Local Hypersensitivity Reactions Research Articles

Insulin treatment in children and adolescents with diabetes

Department of Pediatrics, Uddevalla Hospital, Uddevalla,SwedenCorresponding author:Hans-Jacob Bangstad, MDDepartment of PaediatricsOslo University HospitalUlleval˚Kirkeveien 166Oslo N-0407Norway.Tel: 0047-22118765;fax: 0047-22118663;e-mail: haba@uus.noConflicts of interest: RH has received lecture honoraria fromNovo Nordisk, Lilly, Sanofi-Aventis, Medtronic and Roche. PJ-Chas received lecture fees from Eli Lilly, Novo-Nordisk, Sanofi-Aventis, Abbott, Bayer, Medtronic and Roche.The remainingauthors have declared no potential conflicts.Editors of the ISPAD Clinical Practice Consensus Guide-lines 2009 Compendium: Ragnar Hanas, Kim Donaghue,Georgeanna Klingensmith, and Peter Swift.This article is a chapter in the

Late Stent Thrombosis After Drug-Eluting Stent

Following the inspiration of Dr S. Windecker, the team from Bern, Switzerland, has contributed >30 studies on drug-eluting stent efficacy and safety, several of which represent essential pieces in the puzzle. The article in this issue of Circulation by Cook et al1 belongs to that select group of key references. The series of robust and detailed reports on the Bern-Rotterdam cohort studies have coined the 0.6% yearly linear rate of definite late stent thrombosis associated with the permanent coronary implantation of first-generation drug-eluting stents.2 Intravascular ultrasound imaging of the thrombosed stents has revealed the strong association of incomplete strut apposition with the event.3 At the same time, collective analysis of all the available evidence4 demonstrated that a reduction in restenosis with drug-eluting stents prevented adverse events caused by the treatment of the more frequent recurrences with bare metal stents. With the former compensating for the latter, the net result of this balancing act between safety and efficacy resulted in no difference in death and myocardial infarction rates up to 4 years after the initial procedure. Article see p 391 In the present study, late hypersensitivity reaction was identified as a cause for late stent thrombosis, in association with stent malapposition caused by necrotizing vasculitis around the stent struts. Histopathological analysis of aspirated thrombus showed eosinophilic infiltration typical for type IVb hypersensitivity reaction following implantation of sirolimus-eluting stents. Macrophage infiltration typical for type IVc hypersensitivity was seen with paclitaxel-eluting stents. The biomarker gradient between coronary and peripheral blood was significant for high-sensitivity C-reactive protein and myeloid-related protein 8/14, both markers of local inflammatory reaction. These patterns were not observed with early drug-eluting stent thrombosis, early …

Late stent malapposition with marked positive vascular remodeling observed only at the site of drug-eluting stents after multivessel coronary stenting

A 74-year-old woman presented with effort-induced chest pain. Diagnostic coronary angiography revealed three-vessel disease. A successful angioplasty was performed with two sirolimus-eluting stents placed in the left anterior descending artery (LAD) and left circumflex artery (LCX). The right coronary artery (RCA) was treated with a bare-metal stent. Follow-up angiography and intravascular ultrasound (IVUS) assessment were performed 8 months later, which showed late stent malapposition (LSM) with marked positive vascular remodeling around the drug-eluting stents (DES) in both LAD and LCX lesions, but there was no evidence of ectatic area around the BMS in the RCA lesion. Compared with the baseline IVUS, a significant increase in external elastic membrane (EEM) cross-sectional area was found. Twenty-seven months later, we performed repeat follow-up angiography. Intravascular ultrasound still showed vessel malapposition. A previous report showed that aneurysmal dilatation of the stented segment with severe localized hypersensitivity reaction could be a potential cause of late thrombosis after DES implantation. If LSM is related to hypersensitivity of the DES, it may have a potential risk of adverse events. Although there is a paucity of data regarding malapposition as the cause of adverse events, careful long-term follow-up of patients with vessel enlargement after DES placement is recommended.

B-1 cells modulate oral tolerance in mice

Although the origin and functions of B-1 cells are controversial, they are considered as a cellular element of innate immunity due to their ability to produce natural autoantibodies of the IgM type. These antibodies are encoded by a relatively limited repertoire of V genes, and their resulting diversity is smaller than that produced by conventional B cells. B-1 cells constitute the larger fraction of B cells in the peritoneal cavity and migrate to non-specific inflammation sites. In addition, they contribute to the production of IgA antibodies in the intestinal lamina propria. It has been demonstrated that they participate in the induction and maintenance of peripheral tolerance. Herein, the participation of B-1 cells in inducing oral tolerance is evaluated. Unexpectedly, BALB/Xid mice, the animals deficient in B-1 cells, are not tolerized to OVA but instead are responsive to oral immunization. Conversely, BALB/c mice respond to oral tolerance to this antigen. We used these biological characteristics of these animals to investigate whether B-1 cells are involved in the induction of oral tolerance to OVA. Results show that B-1 cells from BALB/c mice, treated orally with OVA and adoptively transferred to BALB/Xid mice were able to suppress local hypersensitivity reaction and lymphoproliferative cellular response observed in BALB/Xid mice. These data demonstrate that B-1 cells have regulatory properties and are involved in the induction of oral tolerance.

Thrombosis after Stent Implantation: How Much of a Problem is there?

Drug-eluting stents reduce the occurrence of in-stent restenosis and the need for subsequent target vessel revascularization when compared with bare-metal stents. However, drug-eluting stents may be associated with delayed (or absent) endothelialization, localized hypersensitivity reactions and late stent thrombosis. Stent thrombosis is a catastrophic event, resulting in life-threatening complications. Although larger, adequately powered, randomized trials are needed to fully assess the net clinical effects of drug-eluting stents compared with bare-metal stents, the evidence, thus far, appears to suggest that the net clinical benefit of drug-eluting stents may outweigh their risks. Premature discontinuation of antiplatelet therapy is the most important predictor of stent thrombosis; therefore, patients who are candidates for implantation of drug-eluting stents should be screened for their ability to receive and tolerate uninterrupted antiplatelet therapy longer than is necessary with bare-metal stents.

Allergen-IgE Complexes Trigger CD23-Dependent CCL20 Release From Human Intestinal Epithelial Cells

In food allergic individuals, exposure to food allergens by the oral route can trigger immediate (within minutes) local hypersensitivity reactions in the intestine followed by a late-phase inflammatory response. Previous work has shown that CD23 is constitutively expressed by human intestinal epithelial cells and mediates the uptake of allergen-IgE complexes. We hypothesized that allergen-IgE complexes could also signal via CD23 to trigger an inflammatory cascade in the local environment. Caco-2 monolayers were stimulated with human IgE-antigen (Ag) complexes. IL-8 and CCL20 mRNA and protein were determined by RT-PCR and ELISA, respectively. Signaling pathways were assessed by immunoblotting. Endogenous CD23 expression was knocked down by stable transfection with CD23 shRNA retroviral plasmid. Migration assays were performed using human monocyte-derived dendritic cells. Stimulation of Caco-2 cells with IgE-Ag complexes triggered upregulation of IL-8 and CCL20 at the mRNA and protein level. Allergen complexes induced phosphorylation of ERK and JNK, but not p38 MAP kinase or NK-kappaB, and resulted in AP-1 activation. Cross-linking of CD23 replicated the findings with IgE-Ag complexes, and silencing of CD23 expression abrogated the response to allergen-IgE complexes. Supernatant from IgE-Ag-stimulated epithelial cells induced migration of dendritic cells in a CCL20-dependent manner. Finally, immunostaining of duodenal biopsies demonstrated that CCL20 was constitutively expressed by epithelial cells in vivo. Signaling via epithelial CD23 may participate in the late-phase inflammatory response by the release of chemokines capable of recruiting antigen presenting cells and effector cells of allergic inflammation.

GM-CSF Plus Antigenic Peptide Vaccination in Locally Advanced Melanoma Patients

Twenty-four (24) pretreated patients with relapsed high-risk resected The American Joint Committee on Cancer (AJCC) stage IIA-IV melanoma received adjuvant peptide vaccinations derived from the melanosomal antigens MelanA/MART1, MAGE-1, gp100, and tyrosinase, according to patient tumor-associated human leukocyte antigen (HLA) restricted antigen expression, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). Pretreatment was comprised of surgery (n=23 primary tumor; n=23 metastases), local radiotherapy (n=2), immunotherapy (n=23), chemotherapy (n=10), and chemoimmunotherapy (n=1), respectively. All patients received peptide vaccines in an adjuvant setting. Seven (7) patients were relapse free for 3+ up to 25+ months. Of the patients exhibiting progressive disease (n=17), 13 patients developed metastases during vaccination (9 local, 4 distant), and 4 patients developed metastases (2 local, 2 distant) after finishing vaccine therapy. Two (2)-year local and distant metastases-free survival, 2-year distant metastases-free survival, and 2-year overall survival were calculated as 8.6%, 68%, and 85%, respectively. Vaccine treatment was well tolerated, with no severe side-effects. Twenty (20) of 24 patients developed local delayed-type hypersensitivity (DTH) reactions to synthetic peptide vaccination. Transient fever (n=2) and pain in muscle/bone (n=2) occurred rarely. In conclusion, antigenic peptide vaccination, combined with GM-CSF, is safe and may yield clinical benefits in relapsed high-risk resected melanoma patients.

Coronary dilatation 10 weeks after paclitaxel-eluting stent implantation. No role of shear stress in lumen enlargement?

We report a patient with coronary dilatation 10 weeks after paclitaxel-eluting stent implantation in the right coronary artery (RCA). Coronary angiography demonstrated a double-locular lumen dilatation in the body of the stented segment of the RCA, and intravascular ultrasound interrogation revealed the corresponding region with evidence of tissue regression behind the stent struts, incomplete stent apposition, and lumen enlargement. After three-dimensionally (3D) reconstructing the RCA, we applied computational fluid dynamics to the 3D RCA model, representing the lumen of the artery at the moment of stent implantation, and investigated the correlation of both neointimal thickness and tissue regression depth with shear stress in the stent. Neointimal thickness was found to be inversely related to shear stress, but there was no significant association of tissue regression depth with shear stress. Post-procedural stent malapposition, thrombus dissolution, and less possibly, a localized hypersensitivity reaction are potential mechanisms for the lumen enlargement in this case.

Drug-Eluting Stent Update 2007

Received May 14, 2006; January 26, 2007. Analyst projections for the drug-eluting stent (DES) market estimated that the total number of DES implanted in 2010 would go beyond 4.5 million worldwide. Although the initial results seemed promising, longer-term follow-up in a broader range of patients revealed some pitfalls. Delayed neointimal growth, enhanced platelet aggregation, a local hypersensitivity reaction against the polymer coating, stent fracture, and a failure of sirolimus-, paclitaxel-, and tacrolimus-eluting stents to reduce neointimal hyperplasia at 90 and 180 days in animals, when the drug was completely eluted from the stent, are just several examples.1–8 The number of stents currently under investigation is substantial. They are all loaded with drugs that interfere with pathways in the process of inflammation and neointimal proliferation. However, the process of restenosis is a sequence of complex events that has been only partly elucidated over the last 2 decades.9 Locally acting DES provide the opportunity to interfere with the various mechanisms responsible for each step in the restenotic cascade, and a wide variety of different agents are currently available. Although only sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) have received US Food and Drug Administration (FDA) approval to date, multiple alternative devices are attempting to find their way to achieve the same goal, namely a reduction of restenosis and the need for repeat interventions. Six Limus family–related drugs are currently being studied in DES, namely sirolimus, everolimus, biolimus A9, zotarolimus, tacrolimus, and pimecrolimus. Sirolimus, everolimus, biolimus A9, and zotarolimus all bind to the FKBP12 binding protein, which subsequently binds to the mammalian target of rapamycin (mTOR) and thereby blocks the cell cycle mainly of the smooth muscle cell from the G1 to S phase. The mechanisms of action of tacrolimus and pimecrolimus are different. Both drugs bind to FKBP506. The tacrolimus/pimecrolimus …

Burning Mouth Syndrome: Will Better Understanding Yield Better Management?

"Burning mouth syndrome" (BMS) refers to a chronic orofacial pain disorder usually unaccompanied by mucosal lesions or other clinical signs of organic disease. BMS is typically characterized by a continuous, spontaneous, and often intense burning sensation as if the mouth or tongue were scalded or on fire. Burning mouth syndrome is a relatively common condition. The estimated prevalence of BMS reported in recent studies ranges between 0.7 and 4.6% of the general population. About 1.3 million American adults, mostly women in the postmenopausal period, are afflicted with BMS. The etiology of this disorder is poorly understood even though new evidence for a possible neuropathic pathogenesis of idiopathic BMS is emerging. Burning mouth syndrome may present as an idiopathic condition (primary BMS type) distinct from the symptom of oral burning that can potentially arise from various local or systemic abnormalities (secondary BMS type), including nutritional deficiencies, hormonal changes associated with menopause, local oral infections, denture-related lesions, xerostomia, hypersensitivity reactions, medications, and systemic diseases including diabetes mellitus. In more than a third of patients, multiple, concurrent causes of BMS may be identified. It is important to note that the diagnosis of BMS should be established only after all other possible causes have been ruled out. Professional delay in diagnosing, referring, and appropriately managing of BMS patients occurs frequently. Treatment should be tailored to each patient and it is recommended to practice the treatment in a multidisciplinary facility. This article discusses our current understanding of the etiology and pathogenesis of BMS. The authors have tried to emphasize new pharmacological approaches to manage this challenging disorder.

Drug-Eluting Stent-Induced Left Anterior Descending Coronary Artery Aneurysm: Repair by Pericardial Patch—Where Are We Headed?

Deployment of drug-eluting stents has been associated with late thrombosis and restenosis on withdrawal of antiplatelet agents. We report a complication of inflammation and localized coronary artery aneurysms immediately adjacent to the stent after 4 years of implantation. Late chronic inflammatory responses may evolve for up to 4 years after sirolimus-eluting stent implantation and can cause weakening, erosion, and aneurysms of the coronary arteries.

Morphology and electrophoretic protein profiles of female salivary glands in four Oriental black fly species (Diptera: Simuliidae)

Saliva of female flies is responsible for localized hypersensitivity reactions and life-threatening systemic hemorrhagic syndromes in humans and animals. In this study, morphology and electrophoretic protein profiles of female salivary glands of Oriental black flies in the subgenus Simulium Latreille s. str., Simulium (Simulium) nigrogilvum, S. (S.) rufibasis, S. (S.) nodosum, and subgenus Gomphostilbia Enderlein, S. (Gomphostilbia) asakoae were analyzed. The paired female salivary glands of the four simuliid species were morphologically similar and situated on either side of the esophagus. Each gland is composed of two main parts, a secretory arm and a reservoir. In each species, the size of the gland correlated with salivary gland protein contents. SDS-PAGE analysis revealed differences of electrophoretic protein profiles and specifically major protein bands of the female salivary glands in each species, suggesting that protein profiles might be useful for construction of an additional tool to distinguish these black fly species. The information obtained from this study is an initial step for further research on salivary proteins that are involved in vertebrate hemostatic response.

Pathology of Drug-Eluting Stents in Humans: Delayed Healing and Late Thrombotic Risk

This study examined human drug-eluting stents (DES) to determine the long-term effects of these stents on coronary arterial healing and identified mechanisms underlying late stent thrombosis (LST). Although DES reduce the need for repeat revascularization compared with bare-metal stents (BMS), data suggest the window of thrombotic risk for Cypher (Cordis Corp., Miami Lakes, Florida) and Taxus (Boston Scientific Corp., Natick, Massachusetts) DES extends far beyond that for BMS. From a registry of 40 autopsies of DES (68 stents), 23 DES cases of >30 days duration were compared with 25 matched autopsies of BMS implantation. Late stent thrombosis was defined as an acute thrombus within a stent >30 days old. Of 23 patients with DES >30 days old, 14 had evidence of LST. Cypher and Taxus DES showed greater delayed healing characterized by persistent fibrin deposition (fibrin score 2.3 +/- 1.1 vs. 0.9 +/- 0.8, p = 0.0001) and poorer endothelialization (55.8 +/- 26.5%) compared with BMS (89.8 +/- 20.9, p = 0.0001). Moreover, DES with LST showed more delayed healing compared with patent DES. In 5 of 14 patients suffering LST, antiplatelet therapy had been withdrawn. Additional procedural and pathologic risk factors for LST were: 1) local hypersensitivity reaction; 2) ostial and/or bifurcation stenting; 3) malapposition/incomplete apposition; 4) restenosis; and 5) strut penetration into a necrotic core. The Cypher and Taxus DES result in delayed arterial healing when compared with BMS of similar implant duration. The cause of DES LST is multifactorial with delayed healing in combination with other clinical and procedural risk factors playing a role.

Mild Hemifacial Assymetry Caused by a Single Bee Sting

Multiple stings can cause multiple local and systemic effects. The various allergic reactions can range from local edema and erythema to anaphylactic shock and death. Acute renal failure, nephrotic syndrome, and heart and liver toxicity are among the multiple systemic effects of the insect venom [3,6–10]. Venom is a complex mixture of many substances, such as toxins, enzymes, growth factor activators, and inhibitors, that are responsible for the deleterious effects on cells [5]. Envenomation involves activation of the inflammatory response, with the release and activation of proinflammatory cytokines and other mediators, such as nitric oxide. These constituents interact in the body with a large number of proteins and receptors, and this interaction determines the eventual inflammatory effect of the compounds. Cytokines are important for the interactions between cells in the immune and inflammatory responses. Although the pathophysiology of envenomation is not fully understood, venom and immune responses are known to trigger the release of cytokines and nitric oxide. Local hypersensitivity reactions after bee stings are very common and well studied. Local skin reactions after bee stings may result in severe complications such as tissue necrosis if left untreated [4]. Venom therapy also is reported to induce panniculitis [2].

Complication of a Portuguese Man-of-War Envenomation to the Foot: A Case Report

Jellyfish stings have become more prevalent on account of larger commercial presence along coastal waterways. Stings are referred to as envenomations, due to the process of a neurotoxic venom being injected into the victim at the site of the sting. These events are usually mild, and for the most part, confined to local hypersensitivity reactions at the site of the injury. Certain species of jellyfish, however, have been associated with more severe, systemic insults including muscle cramping, respiratory distress, hypotension, circulatory collapse and death. One such example of a more potent venom is the Portuguese man-of-war. Most case reports of Portuguese man-of-war envenomations do not involve local soft tissue necrosis. The purpose of this case report is to present such a consequence after a jellyfish sting to the dorsum of the foot. A large area of skin necrosis developed after an envenomation that required extensive debridement and skin grafting.

Serious allergic reactions following tuberculin skin tests

Reason for posting: Tuberculosis poses an enormous health burden worldwide, and tuberculin skin tests, which are simple and sensitive, are widely used to screen for the infection. Local hypersensitivity reactions are expected, intended and, in fact, an expression of what the test is supposed to

Paravasation von Zytostatika: Prävention und Therapie

Based on the potential to cause local tissue injury drugs are classified as vesicant, irritant and non-irritant. The frequency of extravasation is considered to be between 0.6 % and 6 %. More frequently an inflammatory reaction is caused by thrombophlebitis or a local hypersensitivity reaction following chemotherapy administration rather than by an extravasation. A number of factors are known to increase the risk of extravasation. By the consideration of these risk factors preventive guidelines for the safe administration of chemotherapeutic agents have been published. Central venous devices significantly reduce the risk of extravasation. To date there are no generally approved treatment guidelines for the management of extravasations. Treatment is mostly empirical. Nevertheless some general measures are to be recommended: Firstly, aspiration of the extravasated fluids should be attempted. Furthermore local supportive care such as intermittent topical warming or cooling is at least palliative and to a certain degree reduces the extent of the injury. Beside these non pharmacological therapies the beneficial effects of Dimethylsulfoxid (DMSO) -- or Hyaluronidase-administration dependent on the type of paravasation have been proven. The use of sodium bicarbonate, sodium thiosulfate or corticosteroids is no longer recommended. In the case of extravasation rapid and correct management is crucial for the benefit of any treatment. Therefore, written guidelines for both the handling of cytotoxic agents and also the management of an extravasation should be present in all Departments where cytotoxic agents are administered. In addition to these guidelines an extravasation kit including all necessary materials and drugs to treat extravasations should be available.

Subacute Thrombotic Events Associated with Drug Eluting Cardiac Stents May Be Localized Hypersensitivity Reactions to Polymers.

Background: In October 2003, six months after approval of the first drug-eluting coronary stent (CYPHER™ stent), the FDA reported 50 stent-associated hypersensitivity reactions. In November 2003, FDA officials reported that these reactions were probably due to concomitantly prescribed medications.Methods: All adverse device event reports for CYPHER stent associated hypersensitivity- reactions in the FDA's adverse event reporting system, the published literature, or from RADAR, between April 2003 and June 2004 were reviewed. Causality was evaluated using World Health Organization criteria.Results: Review of FDA reports (n=2,607) identified 161 persons with hypersensitivity symptoms. Fewer than 20 hypersensitivity cases were reported monthly, except for 43 and 42 reports in October and November 2003. Symptoms began within 2 days of stent implantation (21%), between 2 and 7 days (43%) and between 7 and 14 days (19%) following stent implantation and persisted for less than 8 days for 17%, 8–30 days for 29% and > 30 days for 55%. Findings included rash (80%), itching (28%), hives (19%), dyspnea (12%), fever (12%), chest pain (8%), anaphylaxis (7%), joint pain or swelling (7%) and high or low blood pressure (5%). Among persons with rashes, 25% covered the entire body, 21% developed hives, 7% had localized maculopapular eruptions and 4% developed blisters or desquamation. Treatment included emergency interventions (26%) or hospitalization (19%). Outcomes included permanent disability (5%) or death (2%). Aspirin or clopidogrel was discontinued at the time of hypersensitivity onset for 42. Using WHO criteria, clopidogrel, aspirin, ticlopidine and/or the stent itself were classified as possible causes for > 85% of cases. Of 150 events possibly caused by the CYPHER stent, 35 persisted for > 30 days. For 7 probable CYPHER-stent induced hypersensitivity cases identified by RADAR (n=4), the FDA (n=2) or the literature (n=1), symptom onset was < 5 days (n=3) and at 3 weeks, 1 month, 4 months, and 7 months after stent implantation. Findings included rash (n=4), hives (n=1), blisters on both hands (n=1), dyspnea (n=2), eosinophilia (n=1), elevated IgE levels (n=2) and Gallium-67 scan findings at the stent (n=1). Findings did not abate with thienopyridine discontinuation (n=5). Outcomes included resolution of symptoms with hospitalization (n=1) or corticosteroids (n=2), persistent angina (n=1) and subsequent occurrence of fatal cardiac events, with autopsy identification of eosinophilic infiltrates at the stent site (n= 2 patients).Conclusion: Rash, hives, dyspnea and catastrophic cardiac events may represent local and systemic hypersensitivity reactions from the CYPHER-stent. Reporting of these events decreased by > 90% following a FDA advisory that suggested that skin reactions were unrelated to the stent. However, our findings highlight the importance of continued vigilance for hypersensitivity reactions that may represent an early manifestation of a catastrophic hypersensitivity event.

CpG immunostimulatory sequences enhance contact hypersensitivity responses in mice.

Bacterial DNA and synthetic cytidine-phosphate-guanosine-oligodeoxynucleotides (CpG ODN) potently activate dendritic cells (DC) and therefore have been proposed as adjuvants for vaccination strategies. Although CpG ODN are considered as safe adjuvants this study shows that CpG ODN are responsible for enhanced antigen-specific skin inflammatory reactions. We used the murine model of contact hypersensitivity (CHS) to 2,4-dinitrofluorobenzene (DNFB) in which hapten-specific CD8+T cytotoxic 1 cells are effector cells. Subcutaneous injection of CpG ODN, 1 d before sensitization enhanced the CHS response to DNFB and resulted in increased recruitment of CD8+ T cells at the challenge sites, whereas control ODN injection did not have any effect. This effect was local and not systemic as it was only observed when DNFB was applied at the same site as the CpG motifs. CpG ODN-induced enhancement of CHS was due to increased antigen-presenting cell functions of DC since: (i) CpG ODN-injected skin revealed upregulated expression of major histocompatibility complex class II, CD80, and CD86 molecules and (ii) CpG ODN treatment of DNFB-derivatized DC enhanced the intensity of CHS responses after in vivo transfer. Taken together, the results show that CpG ODN may be responsible for immune side-effects such as worsening of T cell-mediated skin diseases.

Allergen-specific immunosuppression by mucosal treatment with recombinant Ves v 5, a major allergen of Vespula vulgaris venom, in a murine model of wasp venom allergy.

Up to 5% of the population suffer from systemic, 19% from local allergic hypersensitivity reactions to stinging insects. Even though specific immunotherapy is very effective in treating allergy to insect venom, new concepts of treatment strategies with only the disease eliciting allergen in recombinant form, along with antigen application via a less invasive route might be suggested for enhanced treatment efficacy and compliance. In the present study we aimed (i) to establish a mouse model of wasp venom allergy, mimicking the natural mode of sensitization, and (ii) to develop a prophylactic treatment strategy based on mucosal tolerance induction, using one major wasp venom allergen in recombinant form, i.e. recombinant (r)Ves v 5. Immunization with wasp venom--with or without the use of the adjuvant aluminium hydroxide--led to comparable T helper 2-like immune responses in vivo and in vitro. Intranasal administration of rVes v 5 prior to sensitization with wasp venom resulted in a significant reduction of wasp venom-specific antibody levels (immunoglobulin E (IgE)/IgG2a), type I hypersensitivity reactions in vivo and cytokine production in vitro. Pretreatment with the whole venom was less effective and caused toxic side reactions in higher concentrations, suggesting a favourable use of the recombinant venom allergen for mucosal application. Increased mRNA levels of transforming growth factor-beta and interleukin-10, along with adoptive cell transfer experiments indicated that the immunosuppression after intranasal rVes v 5-application has been mediated by regulatory mechanisms. This is further supported by the fact that the immunosuppression to rVes v 5 was associated with a bystander suppression to the unrelated aero-allergen Bet v 1. In conclusion, we demonstrated that the intranasal application of recombinant Ves v 5 prevented subsequent allergic sensitization to all components of the whole wasp venom. As allergy to insect venom develops in dependence of the frequency of insect stings, a prophylactic treatment based on mucosal tolerance induction with recombinant allergens might be of interest for people at high risk to frequent exposure to the stinging insects.