Effect of amlexanox on experimental allergic rhinitis in actively sensitized guinea pigs

The effect of amlexanox given orally for 3 weeks was studied on the IgE-mediated experimental allergic rhinitis in the actively sensitized guinea pigs. The intranasal instillation of antigen (egg albumin) induced the increase of nasal vascular permeability (dye leakage), histamine content in nasal perfusate and nasal resistance in sensitized guinea pig. Amlexanox, 20 and 60 mg/kg/day given orally for 3 weeks significantly inhibited the increase of dye leakage into the nasal cavity, histamine content and nasal resistance in a dose-dependent manner. These results suggest that amlexanox given orally may be useful therapeutic agent for human allergic rhinitis.     

Effect of oral antigen administration on nasal blockage in experimental allergic rhinitis in guinea pigs

OBJECTIVE AND DESIGN: We evaluated the effectiveness of oral treatment with Japanese cedar pollen on experimental allergic rhinitis in guinea pigs. SUBJECTS: Male Hartley guinea pigs. TREATMENT: From 16 days before the first sensitisation, 1 and 100 mg/time/animal pollen suspension was orally administered twice weekly. Animals were then sensitised and repeatedly challenged with the pollen. METHOD: Guinea pigs were sensitised by intranasal instillation of cedar pollen extracts adsorbed onto Al(OH)3 at a dose of 0.3 microg pollen protein/0.3 mg Al(OH)3/3 microl/nostril twice a day for 7 days. Then the animal was challenged by inhalation with cedar pollen (1.8 mg/nostril) once every week. We evaluated the effects of the oral treatment with antigen on: 1) sneezing frequency, 2) nasal blockage after antigen challenge, 3) nasal hyperresponsiveness to histamine and leukotriene D4, and 4) titres of anaphylactic antibodies. RESULTS: During the course of the high dose administration, several animals died from a possible cytotoxicity, whereas the low dose caused no discernible change. The oral administration of the pollen at both the doses significantly inhibited nasal blockage, and the hyperresponsiveness to the stimuli was also strongly suppressed by the oral treatment. Inhibitory effectiveness did not differ substantially between the 1 and 100 mg/animal-treated groups. In contrast, neither sneezing frequency nor the increasing level of anaphylactic antibodies was influenced by the oral administration. CONCLUSIONS: In this study, we found that the pollen-induced nasal blockage and hyperresponsiveness were suppressed by the oral administration of the pollen in the sensitised guinea pig.     

Effect of surfactant inhalation on allergic bronchoconstriction in guinea pigs

Background In the small airway, surfactant reduces surface tension, prevents liquid filling of bronchioles, thereby maintaining patency in the small airways. Recent reports demonstrated that surfactant dysfunction develops in experimental asthma in immunized guinea pigs. However, there are few reports concerning surfactant and lung function in an experimental asthma model. Objective To examine whether inhaled surfactant improves lung mechanics in antigen-induced bronchoconstriction in guinea pigs. Method We developed a passively immunized guinea pig model for allergic bronchoconstriction induced by antigen inhalation. Using this model, we investigated the effect of inhaled exogenous surfactant, surfactant TA. on the airway opening pressure (Pao) after antigen challenge. Results Aerosol antigen challenge produced a gradual and long-lasting increase in Pao. Twenty minutes after antigen challenge, aerosolized surfactant TA, 20 mg/ml. was inhaled for 90 s, and it significantly reduced the Pao by 32.8% in 12 min, while a 10.2% reduction was observed in a control group in the same period. When surfactant TA was administered by 90-s inhalation before antigen challenge, it inhibited the Pao increase in a dose-dependent manner: mean inhibitory rates of Pao were 33.6% in surfactant TA 10 mg/ml and 61.9% in surfactant TA 20 mg/mI, respectively. Conclusion Inhaled surfactant showed preventive and recovery effects on antigeninduced bronchoconstriction in an immunized guinea pig model.     

Suppression of experimental allergic thyroiditis in guinea pigs by homologeous and heterologeous thyroglobulin

Summary Guinea pigs with experimental allergic thyroiditis, induced by three intradermal injections of thyroglobulin in complete Freund's adjuvant, were treated by daily injections of thyroglobulin emulsified in incomplete Freund's adjuvant over a period of 12 days. Besides lightmicroscopical, ultrastructural and immunohistochemical studies the serum antibody titers were determined and skin tests for delayed hypersensitivity were performed in all animals. The following results were obtained.1. Specific suppression of experimental thyroiditis by homologeous or heterologeous thyroglobulin resulted in almost complete absence of the inflammatory infiltrate in the thyroid glands.2. The cellular hyperactivity and the toxic-degenerative changes of the thyroid cells were still present in the desensitized animals. These changes were regarded as residues of the former inflammation of the glands.3. There was a good correlation between the presence of thyroiditis and delayed hypersensitivity in all animals. Such a correlation was not apparent between thyroiditis and antibody titers.The data, presented in this study, further support the role of cellular immunity in the pathogenesis of experimental allergic thyroiditis. The mechanism by which the suppressive effect is mediated is discussed.

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Zusammenfassung Meerschweinchen mit einer experimentell induzierten Thyreoiditis wurde über einen Zeitraum von 12 Tagen täglich Thyreoglobulin, emulgiert in incomplettem Freundschem Adjuvans, injiziert. Neben licht- und elektronenmikroskopischen sowie immunhistochemischen Studien wurden Untersuchungen zur Überempfindlichkeit vom Spättyp an Hand von Hauttesten durchgeführt. Weiterhin wurde bei allen Tieren der Serum-Antikörpertiter gegen Thyreoglobulin bestimmt. Folgende Ergebnisse wurden erzielt.1. Eine spezifische Desensibilisierung durch homologes oder heterologes Thyreoglobulin führte bei den Versuchstieren mit experimenteller Thyreoiditis zu einem fast vollständigen Rückgang der Entzündung innerhalb der Schilddrüse.2. Das Fortbestehen stimulierter Follikelepithelien und toxisch-degenerativer Veränderungen in den Schilddrüsen desensibilisierter Tiere wurde als Hinweis für die vorausgegangene Entzündung gedeutet.3. Zwischen dem Vorhandensein einer Thyreoiditis und der Überempfindlickeit vom verzögerten Typ (Hauttest) besteht in allen Untersuchungsgruppen eine deutliche Korrelation. Eine solche Korrelation ließ sich nicht zwischen Thyreoiditis und Antikörpertiter nachweisen.Die Befunde stützen die Hypothese, daß die celluläre Immunität für das Zustandekommen der experimentellen Thyreoiditis den wesentlicheren Faktor darstellt. Die Mechanismen, die zur Desensibilisierung führen, werden in der vorliegenden Arbeit diskutiert.

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This work was supported by the Deutsche Forschungsgemeinschaft.     

Effect of polymorphonuclear depletion on experimental Argentine hemorrhagic fever in guinea pigs

The role that polymorphonuclear leukocytes (PMN) may play in Argentine hemorrhagic fever (AHF), an endemo-epidemic disease caused by Junín virus (JV), was investigated in experimentally infected guinea pigs depleted of PMN by means of specific antiserum. In leucopenic animals the evolution of the infection with a highly pathogenic strain of JV was more severe, with earlier mortality and higher virus yields in blood and viscera. The pathological study showed similar lesions in both the control and PMN-depleted animals with the exception of the lung, which showed the pathological picture of the human "pulmonary distress syndrome of the adult" in nontreated guinea pigs and appeared histologically unaltered in the PMN-depleted animals. On the basis of these results it is suggested that in AHF, PMN play a dual role. In the first stage of infection they display a defensive antiviral action, but later on they participate in the pathogenesis of tissue damage.     

实验性过敏性哮喘豚鼠外周血液淋巴细胞β肾上腺素能受体系统的变化

在建立外周血液淋巴细胞β受体测定法的基础上,动态地观察了实验性过敏性哮喘豚鼠外周血液淋巴细胞中β受体最大结合容量(Bmax)、cAMP含量,以及血浆中儿茶酚胺(CA)含量的变化,发现它们都呈明显的时相性改变。通过分析它们发生的时间过程和相互关系,认为:在过敏性哮喘时所观察到的淋巴细胞β受体Bmax值的降低,乃是高水平内源性儿茶酚胺所致受体失敏的结果;并对所观察到的变化的意义作了初步探讨。     

Investigation of the blast transformation reaction of lymphocytes in guinea pigs with experimental allergic encephalomyelitis

Experimental allergic encephalomyelitis (EAE) was induced in guinea pigs by injection of myelin from homologous brain in Freund's complete adjuvant. In the incubation period of EAE some animals showed a marked increase in the spontaneous proliferative activity of the blood lymphocytes, assessed in cultures using thymidine-H³. With the development of clinical manifestations of the disease, the spontaneous activity of the lymphocytes reached a maximum and was exhibited in the overwhelming majority of animals. When the clinical picture of EAE was well marked, the response of the lymphocytes to stimulation by myelin preparations was observed mainly if the spontaneous mitotic activity of the cells was low or only moderately increased. Specific antigenic stimulation in vivo connected with the immunopathological process could be the cause of the increasing spontaneous activity of the lymphocytes. The state of nonspecific reactivity of the lymphocytes to phytohemagglutinin in EAE was indistinguishable from that in the control animals.     

Formed blood elements in peritoneal effusion and the macrophage migration inhibition test in healthy guinea pigs and in guinea pigs with experimental allergic encephalomyelitis.

An attempt was made to correlate the percentages of macrophages, lymphocytes and granulocytes in the peritoneal effusion in healthy guinea pigs and guinea pigs with experimental allergic encephalomyelitis (EAE), with the macrophage migration inhibition (MMI) test. Varying percentages of the cells had no influence on values of MMI. Similarly, in guinea pigs with EAE, percentages of formed elements in peritoneal effusion were not correlated with intensity of MMI or with histopathologic lesions in the brain and spinal cord. It is suggested that the observed differences are due to individual immunologic responsiveness of animals and, probably, to other hitherto unknown mechanisms.     

Substance P as a potent stimulator of sneeze responses in experimental allergic rhinitis of guinea pigs

Substance P was examined for sneeze-inducing activity and its involvement of sneeze responses in experimental allergic rhinitis. Substance P, dripped into a nostril of guinea pigs, at concentrations of 100 pM and above induced sneezing in a dose-dependent fashion. The activity of substance P was not affected by the previous subcutaneous injections of capsaicin that depleted substance P in nerve fibers. Histamine induced sneezing at concentrations of 30 mM and above and the activity was reduced by capsaicin treatment. The frequency of antigen-induced sneezing was proportional to the substance P content in nasal mucosa of sensitized guinea pigs treated with increasing doses of capsaicin; correlation coefficient 0.91. These results suggest that substance P plays an important role as a stimulator of sneeze responses in experimental allergic rhinitis in guinea pigs.     

Passive transfer of experimental allergic encephalomyelitis with lymphocytes collected from brains of immunized guinea pigs

Lymphocytes were collected from the brains of guinea pigs immunized with syngeneic spinal cord emulsified in complete Freund's adjuvant. Sixteen to 32 X 10(6) lymphocytes were inoculated into the vein of each inbred guinea pig (NIH 13). Recipient animals without clinical signs of experimental allergic encephalomyelitis (EAE) were sacrificed 20 days later. Some of the recipients had perivascular infiltrates of a large number of mononuclear cells mostly in choroid plexus and meninges of the brain and spinal cord. Demyelination, which was not so intense, was also observed in the vicinity of the perivascular infiltrates. Thus, the lymphocytes from the brain as well as lymph node and spleen were clear to have the ability to transfer EAE.     

Adoptive transfer of suppression of experimental allergic orchitis with lymphoid cells from antigen-pretreated guinea pigs

The injection of lymph node cells or spleen cells, obtained from strain 13 guinea pigs rendered unresponsive to experimental allergic orchitis (EAO) by pretreatment with testicular antigen (TA) in incomplete Freund's adjuvant, into normal syngeneic recipients markedly prevented the development of EAO, especially of the interstitial inflammatory cell response, which was expected to occur 2 weeks following orchitogenic challenge with TA in complete Freund's adjuvant (CFA). The suppressive effect of thymus cells from the same donors was much less prominent. The inhibition of EAO by suppressor cells was specific for the relevant antigen TA. In such EAO-suppressed animals delayed skin reaction to TA was suppressed, whereas antisperm antibody formation was not impaired. The active suppressor cells residing in the lymph nodes had characteristics of T lymphocytes, in that they did not adhere to the plastic dish surface and nylon wool and in that they formed rosettes with rabbit erythrocytes. B lymphocytes from the same animals did not have detectable suppressive properties. Lymph node cells from protected donors that had been treated with a single dose of cyclophosphamide (CY) 3 days before cell transfer were unable to transfer unresponsiveness to EAO. The results suggest that the immune prevention against EAO is explainable at least in part by the generation of CY-sensitive suppressor T lymphocytes with the capacity of inhibiting development of effector T cells after antigenic stimulation and that suppressor cells that mediated unresponsiveness to EAO may also regulate the cellular hypersensitivity to TA.     

An experimental allergic conjunctivitis induced by topical and repetitive applications of Japanese cedar pollens in guinea pigs

OBJECTIVE AND DESIGN: To develop a model of experimental allergic conjunctivitis, guinea pigs were given repetitive and topical applications of Japanese cedar pollen as an antigen, and the resulting allergic reaction was characterised. SUBJECTS: Male Hartley guinea pigs. TREATMENT: Guinea pigs were sensitised by insertion of small gelatin sponge pieces (3 pieces/eye, both eyes) containing the pollen extracts + Al(OH)3 into the palpebra superior/inferior sulci of both eyes for 8 h/day for 6 days. Then the animals were challenged by dropping pollen suspension in each eye once every week. METHODS: Time-course changes of conjunctivitis intensity score (CIS), which represents oedema and redness, and scratching frequency, and gamma1 and IgE levels in sera were assessed following the respective 1st-17th challenges. Ophthalmic lavage was performed to assay for albumin leakage and migrated leukocytes at each of the odd-numbered challenges. RESULTS: At relatively early stages of the repeated challenge, only a gradual increase of CIS was observed. However, thereafter, considerably higher CIS with the maximum at 30 min after the challenge was provoked at the 12th-17th challenges. Quite interestingly, there were differences in the CIS between the right and left eyes, depending on the individuals. Scratching, and albumin leakage and neutrophil influx into the lavage fluid were also developed during the challenges. Although the anaphylactic antibodies against the antigen were detected in the sera from half of the animals, the levels were not correlated to severity of the symptoms. CONCLUSIONS: The present sensitisation/challenge procedures are unique in terms of topical application of antigen. The lack of any correlation between the levels of the anaphylactic antibodies and severity of anaphylactic symptoms, and the difference of CIS between the left and right eyes of an individual strongly suggest that the anaphylactic antibodies are formed in locally limited tissue surrounding an eye. The present method should be useful for analysing the mechanisms of allergic conjunctivitis.