Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease induced in susceptible rat strains by a single immunization with myelin basic protein (MBP). The Lewis (LEW) strain is susceptible to disease induction while the Brown Norway (BN) strain is resistant. This resistance involves non-MHC genes since congenic BN-1L rats, with LEW MHC on a BN-derived background, are also resistant. In the present study we show that, upon immunization with MBP, the non-MHC-encoded resistance to develop clinical EAE in BN-1L rats is associated with a decreased production of IFN-gamma. This may be due to a difference between LEW and BN-1L rats in their ability to produce regulatory cytokines such as IL-4, IL-10 and TGF-beta. In comparison to LEW rats, immune lymph node cells from BN-1L rats express an increased amount of IL-4 mRNA but produce less IL-10. Furthermore, the sera from BN-1L rats contain higher amounts of active TGF-beta1. Therefore, we have investigated the involvement of IL-4 and TGF-beta in the resistance of BN-1L rats to develop EAE using neutralizing mAb. Neutralization of TGF-beta, but not IL-4, renders BN-1L rats susceptible to clinical EAE without affecting the proliferation or the cytokine repertoire of immune lymph node cells. With respect to the origin of the endogenous TGF-beta production, we excluded the involvement of CD8 T cells and discuss a possible role of platelets and of CD4 T cells exhibiting the CD45RC(low) phenotype.
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PMID:Essential role of TGF-beta in the natural resistance to experimental allergic encephalomyelitis in rats. 1129 38

We examined the effects of different immunomodulators administered topically on asthmatic responses in a rat model of asthma. Sensitised Brown-Norway rats were administered rapamycin, SAR943 (32-deoxorapamycin), IMM125 (a hydroxyethyl derivative of D-serine(8)-cyclosporine), and budesonide by intratracheal instillation 1 h prior to allergen challenge. Allergen exposure induced bronchial hyperresponsiveness, accumulation of inflammatory cells in bronchoalveolar lavage fluid, and also an increase in eosinophils and CD2+, CD4+ and CD8+ T cells in the airways. Interleukin-2, interleukin-4, interleukin-5, interleukin-10, and interferon-gamma mRNA expression was upregulated by allergen exposure. Budesonide abolished airway inflammation, suppressed the mRNA expression for interleukin-2, interleukin-4, and interleukin-5 (P<0.03), and bronchial hyperresponsiveness (P<0.05). IMM125 suppressed airway infiltration of eosinophils, and CD8+ T cells (P<0.02), and prevented the upregulated mRNA expression for interleukin-4, interleukin-5, and interferon-gamma (P<0.02). Rapamycin suppressed CD8+ T cell infiltration in airway submucosa (P<0.03), and mRNA expression for interleukin-2 (p<0.002), while SAR943 suppressed interleukin-2, interleukin-4, and interferon-gamma mRNA (P<0.05). IMM125, rapamycin and SAR943 did not alter airway submucosal CD2+ and CD4+ T cell infiltration, and bronchial hyperresponsiveness. CD8+ T cells, in contrast to CD4+ T cells, are more susceptible to the inhibition by IMM125 and rapamycin, which also caused greater suppression of Th1 compared to Th2 cytokine mRNA expression. In this acute model of allergic inflammation, differential modulation of Th1 and Th2 cytokines may determine the effects of various immunomodulators on airway inflammation and bronchial hyperresponsiveness.
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PMID:Effect of topical immunomodulators on acute allergic inflammation and bronchial hyperresponsiveness in sensitised rats. 1189 Sep 8

Previous studies have shown that the allergic late airway response (LR) is dependent on the leukotriene (LT) pathway in Brown Norway (BN) rats. In this same model, interleukin-2 (IL-2) has been shown to increase allergic airway responses without increasing LT production. This study examined the relationship between the upregulation of cellular immunity with IL-2 and the LT pathway in ovalbumin-sensitized BN rats. Airway responsiveness to LTD(4) was significantly increased in BN rats pretreated with IL-2 (20,000 U twice a day for 4.5 days). Treatment with montelukast, a cysteinyl LT(1) receptor antagonist, blocked IL-2's induced increase of the LR to ovalbumin challenge. When cytokine expression was assessed either by semiquantitative polymerase chain reaction or in situ hybridization, we found that montelukast decreased the amount of IL-4 mRNA expression in the lungs while increasing the amount of interferon-gamma mRNA expression 8 hours after challenge. These results indicate that upregulation of cellular immunity with IL-2 can increase the sensitivity of the airways to LTD(4) and that inhibition of the LT pathway will block the LR and modulate cytokine expression after antigen challenge.
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PMID:Interleukin-2-induced increased airway responsiveness and lung Th2 cytokine expression occur after antigen challenge through the leukotriene pathway. 1204 30

Brown Norway rats were exposed by intratracheal instillation of saline, carbon black (CB), or diesel exhaust particles (DEP) (5 mg/kg) on day 1, followed by exposure to ovalbumin (OVA, 90 mg/m(3)) or saline for 30 minutes on days 1, 8, 15, and 29. Animals were sacrificed on day 30. The DEP, CB, or OVA exposure alone did not result in abnormal levels of inflammatory cells, lactate dehydrogenase (LDH), or total protein in the lavage fluid. In combined OVA-DEP or OVA-CB exposure, however, these markers were significantly increased. The adjuvant effect of CB and DEP on OVA sensitization was evidenced by the marked increases in serum OVA-specific IgG (5.6-fold) and IgE (3.5-4 fold) levels, and the increase in interleukin-4 (IL-4) mRNA levels in lung tissue. The OVA exposure markedly reduced glutathione (GSH) levels in both cell types. In combined DEP-OVA exposure, the level of GSH in lymphocytes was further decreased, indicating a possible interactive effect between DEP and OVA exposures. These results show that both DEP and CB augmented OVA-induced allergic sensitization, and that particle composition of DEP may not be a critical factor for the adjuvant effect. OVA exposure causes significant depletion of intracellular GSH in lymphocytes, which may play a key role in OVA-mediated immune responses.
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PMID:The effect of diesel exhaust particles (DEP) and carbon black (CB) on thiol changes in pulmonary ovalbumin allergic sensitized Brown Norway rats. 1209 28

Analogous to childhood-onset asthma in humans, rats may develop a chronic asthmalike phenotype, depending on their genetic background and the age at which they experience a viral airway injury. Brown Norway rats develop a postbronchiolitis asthmalike phenotype that may be prevented with supplements of interferon-gamma (IFN-gamma); we hypothesized that the normally resistant F344 rat strain would develop the asthmalike phenotype if the IFN-gamma response were suppressed during viral illness. Weanling F344 rats were pretreated with anti-IFN-gamma or control antibody, and inoculated with Sendai virus or vehicle. Anti-IFN-gamma treatment reduced lung IFN-gamma and increased IL-4 mRNA during the infection. Physiologic studies performed 8 wk later revealed premature airway closure (p = 0.03) and elevated specific pulmonary resistance (p < 0.01) in the postbronchiolitis anti-IFN-gamma group compared with noninfected controls and untreated postbronchiolitis rats. However, unlike the postbronchiolitis asthmalike phenotype in Brown Norway rats, bronchiolar inflammation and fibrosis were absent in the F344 rats. Lung elastic recoil and alveolar surface density also were unchanged compared with noninfected control rats. We conclude that there is an interactive effect of a weak IFN-gamma response and viral bronchiolitis at an early age that may result in persistent postbronchiolitis airway dysfunction. The presence of premature airway closure that is independent of airway wall inflammation or changes in lung elastic recoil suggests peripheral airway instability as a mechanism for the airway obstruction.
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PMID:Chronic postbronchiolitis airway instability induced with anti-IFN-gamma antibody in F344 rats. 1219 72

Most patients taking drugs associated with idiosyncratic drug reactions tolerate the drug and do not develop adverse reactions. Understanding the mechanism of tolerance to drugs is important as it could provide insight into why some patients develop idiosyncratic reactions and others do not. The Brown Norway rat model of D-penicillamine-induced autoimmunity was used as a model of idiosyncratic drug-induced autoimmunity. Two weeks of low dose (5 mg/day) D-penicillamine pretreatment completely prevented all clinical signs of autoimmunity normally seen in 60-80% of rats treated with high dose (20 mg/day) D-penicillamine. Low dose pretreatment also prevented the increase in IgE and IL-4 mRNA characteristic of the response to high dose D-penicillamine. Experiments were conducted to determine whether low dose tolerance is metabolic or immunological. It was found that low dose tolerance possesses key characteristics of immune-mediated tolerance: memory, splenocytes that adoptively transfer tolerance, and regulatory cytokine production. To provide an understanding of the factors that can prevent or reverse established tolerance, the conditions for inducing and maintaining tolerance were investigated. Tolerance induction was investigated by manipulating the immune system during the period of low dose exposure. The induction of tolerance was partially prevented by depleting the macrophage subset of antigen presenting cells with clodronate-filled liposomes or by inhibiting T cells with tacrolimus during the period of low dose exposure. As well, the induction of tolerance was completely prevented by repeatedly stimulating the immune system throughout the period of low dose pretreatment with poly I:C. To investigate the permanence of tolerance, the immune system was stimulated after tolerance induction in an attempt to break tolerance. Both LPS and poly I:C reversed tolerance in a dose-dependent manner. These results demonstrate that immune tolerance to D-penicillamine autoimmunity can be induced by short-term low dose pretreatment.
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PMID:Tolerance induced by low dose D-penicillamine in the brown Norway rat model of drug-induced autoimmunity is immune-mediated. 1472 22

Helper T-lymphocytes have been shown to differentiate into two mutually regulatory subsets. Cells primarily secreting interleukin-2 (IL-2) and interferon-gamma are known as Th1 cells and mediate classical cell-mediated immune responses such as delayed-type hypersensitivity. Cells secreting interleukin-4 (IL-4) are known as Th2 cells and promote humoral immune responses, in particular the production of IgE and IgG4 (human) or IgG1 (rodents). Over-activity of either cell type can result in tissue-damaging autoimmune disease. A number of human diseases including asthma and some kidney diseases are thought to be caused by a Th-2 type autoimmune response. Study of an animal model of Th2-driven autoimmunity (mercuric chloride-induced autoimmunity in Brown Norway rats) has yielded insights into a possible role for oxidant stress in the generation of Th-2 driven autoimmune responses. Mercuric chloride probably causes oxidant stress by the generation of free-radicals, activating NK-kappaB, a transcription factor for the IL-4 gene. Treatment with the antioxidants N-acetlcysteine and desferrioxamine has been shown to suppress vasculitis and IgE production in this model. These findings suggest a possible clinical role for antioxidants in the therapy of human autoimmune disease.
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PMID:Reactive oxygen species in the initiation of IL-4 driven autoimmunity as a potential therapeutic target. 1503 93

Jun N-terminal kinase (JNK) has been implicated in the pathogenesis of inflammatory diseases including asthma. We examined the effect of SP600125 (anthra [1,9-cd] pyrazol-6 (2H)-one), a novel inhibitor of JNK in a model of asthma. Brown-Norway rats were sensitized to ovalbumin and treated with SP600125 intraperitoneally (90 mg/kg in total). SP600125 inhibited allergen-induced, increased activity of phosphorylated c-jun but not of phosphorylated-MAPKAPK2, indicative of activation of p38 MAPK, in the lung. SP600125 inhibited macrophage (P < 0.04), lymphocyte (P < 0.05), eosinophil (P < 0.04) and neutrophil (P < 0.005) numbers in bronchoalveolar lavage. Eosinophil and T-cell accumulation in the airways, mRNA expression for interleukin-1beta, tumour necrosis factor-beta, interleukin-3, interleukin-4 and interleukin-5, serum levels of allergen-specific immunoglobulin E and bronchial hyperresponsiveness were not affected by SP600125. Selective inhibition of JNK reduced inflammatory cell egress into the airway lumen after single allergen exposure. The role of JNK mitogen-activated protein kinase activation may be limited in the pathogenesis of bronchial hyperresponsiveness after single allergen exposure.
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PMID:Effect of an inhibitor of Jun N-terminal protein kinase, SP600125, in single allergen challenge in sensitized rats. 1519 13

Since airway hyperresponsiveness (AHR) and allergic inflammatory changes are regarded as the primary manifestations of asthma, the main goals of asthma treatment are to decrease inflammation and maximize bronchodilation. These goals can be achieved with aerosol therapy. Intravenous administration of the anesthetic, ketamine, has been shown to trigger bronchial smooth muscle relaxation. Furthermore, increasing evidence suggests that the anti-inflammatory properties of ketamine may protect against lung injury. However, ketamine inhalation might yield the same or better results at higher airway and lower ketamine plasma concentrations for the treatment of asthma. Here, we studied the effect of ketamine inhalation on bronchial hyperresponsiveness and airway inflammation in a Brown-Norway rat model of ovalbumin (OVA)-induced allergic asthma. Animals were actively sensitized by subcutaneous injection of OVA and challenged by repeated intermittent (thrice weekly) exposure to aerosolized OVA for two weeks. Before challenge, the sensitized rats received inhalation of aerosol of phosphate-buffered saline (PBS) or aerosol of ketamine or injection of ketamine respectivity. Airway reactivity to acetylcholine (Ach) was measured in vivo, and various inflammatory markers, including Th2 cytokines in bronchoalveolar lavage fluid (BALF), as well as inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in lungs were examined. Our results revealed that delivery of aerosolized ketamine using an ultrasonic nebulizer markedly suppressed allergen-mediated airway hyperreactivity, airway inflammation and airway inflammatory cell infiltration into the BALF, and significantly decreased the levels of interleukin-4 (IL-4) in the BALF and expression of iNOS and the concentration of NO in the inflamed airways from OVA-treated rats. These findings collectively indicate that nebulized ketamine attenuated many of the central components of inflammatory changes and AHR in OVA-provoked experimental asthma, potentially providing a new therapeutic approach against asthma.
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PMID:Effects of nebulized ketamine on allergen-induced airway hyperresponsiveness and inflammation in actively sensitized Brown-Norway rats. 1748 Feb 24

The objective of the present study was to characterize the antigenic specificity of purified soybean beta-conglycinin and to investigate its effects on the growth and immune responses of rats. Thirty-two Brown Norway rats, 3 weeks of age, were randomly allotted to one of four treatments and individually fed casein-cornstarch based diets. Rats were sensitised by means of intragastric gavage with purified beta-conglycinin (0, 5, 10 or 20 mg protein/ml in phosphate buffered saline at pH 7.4) on day 0, 7, 14, and 21 (1 ml/animal). On day 28, rats received a double dose of beta-conglycinin. Blood was obtained at weekly intervals after initiation of challenge. Growth declined linearly with increasing the concentration of soybean beta-conglycinin (p < 0.05). Both the total IgE and beta-conglycinin-specific IgE levels in serum increased while passive cutaneous anaphylactic reactions were induced in the rats. Lymphocyte proliferation response to concanavalin A in plasma and spleen was increased linearly with increased levels of soybean (p < 0.01) beta-conglycinin. The percentage of CD4+ lymphocyte subset linearly increased (p < 0.001). As a result, the concentrations of cytokines in plasma and spleen, including interleukin-4 (p < 0.01), interleukin-5 (p < 0.01), and tumour necrosis factor-alpha (p < 0.01) increased linearly with increasing level of purified beta-conglycinin. Our results indicate that purified beta-conglycinin possesses intrinsic immune-stimulating capacity and can induce an allergic reaction. Therefore, dietary soybean beta-conglycinin has negative effects on growth and both cell-mediated and humoral immune function in rats.
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PMID:Characterization of the antigenic specificity of soybean protein beta-conglycinin and its effects on growth and immune function in rats. 1757 61


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