The Zwolle experience with left bundle branch area pacing using stylet-driven active fixation leads.

AIMS: Left bundle branch area pacing (LBBAP) is a novel physiological pacing modality and is regarded as a viable alternative to His bundle pacing. LBBAP has mostly been performed with the lumen-less permanent pacing lead (SelectSecure™ Model 3830, Medtronic, Inc.) with a fixed helix. The aim of this study was to compare the non-stylet driven lumen-less lead (LLL) (Medtronic 3830) with a standard stylet-driven active fixation lead (SDL) (Tendril™ STS Model 2088TC-38, Abbott Laboratories) in terms of lead parameters, procedural success and complication rates. METHODS: Patients receiving a LBBA pacemaker in the Isala Hospital, The Netherlands, were prospectively enrolled. The majority received a standard right ventricular (RV) lead as backup, the implanter chose between LLL and SDL for the LBBAP lead. RESULTS: The study included 94 patients with a mean follow-up of 30 weeks. 30/31 LLL procedures were successful, compared with 62/63 in the SDL group. Including the participants that lost LBBAP during follow-up resulted in success rates of 90.3% for LLL versus 96.8% for SDL, P = 0.199. Mean number of deployments was significantly lower in the SDL group compared with the LLL group (2 ± 2.3 versus 4 ± 3.4, P = 0.005), implantation and procedural times were comparable. Pacing thresholds were low and remained low in both groups (at last follow-up 0.8 ± 0.30 V for LLL versus 0.6 ± 0.20 V for SDL). Complication rates did not differ significantly between both groups, P = 0.805. CONCLUSION: LBBAP using SDL is feasible and has comparable success rates with lower number of deployments of the active fixation screw.

A multi-center assessment to compare residual allergenicity of partial hydrolyzed whey proteins in a murine model for cow's milk allergy - Comparison to the single parameter guinea pig model.

INTRODUCTION: This 4-center study is part of a project to validate a food allergy murine model for safety testing of hydrolyzed infant formulas. AIM: The aim of the current multi-center experiment was to evaluate the residual allergenicity of three partial hydrolyzed whey proteins (pWH) in a multiple-parameter cow's milk allergy murine model and to compare to the classically used guinea pig model. Previous work showed differences in the magnitude of the allergic response to whey between centers. To get a first insight in the effect of housing on the robustness of the mouse model, microbiota composition of non-sensitized mice was analyzed and compared between centers. METHODS: Mice were sensitized intragastrically (i.g.) with whey, pWH or eWH using cholera toxin as an adjuvant. In mice, whey-IgE/IgG1, acute allergic symptoms were determined upon whey challenge. Guinea pigs were orally sensitized ad libitum via the drinking water (day 0-37) and challenged intravenously with whey on day 49. The microbial composition in fecal samples was determined in non-sensitized mice in all 4 research centers before and after conduct of the study. RESULTS: Elevated levels of whey-IgG1 were detected in whey-sensitized mice in all centers. Except for pWH-A in center 4, we observed elevated levels of whey-IgE in whey-sensitized mice and mice sensitized with pWH-A, -B, -C. Center 2 was excluded from further analysis because of non-significant IgE levels in the positive control. In contrast to whey-mice, pWH-A treated mice showed no acute skin response, mMCP-1 release or change in body temperature upon whey challenge in all centers, which corresponds with the absence of anaphylactic shock symptoms in both the mouse and guinea pig model. pWH-B and -C induced anaphylactic shock symptoms in the guinea-pig and mice whereas results on the remaining allergic outcomes in mice were inconclusive. No differences in microbiota composition were measured in response to the challenge and Microbiota composition depended on the location of the centers. CONCLUSIONS: Both animal models showed comparable results on the residual allergenicity of partial hydrolyzed whey proteins, but none of the centers was able to differentiate between the residual sensitizing capacities of the pWH-B and -C based on a single elicitation parameter in the murine model. Differences in microbiota composition might contribute to the robustness of the food allergy murine model. For a well-balanced prediction on the potential allergenicity of hydrolyzed infant formulas a multiple murine parameter model is suggested to decrease the risk of false positive or false negative results. A future challenge is to develop an overall scoring system for proper risk assessment, taking all parameters into account.

Catheter ablation in highly symptomatic Brugada patients: a Dutch case series.

AIMS: In the past few years, promising results were described in targeting the arrhythmogenic substrate of the epicardial right ventricular outflow tract (RVOT) region in patients with Brugada syndrome (BrS). In this report, we describe our experience with endo- and epicardial substrate mapping and ablation in a series of highly symptomatic BrS patients. METHODS: This case series consists of seven patients with clinical BrS diagnosis who underwent catheter ablation in two Dutch hospitals (Isala hospital Zwolle; and Amsterdam University Medical Centre, location AMC, Amsterdam) and Hamad Heart Hospital in Qatar between 2013 and 2017. All patients had an ICD and recurrent ventricular arrhythmia (VA) episodes. All patients underwent endo-and epicardial mapping of the RVOT region. Elimination of all abnormal potentials and disappearance of BrS ECG pattern during the ablation procedure was the aimed endpoint. RESULTS: The study group consisted of seven patients with mean age 45.6 ± 16.9 years. Five patients had SCN5A mutations. One patient was excluded from analysis, since ablation could not be performed due to a very large low-voltage area and was later diagnosed with arrhythmogenic right ventricular cardiomyopathy, associated with an SCN5A mutation. One patient underwent both endo- and epicardial ablation to eliminate VA. During a mean follow-up of 3.6 ± 1.5 years, 5/6 patients remained VA free with two patients continuing quinidine. CONCLUSION: In patients with BrS and drug-refractory VA, ablation of the arrhythmogenic substrate in the RVOT region was associated with excellent long-term VA-free survival. The majority of these highly symptomatic BrS patients had an SCN5A mutation and also low-voltage areas epicardially.

Effective contact and outcome after pulmonary vein isolation in novel circular multi-electrode atrial fibrillation ablation.

INTRODUCTION: Pulmonary vein (PV) reconnection is frequently the cause of recurrence of atrial fibrillation (AF) after ablation. The second-generation gold multi-electrode ablation (Gold-MEA) catheter has a new design possibly resulting in improved lesion formation compared with its predecessor. We aimed to determine the association between effective radiofrequency applications with the Gold-MEA catheter and outcome after AF ablation. METHODS: 50 consecutive patients with paroxysmal AF underwent Gold-MEA (PVAC GOLDTM, Medtronic Inc.) ablation. The Gold-MEA catheter was navigated to the PV ostium by fluoroscopy. Duty-cycled radiofrequency ablations were performed at all PV ostia. Lesions were considered transmural when electrode temperature was >50 °C and power >3 W for >30 seconds. After the ablation procedure, patients visited the outpatient clinic at 3­month intervals including 24-hour Holter ECGs. RESULTS: Mean age was 56 years. All PVs were acutely isolated with the Gold-MEA catheter. Procedure time was 111 ± 22 minutes, ablation time was 24 ± 6.7 minutes and fluoroscopy time was 20 ± 8.1 minutes. No procedure-related complications were observed. One year after ablation, 60 % of patients were still free of arrhythmia recurrences after a single PV isolation attempt. The number of transmural lesions was associated with arrhythmia-free survival: 25.0 % in <72 transmural lesions, 64.3 % in 72-108 transmural lesions and 71.4 % in >108 transmural lesions (p = 0.029). CONCLUSION: PV isolation can be performed successfully with the Gold-MEA catheter, with a favourable safety profile. Transmurality of lesions was associated with ablation success and may improve AF ablation success.

The mycotoxin deoxynivalenol facilitates allergic sensitization to whey in mice.

Intestinal epithelial stress or damage may contribute to allergic sensitization against certain food antigens. Hence, the present study investigated whether impairment of intestinal barrier integrity by the mycotoxin deoxynivalenol (DON) contributes to the development of whey-induced food allergy in a murine model. C3H/HeOuJ mice, orally exposed to DON plus whey once a week for 5 consecutive weeks, showed whey-specific IgG1 and IgE in serum and an acute allergic skin response upon intradermal whey challenge, although early initiating mechanisms of sensitization in the intestine appeared to be different compared with the widely used mucosal adjuvant cholera toxin (CT). Notably, DON exposure modulated tight-junction mRNA and protein levels, and caused an early increase in IL-33, whereas CT exposure affected intestinal γδ T cells. On the other hand, both DON- and CT-sensitized mice induced a time-dependent increase in the soluble IL-33 receptor ST2 (IL-1R1) in serum, and enhanced local innate lymphoid cells type 2 cell numbers. Together, these results demonstrate that DON facilitates allergic sensitization to food proteins and that development of sensitization can be induced by different molecular mechanisms and local immune responses. Our data illustrate the possible contribution of food contaminants in allergic sensitization in humans.

Safety and long-term effects of renal denervation: Rationale and design of the Dutch registry.

BACKGROUND: Percutaneous renal denervation (RDN) has recently been introduced as a treatment for therapy-resistant hypertension. Also, it has been suggested that RDN may be beneficial for other conditions characterised by increased sympathetic nerve activity. There are still many uncertainties with regard to efficacy, safety, predictors for success and long-term effects. To answer these important questions, we initiated a Dutch RDN registry aiming to collect data from all RDN procedures performed in the Netherlands. METHODS: The Dutch RDN registry is an ongoing investigator-initiated, prospective, multicentre cohort study. Twenty-six Dutch hospitals agreed to participate in this registry. All patients who undergo RDN, regardless of the clinical indication or device that is used, will be included. Data are currently being collected on eligibility and screening, treatment and follow-up. RESULTS: Procedures have been performed since August 2010. At present, data from 306 patients have been entered into the database. The main indication for RDN was hypertension (n = 302, 99%). Patients had a mean office blood pressure of 177/100 (±29/16) mmHg with a median use of three (range 0-8) blood pressure lowering drugs. Mean 24-hour blood pressure before RDN was 157/93 (±18/13) mmHg. RDN was performed with different devices, with the Simplicity™ catheter currently used most frequently. CONCLUSION: Here we report on the rationale and design of the Dutch RDN registry. Enrolment in this investigator-initiated study is ongoing. We present baseline characteristics of the first 306 participants.

Characteristics of cardiac device infections in the Isala Hospital; a large volume tertiary care cardiology centre.

AIMS: To determine the frequency, characteristics and risk factors of cardiac device infections in the Isala Hospital. METHODS: We retrospectively studied all patients who underwent cardiac device procedures performed in the cardiac catheterisation lab and the operating room from 2010 to 2012. All patients who developed a cardiac device infection were reviewed for its characteristics. RESULTS: 31/2026 patients developed a cardiac device infection (1.5 %). One (3.2 %) patient died within 30 days of hospitalisation. Device infection rates for procedures in the catheterisation lab and operating room were similar (p = 0.60). Positive cultures were present in 27/31 (87 %) cases. These consisted predominantly of micro-organisms that are part of the skin flora (84 %). The mean time between device procedure and infection was 14 ± 21 months (range 0-79). Cardiac device infection was significantly associated with device revision, (65 % were revisions in patients with device infection vs. 30 % revisions in patients without device infection, p = 0.011) and placement of a left ventricular lead in pacemaker implantations (59 % of patients with vs. 51 % of patients without device infection, p < 0.001). CONCLUSION: The frequency of cardiac device infection was 1.5 % with a mortality of 3.2 % within 30 days, which is lower compared with other registries. Cardiac device infections were associated with device revisions and placement of left ventricular leads in pacemaker implantations.

Association of apical rocking with super-response to cardiac resynchronisation therapy.

BACKGROUND: Super-responders to cardiac resynchronisation therapy (CRT) show an exceptional improvement in left ventricular ejection fraction (LVEF). Previous studies showed that apical rocking was independently associated with echocardiographic response to CRT. However, little is known about the association between apical rocking and super-response to CRT. OBJECTIVES: To determine the independent association of LV apical rocking with super-response to CRT in a large cohort. METHODS: A cohort of 297 consecutive heart failure patients treated with primary indication for CRT-D were included in an observational registry. Apical rocking was defined as motion of the left ventricular (LV) apical myocardium perpendicular to the LV long axis. 'Super-response' was defined by the top quartile of LVEF response based on change from baseline to follow-up echocardiogram. Best-subset regression analysis identified predictors of LVEF super-response to CRT. RESULTS: Apical rocking was present in 45 % of patients. Super-responders had an absolute mean LVEF increase of 27 % (LVEF 22.0 % ± 5.7 at baseline and 49.0 % ± 7.5 at follow-up). Apical rocking was significantly more common in super-responders compared with non-super-responders (76 and 34 %, P < 0.001). In univariate analysis, female gender (OR 2.39, 95 % CI 1.38-4.11), lower LVEF at baseline (OR 0.91 95 % CI 0.87-0.95), non-ischaemic aetiology (OR 4.15, 95 % CI 2.33-7.39) and apical rocking (OR 6.19, 95 % CI 3.40-11.25) were associated with super-response. In multivariate analysis, apical rocking was still strongly associated with super-response (OR 5.82, 95 % CI 2.68-12.61). Super-responders showed an excellent clinical prognosis with a very low incidence of heart failure admission, cardiac mortality and appropriate ICD therapy. CONCLUSION: Apical rocking is independently associated with super-response to CRT.

Endoscopically visible steam pop during high-energy laser pulmonary vein ablation.

A 58-year-old woman with atrial fibrillation underwent laser balloon ablation at our centre. During 12 W ablation in the left superior pulmonary vein, a sudden steam pop was witnessed with displacement of the balloon catheter. Visualisation of the pulmonary vein antrum showed a red discolouration at the last ablation site.

Blood pressure response to renal nerve stimulation in patients undergoing renal denervation: a feasibility study.

During renal sympathetic denervation (RDN), no mapping of renal nerves is performed and there is no clear end point of RDN. We hypothesized high-frequency renal nerve stimulation (RNS) may increase blood pressure (BP), and this increase is significantly blunted after RDN. The aim of this study was to determine the feasibility of RNS in patients undergoing RDN. Eight patients with resistant hypertension undergoing RDN were included. A quadripolar catheter was positioned at four different sites in either renal artery. RNS was performed during 1 min with a pacing frequency of 20 Hz. After all patients successfully underwent RDN, RNS was repeated at the site of maximum BP response before RDN in either renal artery. Mean age was 66 years. During RNS, BP increased significantly from 108/55 to 132/68 mm Hg (P < 0.001). After RDN, systolic BP response at the site of maximum response to RNS was significantly blunted (+43.1 vs +9.3 mm Hg, P = 0.002). In three patients, a systolic BP increase >10 mm Hg was observed after RDN. In conclusion, RNS resulted in an acute temporary BP increase. This response was significantly blunted after RDN. RNS may potentially serve as an end point for RDN.

First Dutch experience with the endoscopic laser balloon ablation system for the treatment of atrial fibrillation.

INTRODUCTION: The endoscopic laser balloon ablation system (EAS) is a relatively novel technique to perform pulmonary vein isolation (PVI) in the treatment of atrial fibrillation (AF). The present study aimed to report the results of the first 50 patients treated in the Netherlands with the EAS in terms of procedural characteristics and AF-free survival. METHODS: Fifty patients successfully underwent EAS PVI. Median follow-up was 17 months. Mean age was 56 years, 82 % had paroxysmal AF. RESULTS: 99 % of the pulmonary veins were successfully isolated with the EAS. Mean procedure time was 171 min and mean fluoroscopy time was 36 min. One procedure was complicated by a temporary phrenic nerve palsy (2 %). During follow-up, 58 % of patients remained free of AF without the use of antiarrhythmic drugs. CONCLUSION: PVI with EAS is associated with a low risk of complications and a medium-term AF-free survival comparable with other PVI techniques.

Incidence of lead dislodgement, malfunction and perforation during the first year following device implantation.

BACKGROUND: The number of cardiac rhythm device implantations has been growing fast due to expanding indications and ageing of the population. Complications of implantation were rare in the trials. However, these involved small numbers and selected patients. Prospective real-life data are necessary to assess cardiac device implantation procedure-related risks. OBJECTIVE: To determine the incidence and predictors of lead-related re-intervention in a Dutch high-volume teaching hospital. METHODS: Data from all patients who underwent cardiac rhythm device implantation between January 2010 and December 2011 were collected in a prospective registry. At least 1 year of follow-up regarding re-intervention was available for all patients. Lead-related reasons for re-intervention were categorised into lead dislodgement, malfunctioning or perforation. RESULTS: One thousand nine hundred twenty-nine devices including 3909 leads were implanted. In 595 patients (30.8 %) a CRT-D/P was implanted. Lead-related re-intervention was necessary in 86 (4.4 %) patients; it was more common in younger and male patients, and due to either lead dislodgement (66 %), malfunctioning (20 %) or perforation (18 %). Coronary sinus lead dislodgement or malfunctioning was 1.4 %. Right atrial dislodgement (1.9 %, p < 0.001) or ICD lead dislodgement (1.8 %, p = 0.002) was more common than right ventricular dislodgement (0.3 %). The incidence of lead malfunctioning was higher (0.8 %) in ICD leads. An apical position of the right ventricular lead and lateral wall position of the right atrial lead were related to cardiac perforation. CONCLUSIONS: The incidence of lead-related re-intervention was comparable with the literature. The majority of re-interventions were due to lead dislodgements, particularly with right atrial and ICD leads. Re-intervention due to coronary sinus lead dislodgement was rare.

The aryl hydrocarbon receptor and food allergy.

The immune system is important for protection against pathogens and malignant cells. However, malfunction of the immune system can also result in detrimental auto-immune diseases, inflammatory diseases, cancers and allergies. The aryl hydrocarbon receptor (AhR), present in numerous tissues and cell subsets, including cells of the immune system, plays an important role in the functioning of the immune system. Activation of the AhR is for example associated with various effects on dendritic cells (DCs), regulatory T cells and the Th1/Th2 cell balance. These cells play a major role in the development of food allergy. Food allergy is an increasing health problem in both humans and animals. Despite the knowledge in risk factors and cellular mechanisms for food allergy, no approved treatments are available yet. Recently, it has been shown that activation of the AhR by dioxin-like compounds suppresses allergic sensitization by suppressing the absolute number of precursor and effector T cells, by preserving CD4(+)CD25(+)Foxp3(+) Treg cells and by affecting DCs and their interaction with effector T cells. Future research should elucidate whether and how AhR activation can be used to interfere in food allergic responses in humans and in animals. This may lead to new prevention strategies and therapeutic possibilities for food allergy.

Interlaboratory evaluation of a cow's milk allergy mouse model to assess the allergenicity of hydrolysed cow's milk based infant formulas.

This study describes two phases of a multi-phase project aiming to validate a mouse model for cow's milk allergy to assess the potential allergenicity of hydrolysed cow's milk based infant formulas (claim support EC-directive 2006/141/E). The transferability and the discriminatory power of this model was evaluated in 4 research centers. Mice were sensitized by oral gavage with whey or extensively hydrolysed whey (eWH) using cholera toxin as an adjuvant. Whey-specific antibodies, mMCP-1 levels, anaphylactic shock symptoms, body temperature and the acute allergic skin response were determined upon whey challenge. In phases I and II, all 4 centers detected elevated levels of whey-specific IgE/IgG1 in whey sensitized animals. Elevated levels of mMCP-1, anaphylactic symptoms, body temperature drop and acute allergic skin response were scored upon whey challenge in 3 out of 4 research centers. In contrast, none of the evaluated parameters were elevated in eWH orally exposed groups. The cow's milk allergy mouse model is capable to distinguish the sensitizing capacity of complete or hydrolysed cow's milk protein. The model uses straightforward parameters relevant to food allergic responses and can be effectively transferred between different laboratories. We propose this mouse model as a new strategy for the screening of new hypoallergenic cow's milk formulas.

Aryl hydrocarbon receptor activation affects the dendritic cell phenotype and function during allergic sensitization.

Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses peanut sensitization by affecting T cell subsets. However, effects of AhR activation on dendritic cells (DC) in an allergic setting were not investigated yet. Therefore, we analysed the effects of AhR activation on DC phenotype in vivo, as well as their ex vivo potency to stimulate allergen-specific splenic T cells and to induce CD4+CD25+Foxp3+ regulatory (T(reg)) cells. C3H/HeOuJ mice were treated with TCDD by gavage and subsequently sensitized to peanut extract (PE). After eight days, mice were sacrificed and DC in spleen and mesenteric lymph nodes (MLN) were characterized or cocultured with PE-specific CD4+ T cells. AhR activation almost doubled the absolute number of CD11c+CD103+ DC, while not affecting CD11b+ DC, the absolute number of DC, the expression of the activation makers MHCII, CD86, CD80, CD40, CD54 and CD8 on CD11c+ and the activation status of CD11c+CD103+ DC in the spleen. In the MLN, TCDD decreased the absolute number of DC and CD103+ DC, while not affecting CD11b+ DC and the expression of activation markers on DC. PE-pulsed splenic DC from TCDD-treated mice suppressed IL-5, IL-13 and IFN-γ production by PE-specific T cells, but did not induce CD4+CD25+Foxp3+ T(reg) cells. This suppression of cytokine production was not mediated by the TCDD-induced increase in CD103+ DC in the spleen. Combined, these results indicate that AhR activation suppresses the initiation of food allergic responses by affecting DC and their interaction with effector T cells.

Activation of the aryl hydrocarbon receptor reduces the number of precursor and effector T cells, but preserves thymic CD4+CD25+Foxp3+ regulatory T cells.

Aryl hydrocarbon receptor (AhR) activation suppresses immune responses, including allergic sensitization, by increasing the percentage of regulatory (Treg) cells. Furthermore, AhR activation is known to affect thymic precursor T cells. However, the effect of AhR activation on intrathymic CD4+CD25+Foxp3+ Treg cells is unknown. Therefore, we investigated the effect of AhR activation on the percentage and number of CD4+CD25+Foxp3+ Treg cells during allergic sensitization in relevant immunological organs. C3H/HeOuJ mice were treated on day 0 with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and subsequently sensitized to peanut. On day 8, mice were sacrificed and thymus, spleen and mesenteric lymph nodes (MLN) were isolated. TCDD treatment decreased the number of CD4-CD8-, CD4+CD8+, CD4+CD8- and CD4-CD8+ precursor T cells, but not the number of thymic CD4+CD25+Foxp3+ Treg cells. TCDD treatment increased the number of splenic CD4+CD25+Foxp3+ Treg cells and decreased Th1, Th2 and cytotoxic T cells in the spleen. This appeared to be independent of allergic sensitization. In MLN, TCDD treatment suppressed the increase of the number of CD4+CD25+Foxp3+ Treg cells, Th1, Th2 and cytotoxic T cells induced by peanut sensitization. Together, TCDD treatment preserves thymic CD4+CD25+Foxp3+ Treg cells and decreases peripheral T helper and cytotoxic T cells. This effect of TCDD may contribute to the increased influence of CD4+CD25+Foxp3+ Treg cells on immune mediated responses and to the understanding of how AhR activation modulates immune mediated diseases, including food allergy.

Activation of the aryl hydrocarbon receptor suppresses sensitization in a mouse peanut allergy model.

Food allergy is an increasing health problem in Western countries. Previously, it has been shown that the intensity of food allergic reactions can be regulated by regulatory T (T(reg)) cells. In addition, it has been shown that activation of the aryl hydrocarbon receptor (AhR) regulates T-cell responses by induction of T(reg) cells. Therefore, we hypothesized that activation of the AhR pathway can suppress development of food allergic responses through the induction of T(reg) cells. This was investigated by using a mouse model for peanut allergy. C3H/HeOuJ mice (AhR(b)(-2)) were sensitized to peanut by administering peanut extract (PE) by gavage in the presence of cholera toxin and were treated with the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.6, 1.7, 5, and 15 µg/kg body weight) on days 3 and 11 orally. The functional role of CD4(+)CD25(+)Foxp3(+) T(reg) cells was investigated by depleting these cells with anti-CD25 mAb during sensitization to PE. TCDD treatment dose dependently suppressed sensitization to peanut (PE-specific IgE, IgG1, and IgG2a and PE-induced IL-5, IL-10, and IL-13, respectively). The percentage, but not the number, of CD4(+)CD25(+)Foxp3(+) T(reg) cells dose dependently increased by AhR activation in both spleen and mesenteric lymph nodes. Depletion of CD4(+)CD25(+)Foxp3(+) T(reg) cells markedly reversed the suppressive effect of TCDD on PE-specific antibody levels and PE-induced IL-5, IL-10, and IL-13 cytokine production. Present data demonstrate for the first time that activation of the AhR by TCDD suppressed the development of Th2-mediated food allergic responses. A functional shift within the CD4(+) cell population toward CD4(+)CD25(+)Foxp3(+) T(reg) cells appeared to underlie this effect. This suggests that the AhR pathway might provide potential therapeutic targets to treat food allergic diseases.

The role of intestinal dendritic cells subsets in the establishment of food allergy.

BACKGROUND: Food allergy affects approximately 6% of children and is the leading cause of hospitalization for anaphylactic reactions in westernized countries. Crucial in the establishment of allergy is the activation of dendritic cells (DC) leading to T helper 2-mediated responses. OBJECTIVE: We, therefore, investigated whether changes in DC subsets precede the establishment of food allergy, and which DC subsets have functional relevance during allergic sensitization in a mouse model. METHODS: Changes in DC populations in the intestine were analysed after exposure to cholera toxin alone and in combination with peanut extract (PE) as an allergen. To study the functional role of DC subsets in relation to food allergy, we used expansion of DC in vivo by treatment with Flt3L. RESULTS: Sensitization to PE in this mouse model was accompanied by a shift in DC subsets in intestinal tissues towards more CD11b(+) DC and less CD103(+) DC. No significant changes in the plasmacytoid DC (pDC) numbers were observed. Flt3L treatment, resulting in the expansion of all DC subtypes, inhibited allergic manifestations in our model, including Th2 cytokine production, PE-specific IgE and PE-induced mast cell degranulation. pDC depletion reversed Flt3L-induced inhibition of IgE responses and mast cell degranulation. conclusions and clinical relevance: The establishment of food allergy is accompanied by profound changes in DC subsets in the intestine towards more inflammatory CD11b(+) DC. In addition, expansion of DC numbers by Flt3L, in particular pDC, inhibits the establishment of allergic manifestations in the intestine. These findings are of relevance for understanding the role of DC subsets early during the process of allergic sensitization, and may lead to new therapeutic or prophylactic opportunities to prevent food allergy.