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)

It is now currently thought that Th1 autoreactive cells may induce organ specific autoimmune disease and in these situations Th2 cells are considered as regulatory cells. However, in other situations Th2 cells may be pathogenic. Thus, some chemicals (HgCl2, gold salts or D-penicillamine) may induce Th2-mediated systemic autoimmune disorders in susceptible Brown-Norway (BN) rats. In contrast, HgCl2 induces non antigen specific immunosuppression in Lewis (LEW) rats and protects this strain against organ-specific autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE). Anti-self MHC class II T cells have been detected in both susceptible and resistant strains upon exposure with these chemicals. Autoreactive T cell lines that recognize self MHC class II molecules have been derived from gold salt-injected BN rats (BNAu lines) and from HgCl2-injected LEW rats (LEWHg lines). BNAu T cell lines produced IL-4 and transferred antibody-mediated autoimmunity in BN rats deprived of CD8+ cells. In contrast, HgCl2 protects susceptible rats from Th1-mediated autoimmunity, (autoimmune uveoretinitis). LEWHg lines produced IL-2, IFN-gamma and TGF-beta and were able to protect LEW rats against cell-mediated autoimmunity (EAE) and (LEW x BN)F1 hybrids from antibody-mediated, HgCl2-induced autoimmunity. Several points will be discussed: the specificity of these autoreactive T cells, the mechanisms by which chemicals may induce these cells and the mechanisms by which the immune system maintains or reestablishes self tolerance in rats exposed to these agents.
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PMID:Th2 and Th1 autoreactive anti-class II cell lines in the rat suppress or induce autoimmunity. 873 66

A subset of patients with rheumatoid arthritis occasionally develops skin reactions and glomerulonephritis and exhibits an increase in serum IgE concentration when treated with gold salts. Brown-Norway (BN) rats injected with aurothiopropanolsulfonate (ATPS) also manifest an autoimmune glomerulonephritis and increased serum IgE concentration, whereas Lewis (LEW) rats are resistant to complications. Here, we show linkage between responses to ATPS in a (BN x LEW) F2 cohort and the major histocompatibility complex (RT1) on rat chromosome 20 and between markers in the region of IL4 and other candidate genes on rat chromosome 10. Recently, human serum IgE concentration has been reported to be linked to the IL-4 region. Taken together, these findings raise the possibility that homologous genes could be implicated in ATPS manifestations in the rat and in the regulation of IgE levels in the human.
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PMID:Serum IgE concentration and other immune manifestations of treatment with gold salts are linked to the MHC and IL4 regions in the rat. 880 87

Lewis (LEW) rats received (Lewis x Brown Norway)F1 (LBNF1) small intestinal allografts (SIT) with graft venous drainage to either the portal vein (pv) or inferior vena cava (iv), along with immunization (pv or iv) with irradiated LBNF1 spleen cells. As reported earlier, in rats with pv drained grafts there was an increase in gammadeltaTCR+ cells infiltrating the Peyer's patches (PP) and mesenteric lymph node (MLN) compared with iv drained grafts. After restimulation in culture with irradiated LBNF1 spleen stimulator cells these PP and MLN cells from SIT rats with pv graft drainage were a prominent source of TGFbeta, IL-4, and IL-10. When subpopulations of cells from PP preparations were analyzed, an enriched (<2%betaTCR+) gammadeltaTCR+ population from SIT rats with pv graft drainage, but not iv drainage, was detected that suppressed in vitro type-1 cytokine production (IL-2, IFNgamma) from alphabetaTCR+ (<2%gammadeltaTCR+) cells derived from the MLN or peripheral lymph nodes (PLN) of these same animals. On adoptive transfer to naive LEW rats simultaneously receiving LBNF1 SIT, gammadeltaTCR+ enriched PP cells from these primary donors (pv immunized, SIT rats with pv graft drainage) produced prolonged graft/ animal survival compared with PP cells obtained from primary donors that had iv drained grafts. In addition, simultaneous infusion of anti-gammadeltaTCR monoclonal antibody into SIT rats with pv graft drainage blocked the graft enhancement normally seen in these animals. These data are consistent with an important role for type-2 cytokine producing gammadeltaTCR+ cells in the regulation of graft rejection in this model.
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PMID:A role for gamma(delta)TCR+ cells in regulation of rejection of small intestinal allografts in rats. 882 87

In Brown Norway to Lewis rat lung transplantation, short-term administration of cyclosporine produces permanent adoption of allografts; however, the adopted grafts show symptoms of chronic rejection. To clarify the difference in cytokine production in acute an chronic rejection of the allografts, an immunohistochemical study was performed. In acute rejection, positive cells for respective cytokines were observed in infiltrating cells, increasing in number as the days after transplantation passed, and reaching a maximum on the fifth day. The strongest reactivity was observed perivenously. In chronic rejection, TNF-alpha positive cells were observed in the perivascular and peribronchial regions, especially around class II positive epithelia. The number of positive cells was, however, less than that in the vascular phase of acute rejection. Few cells were positive for IL-1 beta, IFN-gamma and, unexpectedly, for IL-4. These facts indicate the functional difference of infiltrating cells between acute and chronic rejection.
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PMID:Difference in cytokine production in acute and chronic rejection of rat lung allografts. 895 33

Sensitizing chemicals can induce various types of allergic disease, including contact dermatitis and occupational asthma. In the present study we have examined the nature of the immune response induced in Brown Norway (BN) rats by oxazolone (OX), a potent contact allergen, and by trimellitic anhydride (TMA), a chemical known to cause sensitization of the respiratory tract and occupational asthma. BN rats were exposed topically to either OX or TMA at doses selected to achieve similar levels of proliferative activity by draining LNC. Both chemicals stimulated hapten-specific IgG antibody responses, but only TMA induced specific IgE antibody, an increase in total serum IgE and active sensitization of mast cells. Draining LNC from OX-treated rats expressed elevated IFN-gamma mRNA, whereas those from TMA-treated rats expressed elevated IL-5 mRNA compared to controls. Furthermore, Con A-activated draining LNC from rats exposed to TMA, but not OX, released significantly increased concentrations of IL-4. In conclusion, different chemical allergens can induce in the BN rat divergent patterns of IgE response and cytokine expression.
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PMID:Selectivity of IgE responses, mast cell sensitization, and cytokine expression in the immune response of Brown Norway rats to chemical allergens. 896 87

Late allergic airway responses can be transferred by CD4+ T cells in the rat. To investigate the role of T-cell cytokines in these responses, we examined the expression of mRNA for Th2 (interleukin [IL]-4 and IL-5) and Th1 (IL-2 and interferon gamma [INF-gamma])-type cytokines in Brown Norway rats that were administered either antigen-primed W3/25(CD4)+ or OX8(CD8)+ T cells. Donors were actively sensitized by subcutaneous injection of ovalbumin (OVA) in the neck and T cells were obtained from the cervical lymph nodes by immunomagnetic cell sorting for administration to unsensitized rats. Control rats received bovine serum albumin (BSA)-primed CD4+ and CD8+ T cells. Two days later, recipient rats were challenged with aerosolized OVA, and bronchoalveolar lavage (BAL) was performed 8 h after challenge. BAL cells expressing mRNA for IL-2, IL-4, IL-5, and INF-gamma were analyzed using the technique of in situ hybridization. Recipients of OVA-primed CD4+ T cells had an increase in the fraction of BAL cells expressing mRNA for IL-4 and IL-5 compared with BSA-primed CD4+ or OVA-primed CD8+ cells (P < 0.001). Recipients of CD8+ T cells had an increase in INF-gamma mRNA expression after OVA challenge compared with recipients of BSA-primed-CD8+ or OVA-primed CD4+ T cells (P < 0.001). In conclusion, T-cell-dependent allergen-induced late responses are associated with the expression of mRNA for IL-4 and IL-5, indicating Th2 cell activation. Furthermore, the increased expression of INF-gamma in allergen challenge recipients of antigen-primed CD8+ T cells suggests that CD8+ T cells may be important in modulating allergic responses.
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PMID:Adoptively transferred late allergic airway responses are associated with Th2-type cytokines in the rat. 899 81

To identify the immunologic mechanisms that influence susceptibility to GN, we compared the severity of accelerated anti-glomerular basement membrane (GBM) nephritis between Lewis (LEW) and Brown Norway (BN) rats and analyzed differences in their immune responses to the nephritogenic immunoglobulin. Lewis (LEW) rats preimmunized with sheep IgG developed proliferative GN with marked proteinuria [peak protein excretion (mean +/- SEM) = 85.3 +/- 15.3 mg/24 hr; normal = 6.4 +/- 0.8 mg/24 hr] after receiving a subnephritogenic dose of sheep anti-rat GBM antiserum. Identically treated Brown Norway (BN) rats, on the other hand, had minimal renal pathology and minimal proteinuria (peak protein excretion = 22.6 +/- 3.1 mg/24 hr; normal = 13.0 +/- 0.6 mg/24 hr). Serum titers of rat anti-sheep IgG isotypes and intraglomerular binding of sheep IgG, rat IgG, and rat complement (C3) were comparable in both strains. In contrast, only LEW rats developed a strong cellular immune response to sheep IgG represented by intrarenal T lymphocyte (OX19+) and monocyte (ED1+) accumulation [LEW vs. BN (mean +/- SEM): OX19+ = 0.60 +/- 0.10 vs. 0.14 +/- 0.01 cells/glomerulus, control = 0.02 +/- 0.01; ED1+ = 4.0 +/- 0.4 vs. 1.0 +/- 0.2 cells/glom., control = 0.8 +/- 0.3] and a significant cutaneous delayed-type hypersensitivity (DTH) reaction [LEW versus BN (mean +/- SEM): delta ear thickness = 0.22 +/- 0.02 vs. 0.05 +/- 0.03 mm; control = 0.04 +/- 0.02 mm]. Upon rechallenge with sheep IgG in vitro, LEW splenocytes expressed a T helper 1 (Th1) cytokine pattern (IFN gamma and IL-2 mRNA, but little IL-4 mRNA) which is associated with delayed-type hypersensitivity reactions. BN splenocytes, on the other hand, expressed IL-4 in addition to IL-2 and IFN gamma mRNA that is consistent with an undifferentiated (Th0) cytokine profile. These studies suggest that humoral immunity to heterologous immunoglobulin planted in the kidney is not sufficient for full expression of accelerated anti-GBM nephritis, and that additional cellular immune mechanisms are required. We conclude that susceptibility to accelerated anti-GBM nephritis is strongly influenced by the host's propensity to mount a Th1-type response and DTH reaction to the disease-inciting immunoglobulin.
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PMID:Immunologic determinants of susceptibility to experimental glomerulonephritis: role of cellular immunity. 906 95

D-penicillamine (DP) and gold salts which are used as immune-modulating agents in the treatment of rheumatoid arthritis are known to be capable of causing autoimmune manifestations. Most autoimmune diseases in man are dominated by Th1-type responses, and one might presume that effective immunotherapy counteracts Th activity, perhaps by causing a shift to a Th2 response. The mechanism of action of gold and DP is not clear, but some clues may be obtained from their effects in animal models. DP, gold salts and mercuric chloride (HgCl2) are known to induce Th2-dominated autoimmune syndromes in genetically susceptible rodent strains, and we have demonstrated recently that HgCl2 up-regulates messenger RNA (mRNA) for IL-4 in the Brown Norway (BN) rat. In the BN rat HgCl2 treatment is also associated with the development of vasculitis, and anti-myeloperoxidase (MPO) antibodies are found in the serum. The present study examined and confirmed the hypothesis that, since gold and DP induce an autoimmune syndrome similar to HgCl2 in the BN rat, they may also induce vasculitis and an up-regulation in mRNA for IL-4. Tissue injury was assessed macroscopically and histologically on day 5 and day 15 after the start of injections with gold, DP or HgCl2, serum titres of IgE and presence of anti-MPO antibodies were determined using ELISA, and a semi-quantitative assay using reverse transcription-polymerase chain reaction was used to assay the level of mRNA for IL-4 in spleen and caecum. The relative degree of tissue injury reflected the potency of induction of IgE by the three agents (HgCl2 being most potent and DP least potent). The lesions were identical histologically, supporting the premise that the vasculitis is a manifestation of the autoimmune syndrome rather than non-specific HgCl2 toxicity. Both gold and DP induced less up-regulation of mRNA for IL-4 than HgCl2. HgCl2 (but not gold or DP) induced anti-MPO antibodies. It would be interesting to examine patients treated with gold and DP to see if there is evidence of a Th2-type response in those developing autoimmune complications, and whether or not the bias to a Th2 environment contributes to efficacy of treatment of the underlying disease.
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PMID:Gold and D-penicillamine induce vasculitis and up-regulate mRNA for IL-4 in the Brown Norway rat: support for a role for Th2 cell activity. 918 89

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

Mercuric chloride (HgCl2) induces T helper 2 (Th2) autoreactive anti-class II T cells in Brown Norway rats. These cells produce interleukin (IL)-4 and induce a B cell polyclonal activation that is responsible for autoimmune disease. In Brown Norway rats, HgCl2 triggers early IL-4 mRNA expression both in vivo and in vitro by T cells, which may explain why autoreactive anti-class II T cells acquire a Th2 phenotype. The aim of this study was to explore the transduction pathways by which this chemical operates. By using two murine T cell hybridomas that express IL-4 mRNA upon stimulation with HgCl2, we demonstrate that: 1) HgCl2 acts at the transcriptional level without requiring de novo protein synthesis; 2) HgCl2 induces a protein kinase C-dependent Ca2+ influx through L-type calcium channels; 3) calcium/calcineurin-dependent pathway and protein kinase C activation are both implicated in HgCl2-induced IL-4 gene expression; and 4) HgCl2 can activate directly protein kinase C, which might be one of the main intracellular target for HgCl2. These data are in agreement with an effect of HgCl2 which is independent of antigen-specific recognition. It may explain the T cell polyclonal activation in the mercury model and the expansion of pathogenic autoreactive anti-class II Th2 cells in this context.
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PMID:HgCl2-induced interleukin-4 gene expression in T cells involves a protein kinase C-dependent calcium influx through L-type calcium channels. 940 50


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