In vitro responses of BN strain inbred rats.
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Animals↗
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Effects of glutaraldehyde on experimental arterial iso- and allografts in rats.
The effects of glutaraldehyde pretreatment and allograft rejection in arterial grafts were assessed, using iso- and allografts in rats. An in situ glutaraldehyde fixation procedure was used to obtain homogeneous cross-linked vascular biografts. Ten Lewis rats were isografted, ten were isografted with a glutaraldehyde-treated aortic segment, ten were allografted with aortic segments from brown Norway (BN) inbred rats, and ten were allografted with glutaraldehyde-treated BN aortas. The macroscopic and microscopic appearances of the grafts were analyzed 3 weeks after the initial surgery. Immunological injury to the media and the intimal response were quantified morphometrically after monochromatic staining of cell nuclei (hematoxylin after periodic acid), elastin (orcein), and calcification (Von Kossa). Untreated isografts were normal. Untreated allografts showed the classical signs of arterial wall rejection: adventitial inflammatory granuloma, reduced medial thickness and smooth muscle cell density, and greatly increased intimal thickness (P < 0.005). Glutaraldehyde treatment significantly decreased the medial thickness in both iso- and allografts (P < 0.001) and prevented the intimal proliferative response (P < 0.005), but did not change adventitial inflammation. It also induced massive calcification mainly in isografts (P < 0.001). Histomorphological modifications of glutaraldehyde-treated grafts are consistent with a partial protective effect of glutaraldehyde against the rejection process, but also with an induction of a nonspecific inflammatory reaction. Glutaraldehyde-induced cross-linking of the extracellular matrix was responsible for ectopic calcification of the arterial grafts which was independent of the rejection process.
Animals↗
Preferential synthesis of IgE reaginic antibodies in rats immunized with alum-adsorbed antigens.
The reaginic antibody response to alum-precipitated ovalbumin (OA) and the dialyzed water-soluble extracts of ragweed (DWSR) and Alternaria tenuis (DWST) in several strains of rats appeared to be wholly an IgE response. There was no evidence of a heat-stable (IgGa) antibody to OA, DWSR and DWST in the sera of the rats immunized with these antigens suspended in alum. Wistar-Furth and Lew inbred and hooded outbred rats produced comparable amounts of reaginic antibody after immunization with DWST, but BN inbred rats failed to generate a reaginic response to this antigen. The amount of antigen-induced histamine release from rat peritoneal mast cells did not always correlate with the level of circulating IgE-specific antibody.
Adsorption↗
Physical map and expression profile of genes of the telomeric class I gene region of the rat MHC.
The rat is an important model for studying organ graft rejection and susceptibility to certain complex diseases. The MHC, the RT1 complex, plays a decisive role in controlling these traits. We have cloned the telomeric class I region of the RT1 complex, RT1-C/E/M, of the BN inbred rat strain in a contig of overlapping P1-derived artificial chromosome clones encompassing approximately 2 Mb, and present a physical map of this MHC region. Forty-five class I exon 4-hybridizing BAM:HI fragments were detected, including the previously known rat class I genes RT1-E, RT-BM1, RT1-N, RT1-M2, RT1-M3, and RT1-M4. Twenty-six non-class I genes known to map to the corresponding part of the human and mouse MHC were tested and could be fine mapped in the RT1-C/E/M region at orthologous position. Four previously known microsatellite markers were fine mapped in the RT1-C/E/M region and found to occur in multiple copies. In addition, a new, single-copy polymorphic microsatellite has been defined. The expression profiles of several class I genes and the 26 non-class I genes were determined in 13 different tissues and exhibited restricted patterns in most cases. The data provide further molecular information on the MHC for analyzing disease susceptibility and underline the usefulness of the rat model.
Animals↗
Heterogeneity of inbred BN strain rats for the RT2 locus.
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Alleles↗
Effect of antigen dose on the secondary IgE response in BN rats.
Inbred Brown Norway rats were immunized at day 0 with a single dose of ovalbumin and 1 mg A1(OH)3. Various doses of ovalbumin without adjuvant were given at day 28. The secondary IgE antibody was antigen dose-dependent. Total serum IgE levels decreased after immunization and during the IgE antibody response.
Aluminum Hydroxide↗
Effects of adrenalectomy and of mineralocorticoid receptor/glucocorticoid receptor ligands in female Brown Norway and Fischer 344 rats and f1 hybrids.
Our previous studies suggested that the mineralocorticoid receptor (MR) of Brown Norway (BN) male rats is active independently of the presence of its ligands (i.e. constitutively active), and that glucocorticoid receptor (GR)-mediated mechanisms are more efficient in BN than in Fischer 344 (F344) male rats. Such functional differences in corticosteroid receptors led us to compare the effect of adrenalectomy (ADX) and MR/GR-mediated actions (treatments with deoxycorticosterone, DOC and RU 28362, respectively) on female rats from both strains, and, within the framework of a genetic study, to investigate how these differences were inherited in rats of the first generation (F1) born from the crossbreeding between BN and F344 inbred rats. This study extends our previous hypotheses of a constitutive activation of MR and of a greater efficiency of GR in males to females of the BN strain. In both strains, female rats were less sensitive to ADX and to treatments with DOC or RU 28362 than males. Globally, F1 hybrid BNxF344 rats inherited the functional characteristics of MR and GR of BN rats.
Adrenal Glands↗
[Orthotopic liver transplantation in rats. Prolonging of survival time of allotransplants using cyclosporin A in an acute rejection model].
Livers from inbred DA rats were transplanted orthotopically into inbred BN rats. Within 15 days all animals died due to rejection of the transplant. However, when rats were treated with Cyclosporin A (four different regimens) they survived for at least 60 days, even if therapy was withdrawn at day 28. It could be shown that the histologic changes in the graft stood in an inverse relationship to the extent of immunosuppressive therapy.
Alkaline Phosphatase↗
Delayed rejection of heart allografts after extracorporeal donor-specific liver hemoperfusion. Role of Kupffer cells.
Liver allografts have a privileged status in regard to acute rejection. In this experimental study, we have analyzed the immunosuppressive effects of an extracorporeal liver hemoperfusion. In the LEW-to-BN combination of inbred rats, donor-specific liver hemoperfusion can significantly delay acute rejection of heart allografts. Analysis of the immunological status of these animals revealed a significant decrease in donor-specific lymphocytotoxic antibodies and in cytotoxic T lympholysis. Reactivity in mixed lymphocyte culture was normal. After third-party (DA) liver hemoperfusion or after donor-specific (LEW) splenic hemoperfusion, prolongation of heart allograft survival was moderate. Previous blockade of Kupffer cells suppressed the effects of donor-specific liver hemoperfusion. These results suggest that the sequestration by Kupffer cells of a clone of cytotoxic T cells and/or lymphocytotoxic antibodies may explain the immunosuppressive effects of donor-specific liver hemoperfusion.
Animals↗
Suppression of allergic reactivity by intestinal helminths: susceptibility is a function of IgE responder phenotype.
Animals from two inbred rat strains, Brown Norway (BN) and WAG, expressing high and low-IgE-responder phenotype, respectively, were sensitized to ovalbumin (OV) while parasitized with the intestinal helminth Nippostrongylus brasiliensis (Nb). The animals were challenged intradermally and intravenously with OV, and the severity of their immediate hypersensitivity responses was compared to those of non-parasitized OV-immune controls. Nb infestation depressed hypersensitivity responses in the low-IgE-responder WAG rats, but was without effect in high-IgE-responder BNs.
Animals↗
Genetic control of the in vitro responses of rat blood lymphocytes. II. Number of loci involved and linkage with in vivo antibody formation.
Blood lymphocytes from the inbred rat strains AS and BN differ in the magnitude both of their in vitro proliferative response to different mitogens and of their in vivo antibody response to the mitogenic fraction of phytohemagglutinin (PHA). We have examined the segregation of in vitro responsiveness to PHA in (AS X BN)F1 X BN backcross rats and have tried to correlate it with other characters that vary in backcross rats. In vitro responsiveness is regulated by one or a few loci, is linked to the in vitro responsiveness to B lymphocyte mitogens and the in vivo antibody response to the mitogenic fraction of PHA, but is not linked to the major histocompatibility locus (Ag-B) nor to the frequency of short-lived small Ig-negative lymphocytes in blood. Lymphocytes from high-responder rats have a shorter lag period before the onset of DNA synthesis in vitro than low-responder rats, and possibly also a higher number of in vitro responsing cells. To explain our findings, that the same gene og genes regulate in vitro responsiveness to different mitogens and in vivo antibody response to the mitogenic fraction of PHA, we suggest that the gene or genes act in an immunologically unspecific manner on the regulation of lymphocyte proliferation in vitro as well as in vivo.
Animals↗
Effects of chronic dietary choline on temporal discrimination of BN and WAG rats.
Using rats of the inbred BN and WAG strain, we tested the hypothesis that chronic dietary choline supplementation would especially affect the timing behavior of BN rats because of their lower cholinergic activity and their poor performance in aversively motivated learning and memory tasks. An apparent effect of chronic choline supplementation (2.5 mg choline chloride per ml water) on DRL-8" responding was not confirmed in a second experiment when the choline concentration was doubled. WAG rats treated chronically with choline showed a poorer temporal discrimination performance on a DRL-16" schedule than untreated WAG rats. In contrast, choline supplementation never had an effect on the performance of BN rats. The results of the DRL-16" experiment provide partial support for a hypothesis proposed by Church and Meck that the remembered time of reinforcement is inversely related to the functional activity of brain cholinergic activity: acetylcholine precursor treatment increases memory storage speed, which results in an overestimation of the time elapsed. An alternative explanation, which takes into account the aberrant EEG activities of WAG rats, is also discussed.
Acetylcholine↗
Hypothalamic-pituitary-adrenal response to chronic stress in five inbred rat strains: differential responses are mainly located at the adrenocortical level.
The effects of chronic stress on the hypothalamic-pituaitary-adrenocortical (HPA) axis were studied in five inbred rat strains, i.e. Brown Norway (BN), Fischer (FIS), Lewis (LEW), Spontaneously Hypertensive (SHR) and Wistar Kyoto (WKY). Previously, these rat strains had been shown to display clear behavioral differences in the forced swimming test that presumably measures depression-like behavior, BN and WKY being more passive than the other strains. Here we test the hypothesis that the differences in behavioral immobility might be associated with an abnormal HPA response to chronic immobilization (IMO) stress. In stressnaive rats under basal conditions (morning) there were no differences among strains in adrenal weight, serum adrenocorticotropin hormone (ACTH) and corticosterone (B) levels, cortictropin-releasing factor (CRF) mRNA in the hypothalamic paraventricular nucleus (PVN) and hippocampal glucocorticoid and mineralocorticoid receptor (GR and MR) mRNA. After chronic IMO, basal serum ACTH levels were increased in LEW, SHR and WKY, but not in BN or FIS rats, whereas basal B levels were increased in BN, FIS, SHR and WKY rats, but not in LEW. The increase in adrenal weight was also strain dependent and correlated negatively with chronic IMO-induced hypercorticosteronemia. These peripheral differences among strains were not observed at central levels. Thus, chronic IMO increased the CRF mRNA content in the PVN, analyzed by in situ hybridization, similarly in all strains. In addition, after chronic IMO no differences were found among strains in hippocampal GR mRNA and RM mRNA contents. Considering data from all strains together, chronic IMO reduced the GR mRNA (50-60%) content in the hippocampal CA1, CA3 and DG areas, and slightly diminished (11-13%) MR mRNA levels in CA1 and CA3 areas. The present results indicate that: (i) chronic IMO down-regulates GR mRNA in the hippocampus and slightly up-regulates CRF mRNA in the hypothalamic PVN similarly in all strains; (ii) after chronic IMO interstrain differences were observed in serum ACTH and B levels as well as adrenal hypertrophy; (iii) some changes are probably located at the adrenal level since changes in serum B level and adrenal weight were not related to changes in ACTH; (iv) in LEW and WKY rats, B hyporesponsiveness to chronic IMO might be linked to low adrenal sensitivity to ACTH, and (v) HPA axis changes induced by the chronic IMO procedure are not related to previously reported data on depressive-like behavior of BN and WKY in the forced swimming test.
Adrenal Cortex↗
Linkage analysis of neointimal hyperplasia and vascular wall transformation after balloon angioplasty.
Neointimal hyperplasia (NIH), a result of vascular injury, is due to the migration and proliferation of smooth muscle cells through the media and internal elastic lamina leading to vascular occlusion. We used a rat model to find the genetic regions controlling NIH after endothelial denudation in two divergent inbred strains of rats. The Brown Norway (BN) and spontaneously hypertensive rat (SHR) strains have a 2.5-fold difference in injury-induced NIH. A population of 301 F2 (SHR x BN) rats underwent a standard vascular injury followed by phenotyping 8 wk after injury to identify quantitative trait loci (QTL) responsible for this strain difference. Interval mapping identified two %NIH QTL on rat chromosomes 3 and 6 [logarithm of odds (LOD) scores 2.5, 2.2] and QTL for other injured vascular wall changes on rat chromosomes 3, 4, and 15 (LOD scores 2.0-4.6). Also, QTL for control vessel media width (MW) and media area (MA) were found on chromosome 6 with LOD scores of 2.3 and 2.5, suggesting that linkage exists between these control vessel parameters and NIH production. These results represent the first genetic analysis for the identification of NIH QTL and QTL associated with the vascular injury response.
Angioplasty, Balloon↗
Scanning electron microscopic study of hyperacute rejection in the inbred rat.
Twenty skin-presensitised Lewis rats received kidney transplants from (Lewis X BN)f1 rats. Two grafts each were withdrawn at intervals from 1--120 min and examined using a scanning electron microscopic (SEM). A series of Lewis to Lewis isografts served as control. In hyperacute rejection at just 1 min spider-like fibrin fibres and platelets could be observed in small arteries, where the endothelium was severely altered. In these regions at 2 and particularly 5 min a fibrin network often contained platelet aggregates, mechanically altered erythrocytes as well as different kinds of leucocytes. This coagulation process progressed with time and resulted in a complete vascular occlusion at 30--60 min.
Animals↗
IL-12 reduces the severity of Sendai virus-induced bronchiolar inflammation and remodeling.
The goal of this research was to determine whether differential pulmonary IL-12 gene expression controls susceptibility to Sendai virus-induced chronic airway inflammation and fibrosis in inbred rat strains. Sendai virus-resistant F344 rats and susceptible BN rats were studied from 1 to 14 days following virus inoculation. F344 rats had 3.4-fold higher IL-12 mRNA levels detected by real-time PCR in lung than BN rats as early as two days following inoculation. This increase in mRNA was associated at two days with increased total IL-12 protein and with a 2-fold increase in numbers of bronchiolar, OX-6-positive dendritic cells and an increased number of IL-12 p40-positive, bronchiolar macrophages and dendritic cells (p<0.05). Virus-susceptible BN rats treated with 3 mug of recombinant, mouse IL-12 intraperitoneally at the time of virus inoculation had a 22.1% decrease in severity of chronic bronchiolar inflammation and a 23.8% decrease in fibrosis compared to virus-inoculated BN rats treated with saline. IL-12 treatment induced increased IFN-gamma mRNA and protein expression after virus inoculation (p<0.05). The results demonstrate that there is differential pulmonary IL-12 gene expression between virus-susceptible and resistant rat strains and that IL-12 treatment can provide significant protection from virus-induced chronic airway inflammation and remodeling during early life.
Animals↗
Humoral antibody response in rat renal allotransplantation.
Female inbred Fischer (F344) rats were grafted with kidneys from female BN rats. Humoral antibodies in some of the recipients were demonstrated as early as 3 days after transplantation: (1) antibodies bound to the graft were detected by mixed agglutination tests with graft sections and erythrocytes of the donor as indicator cells; (2) lytic and agglutinating antibodies against donor strain erythrocytes were demonstrated in the recipients' sera by hemolysis in agar gel and dextran hemagglutination tests; and (3) similar antibodies secreted by a significant number of cells were detected in the recipients' spleens by plaque assay. The antibody response of the recipients was directed against a single antigen, designated N, which was shown to be present on erythrocytes of 57% of Fischer strain rats and was shared by erythrocytes of all rat strains tested (BN, Lewis, Wistar, ACI, MAXX, and Buffalo). The N antigen did not seem to belong to any known rat histocompatibility antigen system. Segregation of the gene coding for this antigen within the Fischer strain would indicate residual genetic heterogeneity. Evidence was presented that this antigen is present not only on erythrocytes, but also on other cells including splenocytes.
Adrenal Glands↗
Glucocorticoid negative feedback on the HPA axis in five inbred rat strains.
The aim of the present work was to study the influence of altering glucocorticoid negative feedback on both basal activity of the hypothalamic-pituitary-adrenal (HPA) axis and its response to acute stress (tail shock) in five inbred rat strains known to differ in some depression-like behaviors: Brown Norway (BN), Fischer 344 (F344), Lewis (Lew), spontaneously hypertensive (SHR), and Wistar-Kyoto (WKY) rats. Two complementary approaches were used: 1) enhancement of negative feedback by administration of 0.05 and 0.2 mg/kg dexamethasone (Dex) and 2) attenuation of negative feedback by pharmacological adrenalectomy (PhADX). The results indicate that 1) Lew rats consistently show adrenocorticotropic hormone (ACTH) and corticosterone hyporesponsiveness to stress, 2) interstrain differences in the effect of Dex on the HPA axis were very weak and not related apparently to differences in the metabolism of the steroid, 3) the suppressive effect of the highest dose of Dex on basal corticosterone levels was lower in BN rats than in the other strains, and 4) after PhADX, an increase in ACTH levels was observed in response to acute stress in BN, F344, and WKY but not in Lew and SHR rats, suggesting possible interstrain differences in pituitary sensitivity to neural stimuli induced by stress. In summary, our results indicate that there are differences among the strains with regard to both 1) the suppressive effect of Dex on the HPA axis, BN rats showing a certain degree of resistance, and 2) the capability of PhADX rats to respond to acute stress, which suggests a defective release of ACTH in Lew and SHR rats. The biological meaning of these alterations of corticosteroid negative feedback among the five inbred strains studied remains to be established.
Adrenal Glands↗