectively attenuate airway inflammation and improve airway function, which are comparable to those by natural Treg cell infusion. Therefore, adoptive transfer of in vitro induced Treg cells may be a promising therapeutic approach to prevent and treat severe asthma.
IgE-mediated food sensitization and allergy are common in inner city children, even in the absence of reported clinical reactivity. Clinicians caring for this population should maintain a high index of suspicion for food allergy.
food allergy; sensitization; inner city
Purpose of review
To consider the possible links between food allergy and asthma.
Food allergy and asthma coexist in many children, and recent studies demonstrate that having these co-morbid conditions increases the risk for morbidity. Children with food allergies and asthma are more likely to have near-fatal or fatal allergic reactions to food and more likely to have severe asthma.
Although a causal link has not been determined, increased awareness of the heightened risks of having both of these common childhood conditions, and good patient/parent education and management of both conditions, can lead to improved outcomes..
food; allergy; asthma; prevalence