Immunologic and nonimmunologic responsiveness in ragweed-sensitized dogs.

The relationship between airway responsiveness to inhaled antigen and histamine, immunologic release of lung histamine, immunologic responsiveness of skin, and specific immunoglobulin E (IgE) antibodies were examined in 11 inbred allergic dogs immunized with extracts of ragweed and grass and 5 nonimmunized control dogs from the same colony. Airway responsiveness to antigen and histamine was characterized by the doses that increased the airflow resistance of the total respiratory system to twice the control values (ED200). Highly significant correlations were found between airway responsiveness and cutaneous responsiveness to antigen and other immunologic characteristics (e.g., IgE and histamine released from lung by inhaled antigen) in all dogs. In ragweed-sensitized dogs, there was an inverse correlation between immunologic responsiveness (reflected by the cutaneous response to antigen and histamine released from lung by inhaled antigen) and nonimmunologic responsiveness of airways (histamine ED200: r = 0.73, P less than 0.05 and r = 0.75, P less than 0.01, respectively). Antigen ED200 was also correlated with histamine release from lung after antigen inhalation (r = 0.74; P less than 0.01). We conclude that airway reactions to inhaled antigen in allergic dogs are dependent not only on immunologic factors but also on the degree of nonimmunologic airway responsiveness to histamine and that these factors are correlated inversely.

Histamine release and circulating cells after antigen inhalation in allergic dogs.

Histamine can be recovered from the blood of ragweed-sensitized dogs after aerosol antigen challenge, although its source is unknown. Neutrophils and eosinophils have been recovered from bronchoalveolar lavage fluid (BALF) obtained under identical conditions. We investigated the time course of changes in histamine levels in plasma and BALF taken from ragweed-sensitized dogs after aerosol challenge. Changes in the numbers of circulating neutrophils, eosinophils, lymphocytes, monocytes, and platelets were also studied. After 3 min, total pulmonary resistance (RL) was maximally increased and systolic blood pressure was maximally decreased. Histamine levels in plasma and BALF were increased and circulating eosinophils and neutrophils were decreased. After 15 min, platelet numbers were reduced. By 90 min, changes in RL, blood pressure, plasma and BALF histamine concentrations, and circulating neutrophils and eosinophils had returned to base-line values, but platelet numbers remained significantly decreased. Sham challenge caused no significant changes in any of these variables. Intravenous administration of histamine in doses large enough to attain plasma levels comparable with those achieved after aerosol antigen challenge resulted in no concomitant rise in BALF histamine levels. We conclude that antigen challenge in sensitized dogs causes increases in BALF and plasma histamine levels and is associated with a reduction in circulating neutrophils, eosinophils, and platelets. It is likely that antigen causes airway mast cells to release mediators that move down a concentration gradient from the airways to the pulmonary circulation.

Antigen-induced airway hyperresponsiveness and pulmonary inflammation in allergic dogs.

We studied whether antigen-induced airway hyperresponsiveness was associated with pulmonary inflammation in 11 anesthetized ragweed-sensitized dogs. Airway responsiveness to acetylcholine aerosol was determined before and at 2, 6, and 24 h after ragweed or sham aerosol challenge. Pulmonary inflammation was assessed by bronchoalveolar lavage (BAL) performed at either 2 or 6 h. Total pulmonary resistance increased 11-fold at 5 min after ragweed. Airway responsiveness was unchanged at 2 h but was increased 6.6-fold at 6 h in 8 of 11 dogs (P less than 0.001); hyperresponsiveness persisted from 4 days to 4 mo. Airway responsiveness was unchanged by aerosols of diluent. Neutrophils in BAL fluid increased approximately sixfold at 2 h (P less than 0.02) and at 6 h (P less than 0.02) after antigen challenge. There were fewer eosinophils in fluid recovered at 6 h after antigen compared with 2 h lavages (P less than 0.05). In three nonresponders, BAL showed no significant changes in neutrophils and eosinophils after antigen. Thus antigen-induced hyperresponsiveness is associated with the presence of pulmonary inflammation, presumably arising from the airways and involving both neutrophils and eosinophils.

Immediate hypersensitivity to seminal fluid and atopic dermatitis.

A woman with atopic dermatitis experienced anaphylactic episodes following intercourse with her husband, with subsequent exacerbations of her atopic dermatitis. Skin testing and an in vitro leukocyte histamine release assay established the diagnosis of immediate hypersensitivity to her husband's seminal fluid; delayed hypersensitivity to seminal fluid could not be demonstrated. Antigen was found in the seminal fluid of nonrelated men. Radioallergosorbent testing detected the presence of circulating IgE antibodies specific for seminal plasma protein. Immunotherapy with seminal plasma may have limited the severity of a subsequent reaction. Serum from the husband and nonrelated men also contained antigen that provoked histamine release from the patient's leukocytes in vitro. The antigen in serum was associated with the globulin fraction and had a temporal relationship to ejaculation, appearing within 12 hours of ejaculation and disappearing within four days.

Food allergy in atopic dogs.

The food sensitive dog provides a good animal model for food allergy, whose allergic reaction can be followed serially with repeated challenges both in skin and by oral challenges and by endoscopic direct visualization and serial biopsies. This model is proving useful in showing reduced allergenicity in food allergens-soy, wheat, cow's milk by thioredoxin treatment. Recently Dr. Buchanan has cloned the gene for the NADP-thioredoxin reductase (NTR) which he transferred into barley seeds with a bacterial vector. He is attempting to do the same with wheat and soy seeds to produce genetically hypoallergenic foods. The canine model for food allergy provides an excellent model in which to test such bio-engineered potentially hypoallergenic foods.

Development of gastroscopic food sensitivity testing in dogs.

The aims of this study were to develop a gastroscopic food sensitivity testing (GFST) technique for clinical use in dogs and to determine if the results of GFST were influenced by the feeding of a hypoallergenic diet immediately before the testing period ("unmasking"). The technical requirements for GFST were devised during a total of eight endoscopies performed in four healthy dogs. GFST was performed in anesthetized dogs in sternal recumbency. Food extracts were dripped onto the dependent aspect of the body of the stomach via plastic tubing passed through the endoscope. Changes were observed within 2 to 3 minutes of application, and included localized mucosal swelling and erythema, generalized mucosal erythema, and hyperperistalsis. The influence of "unmasking" was then examined in 6 atopic and 2 healthy dogs, which underwent GFST on three occasions, 4 weeks apart. Before the first and third testing periods, the dogs consumed a commercial dry dog food. For 5 days before the second testing period the dogs were fed a hypoallergenic elemental diet. Oral challenges were performed to identify which of the dogs had clinically overt immediate food sensitivity. Localized swelling was most frequently correlated with positive challenge PO. No positive reactions occurred in response to the negative control extract (lamb). The number of positive GFST results increased after feeding the hypoallergenic diet. In conclusion, these preliminary results indicate that GFST holds substantial promise for the diagnosis of immediate food sensitivities affecting the gastrointestinal tract. The sensitivity of the procedure appears to be enhanced by preceding testing with a hypoallergenic diet.

Immunoglobulin E antibodies to pollens augmented in dogs by virus vaccines.

An inbred "atopic dog colony" was established to study the effect of viruses on immunoregulation of immunoglobulin (Ig) E antibodies. Dogs were selected for high skin reactivity to grass and weed pollens. Their offspring were inoculated with pollen extracts in alum immediately after routine vaccinations (attenuated live-virus vaccines for canine distemper and infectious canine hepatitis, and a killed bacterin for Leptospira). Heat labile antipollen IgE antibodies were measured by passive cutaneous anaphylaxis. Pups vaccinated for canine distemper before being given pollen extracts had many more IgE antibodies than did their control littermates who were not vaccinated until after the last pollen extract injection. This may be a natural example of the "allergic break-through phenomenon."

[Delayed reaction in asthma]. / La réaction retardée dans l'asthme.

IgE mediated type 1 hypersensitivity induces an immediate phase, during the minutes that follow contact with the allergen and is very often associated with a late phase that occurs during the hours that follow contact. The late phase of asthma induced by an IgE--dependent mechanism is linked with a cellular activation (lymphocytes, eosinophils) and release of different mediators (Paf Acether, LTB4, ECFA, MBP, EcP) from those of the immediate phase. Corticosteroids are well known as inhibitors of the late phase. Like cromoglycate, AZELASTINE inhibits both the immediate and late phases.

Allergen immunotherapy with heat-killed Listeria monocytogenes alleviates peanut and food-induced anaphylaxis in dogs.

BACKGROUND: Heat-killed Listeria monocytogenes (HKL) potently stimulates interferon (IFN)-gamma production in CD4 T-lymphocytes, and when used as adjuvant for immunotherapy, reduces immunoglobulin (Ig)E production and reverses established allergen-induced airway hyperreactivity (AHR) in a murine model of asthma. We asked if such treatment could decrease established peanut-induced anaphylaxis or cow's milk-induced food allergy in highly food-allergic dogs. METHODS: We therefore studied four 4-year-old atopic colony dogs extremely allergic to peanut (Group I), as well as five 7-year-old dogs very allergic to wheat, milk and other foods (Group II). All dogs experienced marked allergic symptoms, including vomiting and diarrhea on oral challenge with the relevant foods. The dogs were then vaccinated once subcutaneously with peanut or milk and wheat with HKL emulsified in incomplete Freund's adjuvant. RESULTS: Following vaccination of the allergic dogs with HKL and allergen, oral challenges with peanut (Group I) or milk (Group II) elicited only minor or no symptoms. In addition, skin test end-point titrations showed marked reductions for >10 weeks after treatment, and levels of Ara h 1-specific IgE in serum of peanut sensitive dogs, as demonstrated by immunoblotting, were greatly reduced by treatment with HKL plus peanut allergen. CONCLUSIONS: Thus, HKL plus allergen treatment markedly improved established food allergic responses in dogs, suggesting that such an immunotherapy strategy in humans might greatly improve individuals with food allergy and anaphylaxis.

Immunological development in infants of allergic parents.

Serum immunoglobulins were determined every 4 months from cord blood to age 2 years in ninety-two infants of allergic parents. By 7 months of age, the concentration of IgA was significantly greater in infants who developed atopic dermatitis than those who did not. The IgA was also significantly greater than in matched non-allergic controls. The difference continued to the end of the 2-year study. No significant difference was found in the three groups for levels of IgG and IgM. These findings differ from the results of a previous report and possible explanations are presented.

The development of allergy in infants of allergic parents: a prospective study concerning the role of heredity.

Ninety-four infants of allergic mothers were studied from birth to age 24 months. If the father was also allergic, the family history was termed bilateral (36 infants); if the father was not allergic, the family history was termed unilateral (58 infants). Data concerning family history, methods of feeding (bottle versus breast) and allergic skin reactivity were obtained. Significantly, more infants developed allergy if they were from a bilateral allergic parentage (P = less than 0.044). When skin test negative, bottle-fed infants with a bilateral family history were compared to breast-fed infants with a unilateral family history, there was significantly less asthma in the latter group (P = less than 0.047). During the first three months of life there was significantly less atopic dermatitis in the breast-fed infants with an unilateral family history than in the breast-fed infants with a bilateral family history (P = less than 0.027). In this study it remained unclear why infants with positive allergy skin tests demonstrated a different incidence of allergic disease from those who were skin-test negative when the variables of family history were the same.

Prevention of asthma.

Infants born of allergic mothers but normal fathers, who had eczema and who were fed cows' milk, had a significantly greater incidence of asthma (P less than 0.001) than infants with a similar history but who were breast-fed. An analysis of all breast-fed infants in the study showed that they were less likely to develop asthma than those who were bottle-fed (P less than 0.06). There was a lower incidence of allergy in infants born of families with allergic mothers and normal fathers, than in families in which both parents were allergic (P less than 0.02). In skin tests of both breast or bottle-fed babies, the two most common allergens eliciting reactions were egg and cat dander.

Development of allergy in children. I. Association with virus infections.

Children born into allergic families, with two allergic parents, are at high risk of developing allergy within the first 5 years of life. In order to observe possible external factors in the sensitization process, a prospective study of 13 such children was done, in which serial clinical and immunologic observations were made at 3- to 6-month intervals over a period of 1 to 4 yr. Eleven of these children are now clinically allergic; 5 have asthma. Immunologic evidence for allergic sensitization was observed in these 11 children by RAST, antigen-induced leukocyte histamine release, lymphoblastogenesis, and rise in serum IgE. Upper respiratory infections (URI) occurred in these 11 allergic children 1 to 2 months prior to the onset of allergic sensitization. In 10 of these 11 URI children, complement-fixing antibodies to viruses (parainfluenza, RSV, CMV) increased in the same blood samples in which immunologic allergic sensitization was first evidenced. This coincidence suggests that certain viruses may contribute to the allergic sensitization process.

Leukocyte inhibition factor in delayed-onset food allergy.

To investigate the possiblity of a cellular immune hypersensitivity reaction in patients who developed allergic symptoms 2 or more hours after ingestion of a particular food, two in vitro tests were employed: leukocyte migration inhibition factor (LIF) and lymphoblastogenesis. Of the children and adults with food allergy, 73% (30 of 41) had a positive LIF test with whole cow's milk or its fractions or corn. Of nonallergic or grass-pollen sensitive controls, 15% (four of 26) had positive LIF. Lymphocyte transformation often correlated with LIF results in food-allergic patients but was also positive in 77% of controls (seven of nine). We suggest that many patients with delayed-onset food-induced allergy symptoms may have a cellular immune component to their sensitivity. Serum IgA, where measured, was absent or low in half of these patients.

An ontogenic study of histamine and mast cells in the fetal rhesus monkey.

This study was designed to determine the presence of cell-bound histamine and mast cells, if any, in the lung and skin of nonhuman primate fetuses and neonates. The results indicate that cell-bound histamine can be detected in both tissues of the rhesus monkey fetus by 60 days of gestation, the earliest age examined, at levels that are 2% to 3% of levels present in yearling animals. Levels increase markedly during the least 1 1/2 mo of gestation; however, at birth, levels are only 12% to 46% of those observed in the yearling and are lower than levels observed at 150 days of gestation. Most cell numbers in lung and skin of the fetus closely parallel histamine content.

Cutaneous allergic response in atopic dogs: relationship of cellular and histamine responses.

We studied the cutaneous response to intradermal antigen using clinical, histologic, and physiologic criteria in ragweed-sensitized dogs. The clinical response was measured early (the wheal at 20 minutes) and late (induration at 6 hours). We assessed cutaneous responsiveness to histamine before and 6 hours after injection (intradermally) of ragweed (n = 5, antigen group) and diluent (n = 4, 10% glycerin in 0.9% NaCl, sham group); we measured the wheal in response to histamine (1.0 ng to 0.1 mg, intradermally), constructed a dose-response curve, and interpolated the provocative dose (milligrams) of histamine required to create a wheal 10 mm larger than the response to saline control. Skin biopsy specimens were obtained before and after injection of either ragweed or diluent. Consistent with the human late-phase response, neutrophils and eosinophils were present in the dermis at 1 hour, maximal at 6 hours, and decreased at 24 hours. Mononuclear cells increased significantly at 6 hours and were the predominant cells present at 24 hours after antigen. The late clinical response correlated only with influx of eosinophils (rs = 0.85; p less than 0.005). Histamine responsiveness increased markedly after antigen (p less than 0.0001), did not change after glycerin diluent (sham), and was correlated with the intensity of neutrophil influx at 6 hours (rs = 0.69; p less than 0.05), and to a much greater degree with mononuclear cell influx at 6 hours (rs = 0.85; p less than 0.005).

Hypersensitivity reaction in an infant fed hydrolyzed lactalbumin contained in a semielemental formula.

Following introduction of milk protein formula feedings, a 6-month-old male developed profuse, watery diarrhea progressing to shock, requiring cardiopulmonary resuscitation. Reinstitution of enteral feedings with a formula containing hydrolyzed lactalbumin (Travasorb STD) resulted in recurrence of diarrhea with fever. Intestinal and rectal biopsies showed only nonspecific inflammatory changes. He was discharged on an elemental formula (Vivonex). Twenty-three months later, while admitted for evaluation of hypophosphatemic rickets, immunologic testing using the lymphocyte migration inhibition factor (LIF) test demonstrated positive reactions, especially to alpha-lactalbumin (56% inhibition) and whole cow's milk (22%, normal of less than 20% inhibition). Skin tests revealed sensitivity to cow's milk and eggs. Soy formula also produced diarrhea and bloody stools. Protein hydrolysate formulas, touted as hypoallergenic diets, are useful in infants with intolerance to milk protein. This is the first documented case of an immunological reaction to the hydrolyzed whey protein, lactalbumin. Although protein hydrolysate formulas are effective treatment in most infants with milk protein intolerance, allergic reactions are possible. Caution and close observation should be exercised in immunologically sensitized infants rechallenged with any formula.

Inhibition of the cutaneous response to antigen by a thromboxane-synthetase inhibitor (OKY-046) in allergic dogs.

We studied the effect of a selective thromboxane-synthetase inhibitor, sodium (E)-3-[4-(1-imidazolymethyl)-phenyl]-2-propanoate) (OKY-046) on the late-phase response to antigen in ragweed-sensitized dogs. Skin biopsies were performed before and 1, 6, and 24 hours after ragweed injection. OKY-046 was infused (100 micrograms.kg-1.min) from 1 hour before until 6 hours after intracutaneous ragweed in five dogs. The early clinical response to ragweed (wheal at 20 minutes) was not changed by OKY-046. A late-phase response (induration at 6 hours) was not observed in any of the OKY-046-treated dogs but was present at 6 hours in 4/5 dogs without OKY-046. Typical mast cells responded similarly in both groups with progressive degranulation during 24 hours. Maximal degranulation of atypical mast cells was delayed to 6 hours with OKY-046, whereas these cells responded completely at 1 hour without OKY-046. The inflammatory response to ragweed followed the same pattern in both groups, but the numbers of each cell type were decreased with OKY-046. With OKY-046, the cutaneous response to histamine was not changed significantly from baseline at 6 hours but was increased (p less than 0.05) at 24 hours, whereas without OKY-046, histamine response was significantly increased at 6 hours (p less than 0.001) and 24 hours (p less than 0.01). We conclude that OKY-046 alters the antigen-induced response of atypical mast cells, the subsequent cellular and clinical late-phase response, and prevents the increase in histamine response.