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)

Acute lung allograft rejection is believed to be initiated by passenger leukocytes, such as alveolar macrophages (AM), in the donor organ, which release TNF-alpha, and present alloantigens to host lymphocytes, to up-regulated Th1 cellular and humoral immunity. However, the role of donor AM in local TNF-alpha synthesis, and their ability to induce local Th1 cellular and humoral immunity have not been evaluated. By depleting Brown Norway (BN, RT1n) rat lung allografts of AM before transplantation into Lewis rat (LEW, RT1(1)) recipients, the current study determined the role of donor AM in including the production of TNF-alpha, IFN-gamma (Th1 cytokine), IL-4 (Th2 cytokine), IgG subtypes, and rejection pathology in the allograft. The data show that compared with untreated BN allografts, pretransplant depletion of donor lung AM resulted in significantly less TNF-alpha, and IFN-gamma production in allograft bronchoalveolar lavage fluid with variable effects on local IL-4 production. Depletion of AM in the donor lung before transplantation affected the local production of several IgG subclasses. However, pretransplant depletion of donor AM had no effect on the development of the pathology of severe acute rejection. These data show that donor AM have a central role in the local synthesis of TNF-alpha and induce the production of IFN-gamma and IgG subtypes, locally, during acute lung allograft rejection. However, depletion of AM before transplantation does not prevent the development of severe acute rejection in BN rat lungs, transplanted into LEW recipients.
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PMID:Role of passenger leukocytes in allograft rejection: effect of depletion of donor alveolar macrophages on the local production of TNF-alpha, T helper 1/T helper 2 cytokines, IgG subclasses, and pathology in a rat model of lung transplantation. 937 99

T lymphocytes are exquisitely sensitive to the antiproliferative effects of nitric oxide. We examined the effects of oral administration of two nitric oxide synthase inhibitors, Nw-nitro-L-arginine methyl ester (L-NAME) and L-N6-(1-iminoethyl)lysine (L-NIL), on the course of T cell-dependent autoimmune interstitial nephritis in Brown Norway rats. Kidneys from rats immunized to produce interstitial nephritis display a net generation of nitric oxide end products. By immunohistochemical staining, the cytokine-inducible nitric oxide synthase (iNOS) is expressed in cortical tubular epithelial cells. Treatment with either inhibitor results in markedly more severe disease following immunization. Animals receiving L-NAME were hypertensive, while those treated with L-NIL, a highly selective inhibitor of iNOS, were not. Evaluation of the expression of IFN-gamma, IL-2, and IL-4 in diseased kidneys by quantitative reverse transcriptase-PCR demonstrated that L-NAME-treated animals displayed significantly augmented levels of IFN-gamma and IL-2 with preserved ratios of IFN-gamma/IL-4 and IL-2/IL-4, while L-NIL-treated animals had augmented levels of IL-2 and IFN-gamma with augmented IFN-gamma/IL-4 and IL-2/IL-4 ratios. Animals treated with L-NAME or L-NIL both had augmented Ag-specific IgG responses. The L-NAME group demonstrated increases in both the IgG2a and IgG1 subtypes, with a constant IgG2a/IgG1 ratio, while the L-NIL group demonstrated an increase in the ratio of the IgG2a/IgG1 response. These Ab and cytokine data suggest that the L-NIL-treated animals had a skewing of their immune response toward a Th1-like response. We conclude that in autoimmune interstitial nephritis, generation of nitric oxide through the iNOS pathway has host-protective effects, and suggest that this may be broadly applicable to T cell-mediated pathologies.
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PMID:Inhibition of inducible nitric oxide synthase intensifies injury and functional deterioration in autoimmune interstitial nephritis. 955 Apr 31

The events subsequent to antigen challenge in allergic asthmatics involve the synthesis of pro-inflammatory cytokines. However, little is known how cytokine gene activation prior to allergen challenge may influence this series of events, nor how cytokine gene expression is related to antigen-induced alterations in lung function. Using a novel in vitro explant technique, we hypothesized that the local expression of cytokines influenced the development of antigen-induced late-onset airway responses, and that alterations in cytokine messenger ribonucleic acid (mRNA) expression were associated with antigen-induced changes in airway luminal area. Explants were prepared from excised lungs of ovalbumin-sensitized Brown-Norway rats. Airways were challenged by direct application of ovalbumin or an irrelevant control antigen. Cryostat sections of explants were used for in situ hybridization and mRNA for interleukin (IL)-2, IL-4 and interferon (IFN)-gamma were detected using radiolabelled probes. We found that the presence of high numbers of cells expressing IFN-gamma and IL-2 mRNA within the airways attenuated the development of antigen-induced late airway responses in sensitized rat lung explants. Furthermore, we observed that cytokine mRNA for IL-4 was significantly increased following allergen exposure in sensitized lung explants exhibiting late airway responses. This study implicates the local expression of interferon-gamma and interleukin-2 messenger ribonucleic acid in the failure of sensitized rat lung explants to exhibit late airway responses, and provides evidence linking local interleukin-4 messenger ribonucleic acid expression to the sequelae of events occurring as a result of antigen exposure within the airways.
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PMID:Local cytokine messenger ribonucleic acid expression and in vitro allergic late phase responses in Brown-Norway rats. 959 14

Female Lewis (LEW) rats received orthotopic small intestinal transplantation (SIT), or tail skin grafts from female (Lewis x Brown Norway)F1 (LBNF1) rats, along with peritransplant portal venous (pv) infusion of LBNF1 bone marrow-derived dendritic cells derived from male donors. All animals received im injection with cyclosporin A (5 mg/kg) for 3 consecutive days following transplantation. In some cases rats received intravenous injections, at 2-day intervals, with 1 mg of monoclonal antibodies to ICAM-1 or the integrins alpha 4, alpha L, or beta 2, or combinations of these reagents. Cells were harvested from the recipient rats at different times posttransplantation, and single cell suspensions were analyzed by FACS for expression of CD3+, CD4+, CD8+, alpha beta TcR+, and gamma delta TcR+ cells. Other tissue samples were used for histopathological assessment of rejection. We also investigated donor-specific and third-party (Wistar-Furth, Wi) restimulation of host lymphocytes from MLN, PLN, and PP for production of different cytokines in vitro. Of the various antibodies tested, only anti-alpha 4, but not anti-alpha L, -beta 2, nor -ICAM-1 led to further increased graft survival of LBNF1 SIT beyond that seen with pv-infused cells alone (30 days vs 19 days), while the combination of anti-alpha L (or beta 2) and ICAM-1 produced further significantly increased survival of skin grafts (30 days vs 21 days). For both SIT and skin-grafted animals increased graft survival was associated with decreased production of IL-2 and IFN-gamma and increased production of IL-4 and IL-10 from tissues local to the graft (PP and draining LN, respectively), with less significant alterations in tissues distant to the graft (PLN for SIT, and MLN for skin grafts). While, as reported previously, pv-immunized SIT rats showed increased gamma delta TCR+ cells within the SIT in association with increased graft survival, treatment with anti-alpha 4 diminished this increase in gamma delta TCR+ cells, while simultaneously increasing SIT survival. Nevertheless, the bias toward increased IL-10 production, and decreased IFN-gamma production, from cells of animals showing increased survival was maintained. These data suggest that local graft infiltration with gamma delta TCR+ cells following pv immunization is not necessary for prolongation of survival in this model system, although functional changes in the local cytokines milieu may be important.
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PMID:Differential regulation of rejection of small intestinal and skin allografts in rats by injection of antibodies to ICAM-1 or the integrins alpha 4, alpha L, or beta 2. 962 38

Nitric oxide (NO) plays an important role in non-specific host defense, which can be recognized by its antimicrobial and cytotoxic activity against pathogens. However, there appear to exist interspecies differences in the ability of macrophages to generate NO. The object of this study was to determine whether there exist intraspecies differences in the production of NO. We compared NO formation by alveolar macrophages (AM) from five different rat strains (Sprague Dawley, Wistar, Lewis, Fisher, and Brown Norway), two different stocks of Syrian Golden hamsters, and one stock of Chinese hamsters. The AM were harvested by bronchoalveolar lavage and stimulated in vitro with various concentrations of LPS and/or IFN-gamma. The oxidation product of NO, nitrite, was measured in the AM supernatant by the Griess reaction. Upon stimulation with LPS and/or IFN-gamma, AM from all five rat strains were able to release NO, but the amount of NO produced differed significantly among the rat strains. However, none of the stimuli was able to induce AM from the two stocks of Syrian Golden hamsters as well as AM from the stock of Chinese hamsters to release measurable amounts of NO. These findings point to distinct regulatory mechanisms of the NO pathway in AM from different species and to variations of this mechanism in the AM from the investigated rat strains.
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PMID:Formation of nitric oxide by rat and hamster alveolar macrophages: an interstrain and interspecies comparison. 982 Jun 47

Experimental autoimmune myasthenia gravis (EAMG) is a T cell-dependent, Ab-mediated autoimmune disease induced in rats by a single immunization with acetylcholine receptor (AChR). Although polarized Th1 responses have been shown to be crucial for the development of mouse EAMG, the role of Th cell subsets in rat EAMG is not well established. In the present work we show that while the incidence and severity of EAMG are similar in Lewis (LEW) and Brown-Norway (BN) rats, strong differences are revealed in the immune response generated. Ag-specific lymph node cells from LEW rats produced higher amounts of IL-2 and IFN-gamma than BN lymph node cells, but expressed less IL-4 mRNA. IgG1 and IgG2b anti-AChR isotype predominated in BN and LEW rats, respectively, confirming the dichotomy of the immune response observed between the two strains. Furthermore, although IL-12 administration or IFN-gamma neutralization strongly influenced the Th1/Th2 balance in BN rats, it did not affect the disease outcome. These data demonstrate that a Th1-dominated immune response is not necessarily associated with disease severity in EAMG, not only in rats with disparate MHC haplotype but also in the same rat strain, and suggest that in a situation where complement-fixing Ab can be generated as a consequence of either Th1- or Th2-mediated T cell help, deviation of the immune response will not be an adequate strategy to prevent this Ab-mediated autoimmune disease.
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PMID:Experimental autoimmune myasthenia gravis may occur in the context of a polarized Th1- or Th2-type immune response in rats. 1035 65

Sensitized Brown Norway rats are known to develop eosinophilic bronchial inflammation and airway hyperresponsiveness after Ag exposure. However, we have previously observed that sensitized aged rats of the same strain failed to develop such allergic inflammation. In the present study, we investigated age-associated changes of cytokine mRNA expression in bronchoalveolar lavage (BAL) cells. Both young (8- to 10-wk-old) and aged (100- to 120-wk-old) Brown Norway rats were sensitized with OVA, and BAL was performed 24 h after OVA inhalation challenge. Semiquantitative RT-PCR analysis of BAL cells showed that the cells from aged rats preferentially expressed Th1 type cytokine (IFN-gamma) mRNA, whereas cells from young animals expressed more Th2 type cytokine mRNAs including those for IL-4 and IL-5. Decreased expression of Th2 type cytokine transcripts in aged animals was further confirmed by quantitative analysis, competitive RT-PCR of BAL cells, and in situ hybridization. The age-associated changes of cytokine profile were not restricted to BAL cells but were a general feature of lymphocytes, as shown by examination of popliteal lymph nodes draining the site of sensitization. These findings suggest that decreased allergic inflammation in aged animals is attributable to age-dependent impairment of Th2 generation in response to Ag.
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PMID:Decreased expression of Th2 type cytokine mRNA contributes to the lack of allergic bronchial inflammation in aged rats. 1038 41

Mercuric chloride induces autoimmunity in Brown Norway rats with polyclonal B-cell activation, hyper-IgE and multiple autoantibodies. Pre-treatment with low-dose HgCl2 (one-tenth of the standard dose) induces resistance to later full-dose HgCl2; we have studied the mechanism of this resistance. Brown Norway rats given low-dose HgCl2 showed only a modest increase in serum IgE level, three logs lower than rats given standard-dose HgCl2, and no up-regulation of splenic interleukin (IL)-4 mRNA. There was up-regulation of splenic interferon (IFN)-gamma gene expression and a progressive rise in serum IFN-gamma. Neither IL-12 nor IL-18 were induced, but there was up-regulation of IL-12 receptor beta2-chain (IL-12Rbeta2) expression. IL-10 and transforming growth factor (TGF)-beta expression did not change. Serum IgE and splenic IL-4 mRNA expression remained static when these rats were rechallenged, confirming resistance. Thereafter IFN-gamma expression gradually fell, after which IL-4 expression and serum IgE rose slightly. Our observations suggest that low-dose HgCl2 confers protection in Brown Norway rats to further HgCl2 by up-regulation of IFN-gamma, associated with enhanced IL-12Rbeta2 expression. The immunological response to HgCl2 in susceptible rat strains is more complex than previously appreciated and is dose dependent, with low doses inducing a T helper '(Th)1' type of response in contrast to the 'Th2' type response associated with standard doses.
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PMID:Low-dose mercuric chloride induces resistance in brown norway rats to further mercuric chloride by up-regulation of interferon-gamma. 1044 25

To test the hypothesis that CD8+ T cells may suppress the allergen-induced late airway response (LAR) and airway eosinophilia, we examined the effect of administration of Ag-primed CD8+ T cells on allergic airway responses, bronchoalveolar lavage (BAL) leukocytes, and mRNA expression for cytokines (IL-4, IL-5, and IFN-gamma) in OVA-sensitized Brown Norway rats. On day 12 postsensitization to OVA, test rats were administered 2 million CD8+ T cells i.p. isolated from either the cervical lymph nodes (LN group; n = 8) or the spleen (Spl group; n = 6) of sensitized donors. On day 14, test rats were challenged with aerosolized OVA. Control rats were administered PBS i.p. on day 12, and challenged with OVA (n = 10) or BSA (n = 6) on day 14. The lung resistance was measured for 8 h after challenge. BAL was performed at 8 h. Cytospin slides of BAL were analyzed for major basic protein by immunostaining and for cytokine mRNA by in situ hybridization. The LAR was significantly less in the LN group (1.8 +/- 0.5 U; p < 0.01) and BSA controls (1.4 +/- 0.7; p < 0.01), but not in the Spl group (6.7 +/- 2.2), compared with that in OVA controls (8.1 +/- 1.8). In BAL, the number of major basic protein-positive cells was lower in the LN and Spl groups compared with OVA controls (p < 0.05 and p < 0.01). IL-4- and IL-5-positive cells were decreased in the LN group compared with the OVA controls (p < 0.01). INF-gamma-positive cells were increased in the LN and Spl groups compared with the OVA controls (p < 0.01). Serum OVA-specific IgE levels were unaffected by CD8+ T cell transfers. These results indicate that Ag-primed CD8+ T cells have a potent suppressive effect on LAR.
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PMID:CD8+ T cells modulate late allergic airway responses in Brown Norway rats. 1055 86

Immune responses can be classified, according to the predominant cytokines involved, into type 1 (featuring interferon-gamma, IFN-gamma) and type 2 (featuring interleukin-4, IL-4); imbalance between type 1 and type 2 cytokine compartments has been implicated in many human diseases. Levamisole is a drug with an unknown mode of action that has been used to boost immunity in infectious diseases including leprosy, and in some cancers. To test the hypothesis that levamisole acts by inducing a shift to a type 1 immune response, we used Brown Norway (BN) rats, which are markedly biased to type 2 responses. BN rats treated with levamisole showed a dose-dependent rise in serum IFN-gamma and fall in serum immunoglobulin E (IgE) level. Detailed analysis of cytokine gene expression showed upregulation of IFN-gamma and downregulation of IL-4 messenger RNA. This coincided with marked upregulation of IL-18, a recently characterized cytokine with potent activity in stimulating IFN-gamma production. IL-12 was not induced. Further, the type 2 response induced in BN rats by mercuric chloride was markedly attenuated when rats were pretreated with levamisole: there was a 2-log reduction in maximum serum IgE level and marked attenuation of IL-4 gene upregulation. These data indicate that levamisole acts by resetting the immune balance towards a type 1 response via induction of IL-18. Our findings provide a direction for development of more specific immunomodulating therapy.
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PMID:Levamisole induces interleukin-18 and shifts type 1/type 2 cytokine balance. 1088 98


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