In individual experiments, na?ve mice were challenged intranasally with 1 g recombinant mouse IFN- (endotoxin concentration, 0

In individual experiments, na?ve mice were challenged intranasally with 1 g recombinant mouse IFN- (endotoxin concentration, 0.1 ng per g; BD Pharmingen) in PTZ-343 50 l PBS-bovine serum albumin (BSA) or PBS-BSA alone on 4 consecutive days, and airway hyperresponsiveness was measured 6 h after each challenge. patients (4). spp. are nematode parasites of marine mammals with larval stages that pass through several intermediate hosts. The infectious-stage larvae (L3) are found worldwide in sea fish or cephalopods and can be accidentally ingested by humans (32). If ingested live due to consumption of PTZ-343 PTZ-343 natural or undercooked fish, L3 are able to parasitize humans, causing the zoonotic disease known as anisakiasis. This is usually an acute and transient contamination, with the larvae dying within a few weeks, since the host environment does not permit development into adult worms (6). Within hours of being ingested, L3 penetrate the mucosal layers of the gastrointestinal tract, causing direct tissue damage that may lead Rabbit Polyclonal to APOL4 to abdominal pain, nausea, and/or diarrhea. Furthermore, some patients develop an immunoglobulin E (IgE)-mediated gastroallergic anisakiasis, which presents with clinical manifestations ranging from urticaria to allergic reactions and life-threatening anaphylactic shock (5, 13, 14). To date, nine allergens from to be a leading cause of food allergy in Spain (2) and have found a higher prevalence of sensitization to than to seafood among almost 5 million Japanese (24). is also an important cause of occupational allergy in fish-processing workers, as shown in a recent epidemiological study by our group, including 578 workers from fish-processing factories in South Africa, in which sensitization was associated with dermatitis and nonspecific bronchial hyperreactivity (37). Because sensitization to was associated with increased fish consumption, we investigated the underlying immune mechanisms by infecting mice with L3 and subsequently challenging them orally with an crude antigen extract. This induced striking allergic reactions, including airway inflammation and lung mucus hypersecretion, which were associated with T-helper 2 (Th2)/type 2 responses (37). Furthermore, mice uncovered epicutaneously to proteins developed protein contact dermatitis (36). Local skin pathology was interleukin-13 (IL-13) dependent, as evidenced by the fact that it was abolished in IL-13- and IL-4 receptor alpha (IL-4R)-deficient mice, whereas IL-4 was important for systemic PTZ-343 allergic sensitization (36). Together, these studies show that sensitization by contamination and subsequent oral challenge with PTZ-343 an extract can cause allergic airway disease, while epicutaneous exposure to proteins can lead to dermatitis, explaining the observations of human prevalence studies. However, it is still unclear whether live contamination is needed for the development of allergic airway reactions or whether exposure to nematode-derived protein is sufficient (4). This is an important clinical question in view of the fact that several case and prevalence studies, including ours, indicate that sensitization by inhalation of proteins might be an important cause of work-related allergies (1, 3, 7, 37, 39, 40). Aerosolized food allergens cause as much as 10% of asthma in the occupational environment (41), and allergens aerosolized during fish cleaning, cooking, or fish meal production may therefore present a risk for workers. In this study we aimed to determine whether sensitization through contamination is essential for the induction of allergic airway disease or if exposure to larval proteins or heat-killed larvae is sufficient to induce allergic airway reactions. In addition, we investigated the effects of IL-4/IL-13 signaling by using mice deficient in IL-4R, an important receptor chain in allergic airway disease through which both IL-4 and IL-13 transmission (8). Wild-type and IL-4R?/? mice were either sensitized intraperitoneally (i.p.) with live or heat-killed L3 or sensitized intranasally to an extract and were subsequently challenged by intranasal administration of an extract in order to mimic aerosolized exposure. All sensitization protocols induced symptoms of allergic airway disease, but allergen-specific antibody responses were present only when mice were sensitized intraperitoneally by live or heat-killed larvae. Interestingly, while the development of airway hyperresponsiveness (AHR) was dependent on IL-4R responsiveness when mice were sensitized intranasally, mice sensitized with live or heat-killed L3 developed AHR independently of IL-4R responsiveness. This IL-4R-independent AHR was shown to be dependent on gamma interferon (IFN-). MATERIALS AND METHODS Mice. Experiments were performed with 6- to 8-week-old wild-type BALB/c mice or IL-4R?/? mice on a BALB/c genetic background (34). Animals were housed in the University or college.