Brown Norway Rat

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 297 Experts worldwide ranked by ideXlab platform

Bernard Robaire - One of the best experts on this subject based on the ideXlab platform.

  • The effects of long-term vitamin E treatment on gene expression and oxidative stress damage in the aging Brown Norway Rat epididymis.
    Biology of reproduction, 2004
    Co-Authors: Kathryn M. Jervis, Bernard Robaire
    Abstract:

    The male reproductive tract of the Brown Norway Rat is profoundly affected by aging. In the epididymis, the site of sperm matuRation and storage, aging results in histological and biochemical changes that are suggestive of oxidative stress. Vitamin E is a potent lipid-soluble antioxidant that amelioRates the oxidative stress load associated with some chronic disease conditions. To determine the effects of long-term (18-mo) vitamin E deficiency and supplementation on aging in the epididymis, we assessed gene expression changes using cDNA microarrays and lipid peroxidation using immunohistochemical detection of 4-hydroxynonenal (4-HNE) in 24-mo-old Rats. Plasma vitamin E levels were significantly lower in vitamin E-deficient animals and higher in vitamin E-supplemented animals compared with age-matched controls. Vitamin E deficiency resulted in increased expression of oxidative stress-related transcripts along the epididymis. This effect was most marked in the corpus epididymidis, where expression of glutathione S-transferases pi, 8, and mu, as well as superoxide dismutase, increased by over 50%. The effect of vitamin E supplementation on the expression of oxidative stress-related transcripts was primarily decreased expression; however, the magnitude of the gene expression changes was smaller than that observed for vitamin E deficiency. 4-HNE immunostaining was present throughout the epididymis in control animals. Vitamin E deficiency both increased the intensity and altered the distribution of 4-HNE staining, while vitamin E supplementation had no observable effect. In summary, we found that long-term vitamin E treatment alters the expression of oxidative stress-related transcripts. Moreover, long-term vitamin E deficiency exacerbates the effects of age on the accumulation of oxidative stress damage in the epididymis.

  • Changes in gene expression during aging in the Brown Norway Rat epididymis.
    Experimental gerontology, 2002
    Co-Authors: Kathryn M. Jervis, Bernard Robaire
    Abstract:

    Aging of the Brown Norway Rat is associated with a decline in reproductive function. With advancing age, serum testosterone and sperm production decrease and sperm morphology is altered. In the epididymis, the site of sperm matuRation and storage, dramatic histological and biochemical changes occur with age; these changes occur in a region-specific manner. In order to provide insight into the process of aging in the epididymis, we employed cDNA microarrays to analyze changes in gene expression with age in the initial segment, caput, corpus and cauda epididymidis. The overwhelming effect was a decrease in the relative intensity of gene expression during aging. In the initial segment, corpus and cauda epididymidis, more genes had decreased relative intensity with age than did not change. Interestingly, the magnitude of the decreases in relative intensity was considerably larger in the corpus and cauda epididymidis, where expression of 83% (211 of 254) and 62% (157 of 254), respectively, of the genes decreased by greater than 50% with age. This is in contrast to the initial segment, in which only 31% of genes (78 of 254) had relative intensities that decreased by at least 50%, and the caput epididymidis, the only segment where the largest proportion of genes did not change with age (less than 33% change between young and old). No genes had increased relative intensity with age throughout the tissue, however the expression of four transcripts was increased in a segment-specific manner. The expression of oxidative stress related genes, heat shock proteins and components of intracellular degradation pathways were examined in particular detail. We found that the relative intensity of some gene families decreased with age in a segment-specific manner; these decreases correlated well with the histological changes that occur in the aging epididymis.

  • Sperm structural and motility changes during aging in the Brown Norway Rat.
    Journal of andrology, 2001
    Co-Authors: Patrick Syntin, Bernard Robaire
    Abstract:

    The Brown Norway Rat provides a useful model to study aging of the male reproductive tract because of the selective age-dependent pathological changes that are found in the testis, epididymis, and prostate. In the testis, there is a clear age-dependent decrease in both steroidogenesis and spermatogenesis. In the epididymis, some striking segment-specific changes occur at the histological and biochemical levels prior to the major loss of spermatogenesis. We hypothesized that formation of spermatozoa in the testis and matuRation of spermatozoa in the epididymis (ie, acquisition of motility and loss of the cytoplasmic droplet) may be altered during aging. Changes in the morphology of spermatozoa were assessed by light and electron microscopy. Using computer-assisted sperm analysis, the motility parameters of spermatozoa obtained from the caput and cauda epididymidis of young and old Brown Norway Rats were compared. In old animals, we also compared the motility of spermatozoa from epididymides adjacent to regressed testes with those from epididymides adjacent to nonregressed testes. There was a marked increase with age in the number of spermatozoa with abnormal flagellar midpieces; the nature of these defects did not change with age. In caput epididymidis, the percentage of motile sperm was similar in young and old Rats. In contrast, the percentage of motile spermatozoa was significantly decreased in cauda epididymidis of old Rats; spermatozoa from the regressed testis side had altered motility characteristics. Furthermore, in the cauda epididymidis on the regressed testis side of aged Brown Norway Rats, the proportion of spermatozoa that retained their cytoplasmic droplet was markedly elevated. Some of these effects are likely due to changes taking place in spermatozoa during the process of spermatogenesis in the testis (eg, formation of the flagellum), whereas others could occur during sperm matuRation in the epididymis (eg, acquisition of motility). The multiple effects of aging on sperm morphology, the acquisition of motility, and the shedding of the cytoplasmic droplet clearly indicate that the quality of spermatozoa is affected by aging.

  • Distribution of Immune Cells in the Epididymis of the Aging Brown Norway Rat Is Segment-Specific and Related to the Luminal Content
    Biology of reproduction, 1999
    Co-Authors: Valerie Serre, Bernard Robaire
    Abstract:

    Remarkable changes occur during aging in the testis and epididymis of the Brown Norway Rat. A dramatic increase in the number of halo cells, which are present in the epididymal epithelium and originate from the immune system, is found in animals of increasing age. Halo cells have been postulated to be either lymphocytes or monocytes. We hypothesized that halo cells are a mixture of different immune cells and that their relative composition changes with age. To verify this hypothesis, markers for helper T lymphocytes, cytotoxic T lymphocytes, B lymphocytes, and monocytes-macrophages were used to identify the major categories of immune cells in the epididymides of Brown Norway Rats ranging in age from 3 to 24 mo. The numbers of immunocompetent cells in the epididymis were determined in relation to age, epididymal segment, and luminal content. We found that monocytes, helper T lymphocytes, and cytotoxic T lymphocytes belong to the population of halo cells. In addition, a segment-specific increase with age in the number of these immune cells was noted. Finally, we report a segment-specific recruitment of cytotoxic T lymphocytes and monocytes-macrophages in the epididymal epithelium of aged Rats whose epididymal lumen contained few spermatozoa. We postulate that accumulation of damaged epithelial cells and antigens of germ cell origin, leaking through a dysfunctional blood-epididymis barrier, may contribute to the active recruitment of immune cells with age.

  • paternal age affects fertility and progeny outcome in the Brown Norway Rat
    Fertility and Sterility, 1998
    Co-Authors: Valerie Serre, Bernard Robaire
    Abstract:

    Abstract Objective: To investigate the effects of paternal age on fertility and progeny outcome using the Brown Norway Rat model. Design: Controlled prospective study. Setting: McIntyre Animal Centre, McGill University, Montreal, Quebec, Canada. Intervention(s): Brown Norway male Rats of increasing age were mated to young Sprague-Dawley females. Main Outcome Measure(s): Pregnancy outcome was assessed by counting the numbers of corpora lutea, resorptions, and live fetuses on day 20 of gestation. To evaluate progeny outcome, pups were examined for external malformations and weighed daily for 2 months. Result(s): There were no significant changes in the numbers of resorptions, offspring, or in the incidence of external malformations. However, there was an increase in preimplantation loss (corpora lutea minus implantation sites) in litters fathered by older males. Furthermore, a significant decrease in the average fetal weight was found with increasing paternal age. A significant increase in neonatal deaths for progeny fathered by older males also was found. Conclusion(s): These results indicate that the quality of spermatozoa decreases as males age.

Terry R. Brown - One of the best experts on this subject based on the ideXlab platform.

  • Gene expression changes are age-dependent and lobe-specific in the Brown Norway Rat model of prostatic hyperplasia.
    The Prostate, 2009
    Co-Authors: Carlise R. Bethel, Jaideep Chaudhary, Matthew D. Anway, Terry R. Brown
    Abstract:

    BACKGROUND Benign prostatic hyperplasia (BPH) is an age-related enlargement of the prostate, characterized by increased prolifeRation of stromal and epithelial cells. Despite its prevalence, the etiology of BPH is unknown. METHODS The Brown Norway Rat is a model for age-dependent, lobe-specific hyperplasia of the prostate. Histological analyses of the dorsal and lateral lobes from aged Rats reveal focal areas characterized by increased numbers of luminal epithelial cells, whereas the ventral lobe is unaffected. This study examined differential gene expression by lobe and age in the Brown Norway Rat prostate. The objective was to identify genes with different levels of expression in the prostate lobes from 4-month (young) and 24-month (old) animals, and to subsequently link changes in gene expression to mechanisms of prostate aging. RESULTS The number of age-dependent differentially expressed genes was greatest in the dorsal compared to the ventral and lateral lobes. Minimal redundancy was observed among the differentially expressed genes in the three lobes. Age-related changes in the expression levels of 14 candidate genes in the dorsal, lateral and ventral lobes were confirmed by quantitative RT-PCR. Genes that exhibited age-related differences in their expression were associated with prolifeRation, oxidative stress, and prostate cancer progression, including topoisomerase II alpha (Topo2a), aurora kinase B (Aurkb), stathmin 1 (Stmn1), and glutathione S-transferase pi. Immunohistochemistry for Topo2a, Aurkb, and Stmn1 confirmed age-related changes in protein localization in the lateral lobe of young and aged prostates. CONCLUSION These findings provide clues to the molecular events associated with aging in the prostate. Prostate 69: 838–850, 2009. © 2009 Wiley-Liss, Inc.

  • CastRation-induced apoptotic cell death in the Brown Norway Rat prostate decreases as a function of age.
    Endocrinology, 2000
    Co-Authors: Subhadra Banerjee, Partha P. Banerjee, Terry R. Brown
    Abstract:

    Growth and differentiation of the prostate gland depends upon androgens, yet overgrowth of the human prostate occurs later in life when serum levels of testosterone are declining. We have reported a similar phenomenon in the Brown Norway Rat, but the age-dependent overgrowth of the prostate is confined to the dorsal and lateral lobes and, hence, is lobe specific. Because tissue growth depends upon the balance between prolifeRation and death of cells, the present study was designed to investigate whether cell death differed in the various prostatic lobes of Brown Norway Rats as a function of age. Apoptosis of cells in the ventral, dorsal, lateral, and anterior lobes of the prostate was examined in young (4-month-old) and old (24-month-old) Brown Norway Rats after castRation. Whereas castRation caused tissue weights of all four prostatic lobes to decrease over the course of 10 days, this occurred more rapidly and to a greater magnitude in the ventral than in the dorsal, lateral, and anterior lobes. Tissue D...

  • age dependent and lobe specific spontaneous hyperplasia in the Brown Norway Rat prostate
    Biology of Reproduction, 1998
    Co-Authors: Partha P. Banerjee, Barry R. Zirkin, John D. Strandberg, Subhadra Banerjee, Terry R. Brown
    Abstract:

    : We showed previously that exogenously administered testosterone caused age- and lobe-specific overgrowth of the prostate in Brown Norway Rats. A common feature observed in testosterone-treated animals was cell hypertrophy in each of the ventral, dorsal, and lateral lobes of both young (6 mo old) and old (24 mo old) Rats. By contrast, hyperplasia was seen only in the dorsal and lateral lobes of old Rats treated with testosterone. These observations prompted us to examine whether age- and lobe-specific overgrowth might also occur in untreated Rats as a consequence of the endogenous hormonal milieu. To this end, blood and prostates were collected from a large number (25-30 Rats per group) of 4- to 6-mo-old (young) and 21- to 24-mo-old (old) Brown Norway Rats. Both serum testosterone (-45%) and estradiol (-22%) concentRations decreased significantly with age, but the greater magnitude of the decrement in testosterone relative to estradiol led to a reduction in the serum testosterone:estradiol Ratio. Paradoxically, although the prostate is androgen dependent, the wet weight, protein, and DNA contents increased significantly with age in the dorsal and lateral lobes of old Rats despite the decrease in testosterone level. Histologic examination revealed that the increased weights and DNA contents of the dorsal and lateral lobes in old Rats coincided with an increased number of epithelial cells in the distal and intermediate segments of these lobes, indicative of hyperplasia but independent of change in cell size. Taken together, these results show a spontaneous age-related overgrowth of cells in the dorsal and lateral prostatic lobes of old Brown Norway Rats despite diminished serum testosterone concentRations. The aging Brown Norway Rat, therefore, may be a useful model for studies of some aspects of the pathogenesis underlying spontaneous age-related prostatic hyperplasia.

  • age and lobe specific responses of the Brown Norway Rat prostate to androgen
    Biology of Reproduction, 1994
    Co-Authors: Partha P. Banerjee, Barry R. Zirkin, Subhadra Banerjee, Renee Dorsey, Terry R. Brown
    Abstract:

    : We examined the effects of age and of increasing concentRations of testosterone on the wet weight, protein content, cell number, and cell size of the ventral, dorsal, and lateral lobes of the Brown Norway Rat prostate. Young (3 mo of age) and aged (15, 17, and 21 mo of age) Rats received implants of increasing sizes of testosterone-filled Silastic capsules for 3 mo. Wet weights of the prostate were the same in untreated young (6-mo-old) and aged (18-24-mo-old) Rats. Testosterone administRation resulted in serum testosterone concentRations ranging from physiologic to superphysiologic. Dose-dependent increases in wet weights and protein contents were seen in the ventral, dorsal, and lateral prostatic lobes of both young and aged Rats. For each given dose of testosterone, including doses that resulted in serum testosterone concentRations within the physiologic range, the weights and protein contents of the dorsal and lateral lobes were greater in old (24-mo-old) than in young (6-mo-old) Rats, indicating an effect of age in these lobes. In contrast, ventral prostate weights and protein contents increased equivalently in young and aged Rats with increasing testosterone concentRation. DNA content, a measure of cell number, increased significantly in the dorsal and lateral lobes as a function of testosterone dose and age, but in the ventral lobe did not differ with testosterone dose or age. Quantitative morphologic analyses showed significant hypertrophy of epithelial cells throughout each of the three lobes in both young and aged Rats treated with testosterone. Taken together, these results indicate that the prostate of Brown Norway Rats shows age and lobe-specific responses to androgen with respect to wet weight, protein content, cell number, and cell morphology.

Barry R. Zirkin - One of the best experts on this subject based on the ideXlab platform.

  • Aging and the Brown Norway Rat Leydig Cell Antioxidant Defense System
    Journal of andrology, 2005
    Co-Authors: Lindi Luo, Matthew D. Anway, Haolin Chen, Michael A. Trush, Matthew D. Show, Barry R. Zirkin
    Abstract:

    Previous studies have shown that testosterone production by the Leydig cells of aged Brown Norway Rats is reduced from the relatively high levels produced by Leydig cells of young Rats and that this reduction is not secondary to decreased serum luteinizing hormone concentRation. The free radical theory of aging proposes that imbalance between pro-oxidants and the antioxidant defense system ultimately results in oxidative damage to cellular processes. With this in mind, we hypothesized herein that age-related reductions in steroidogenesis by Brown Norway Rat Leydig cells may be associated with the impairment of the antioxidant defense system of these cells. To begin to test this hypothesis, we compared the activities and steady-state mRNA and protein levels of the antioxidant enzymes copper zinc (CuZn) superoxide dismutase (CuZnSOD, SOD1), manganese (Mn) superoxide dismutase (MnSOD, SOD2), and glutathione peroxidase (GPx) and the levels of reduced and oxidized glutathione in Leydig cells isolated from the testes of young (4-month-old) and aged (20-month-old) Brown Norway Rats. For some studies, Leydig cells were isolated sepaRately from aged testes that either had regressed because of age-related losses of germ cells or that were nonregressed. SOD (total) and GPx activities were found to decrease significantly with age whether or not the testes were regressed. CuZnSOD and MnSOD mRNA levels decreased with aging, though the magnitude of the decreases were considerably lower than the respective decreases in enzyme activities. GPx mRNA levels also decreased, which is consistent with the decreases seen in enzyme activity. MnSOD protein expression declined with age, and to a lesser extent, CuZnSOD did as well. Reduced and oxidized glutathione also exhibited age-related reductions in cells from both normal and regressed aged testes. The age-related decreases in Leydig cell antioxidant enzyme activities, gene expression, and protein levels and in glutathione were consistent with the hypothesis that the loss of steroidogenic function that accompanies Leydig cell aging may result in part from a decrease in the fidelity of the cellular antioxidant defense system.

  • age dependent and lobe specific spontaneous hyperplasia in the Brown Norway Rat prostate
    Biology of Reproduction, 1998
    Co-Authors: Partha P. Banerjee, Barry R. Zirkin, John D. Strandberg, Subhadra Banerjee, Terry R. Brown
    Abstract:

    : We showed previously that exogenously administered testosterone caused age- and lobe-specific overgrowth of the prostate in Brown Norway Rats. A common feature observed in testosterone-treated animals was cell hypertrophy in each of the ventral, dorsal, and lateral lobes of both young (6 mo old) and old (24 mo old) Rats. By contrast, hyperplasia was seen only in the dorsal and lateral lobes of old Rats treated with testosterone. These observations prompted us to examine whether age- and lobe-specific overgrowth might also occur in untreated Rats as a consequence of the endogenous hormonal milieu. To this end, blood and prostates were collected from a large number (25-30 Rats per group) of 4- to 6-mo-old (young) and 21- to 24-mo-old (old) Brown Norway Rats. Both serum testosterone (-45%) and estradiol (-22%) concentRations decreased significantly with age, but the greater magnitude of the decrement in testosterone relative to estradiol led to a reduction in the serum testosterone:estradiol Ratio. Paradoxically, although the prostate is androgen dependent, the wet weight, protein, and DNA contents increased significantly with age in the dorsal and lateral lobes of old Rats despite the decrease in testosterone level. Histologic examination revealed that the increased weights and DNA contents of the dorsal and lateral lobes in old Rats coincided with an increased number of epithelial cells in the distal and intermediate segments of these lobes, indicative of hyperplasia but independent of change in cell size. Taken together, these results show a spontaneous age-related overgrowth of cells in the dorsal and lateral prostatic lobes of old Brown Norway Rats despite diminished serum testosterone concentRations. The aging Brown Norway Rat, therefore, may be a useful model for studies of some aspects of the pathogenesis underlying spontaneous age-related prostatic hyperplasia.

  • Depletion and Repopulation of Leydig Cells in the Testes of Aging Brown Norway Rats
    Endocrinology, 1996
    Co-Authors: Haolin Chen, Ilpo Huhtaniemi, Barry R. Zirkin
    Abstract:

    The capacity of Brown Norway Rat Leydig cells to produce testosterone has been shown to decrease with aging. Our objectives herein were to determine 1) whether ethane dimethanesulfonate (EDS) administRation would eliminate the hypofunctional Leydig cells of the aged Brown Norway Rat testis; 2) if so, whether a new geneRation of Leydig cells subsequently would appear; and 3) if so, whether the steroidogenic capacity of the new Leydig cells would be at the relatively low level of the cells they replaced or at the high level of young adult Leydig cells. Young (3-month-old) and aged (18-month-old) Rats received an injection of EDS (8.5 mg/100 g BW). One, 5, and 10 weeks thereafter, the serum testosterone concentRation and the capacity of the testes and of isolated Leydig cells to produce testosterone were determined. One week after EDS treatment, Leydig cells were not seen in the testes of young or aged Rats, and the serum testosterone concentRation and testicular testosterone production were reduced to undet...

  • age related decreased leydig cell testosterone production in the Brown Norway Rat
    Journal of Andrology, 1994
    Co-Authors: Haolin Chen, Ilpo Huhtaniemi, Matthew P Hardy, Barry R. Zirkin
    Abstract:

    Previous studies have demonstRated that Leydig cell testosterone production diminishes with age in Brown Norway Rats. The objective of the studies presented herein was to test the following possible explanations for age-related decline in steroidogenesis: (1) decline in Leydig cell number; (2) understimulation by luteinizing hormone (LH); (3) reduced ability of individual Leydig cells to produce testosterone; and (4) influence of loss of germ cells. Leydig cells isolated from the testes of young and aged Rats by centrifugal elutriation and Percoll density gradient centrifugation were examined for their ability to produce testosterone when stimulated maximally with LH or with dibutyryl cyclic AMP (dbcAMP). Leydig cell number and volume were examined in situ using stereological methods. Serum LH levels were measured using a highly sensitive immunofluorometric assay. Average Leydig cell volume decreased with age, and consistent with this observation, individual Leydig cells isolated from aging Rats produced significantly less testosterone than those from young Rats whether the cells were cultured in vitro with maximally stimulating LH or with dbcAMP. The age-associated diminished testosterone production could not be explained by changes in Leydig cell number, serum LH levels, Leydig cell responsiveness to LH, or testicular germ cell content. These results, taken together, suggest that the reduced testosterone production seen in aged Rats is related to defects in the steroidogenic pathway beyond the LH receptor-cAMP cascade. The nature of the initial age-related changes that cause reduced steroidogenesis is not known, and therefore it is not known whether such changes are intrinsic or extrinsic to the Leydig cells.

  • age and lobe specific responses of the Brown Norway Rat prostate to androgen
    Biology of Reproduction, 1994
    Co-Authors: Partha P. Banerjee, Barry R. Zirkin, Subhadra Banerjee, Renee Dorsey, Terry R. Brown
    Abstract:

    : We examined the effects of age and of increasing concentRations of testosterone on the wet weight, protein content, cell number, and cell size of the ventral, dorsal, and lateral lobes of the Brown Norway Rat prostate. Young (3 mo of age) and aged (15, 17, and 21 mo of age) Rats received implants of increasing sizes of testosterone-filled Silastic capsules for 3 mo. Wet weights of the prostate were the same in untreated young (6-mo-old) and aged (18-24-mo-old) Rats. Testosterone administRation resulted in serum testosterone concentRations ranging from physiologic to superphysiologic. Dose-dependent increases in wet weights and protein contents were seen in the ventral, dorsal, and lateral prostatic lobes of both young and aged Rats. For each given dose of testosterone, including doses that resulted in serum testosterone concentRations within the physiologic range, the weights and protein contents of the dorsal and lateral lobes were greater in old (24-mo-old) than in young (6-mo-old) Rats, indicating an effect of age in these lobes. In contrast, ventral prostate weights and protein contents increased equivalently in young and aged Rats with increasing testosterone concentRation. DNA content, a measure of cell number, increased significantly in the dorsal and lateral lobes as a function of testosterone dose and age, but in the ventral lobe did not differ with testosterone dose or age. Quantitative morphologic analyses showed significant hypertrophy of epithelial cells throughout each of the three lobes in both young and aged Rats treated with testosterone. Taken together, these results indicate that the prostate of Brown Norway Rats shows age and lobe-specific responses to androgen with respect to wet weight, protein content, cell number, and cell morphology.

Jack Uetrecht - One of the best experts on this subject based on the ideXlab platform.

  • Investigation of the involvement of macrophages and T cells in D-penicillamine-induced autoimmunity in the Brown Norway Rat.
    Journal of immunotoxicology, 2004
    Co-Authors: Mary Jane Masson, Munehiro Teranishi, Jacintha M. Shenton, Jack Uetrecht
    Abstract:

    The initiating events in drug-induced autoimmunity are poorly understood and difficult to study. We examined the role of macrophages and T-cells in the Brown Norway Rat model of D-penicillamine-induced autoimmunity. When activated, macrophages can act as both antigen presenting cells, initiating immune responses, and as phagocytic cells mediating systemic tissue damage. We found that B7+ macrophages are the major antigen-presenting cell type infiltRating the spleen and caecum early in the response to Dpenicillamine. As well, the increase in splenic B7+ macrophages correlates with the incidence of autoimmune disease. Treatments that increase the incidence of disease accentuate the increase in splenic B7+ macrophages, and treatments that prevent disease also prevent the increase in B7+ macrophages. In vivo depletion of macrophages appeared to decrease, but not totally prevent, autoimmune disease. The role of T-cells in D-penicillamine-induced autoimmunity was also examined using the T-cell inhibitor tacroli...

  • D-penicillamine-induced autoimmunity in the Brown Norway Rat: role for both T and non-T splenocytes in adoptive transfer of tolerance.
    Chemical research in toxicology, 2004
    Co-Authors: Béatrice Séguin, Mary Jane Masson, Jack Uetrecht
    Abstract:

    The D-penicillamine autoimmune syndrome observed in Brown Norway (BN) Rats is similar to an idiosyncRatic reaction seen in some patients. We have previously shown that 2 weeks of low dose (5 mg/day) D-penicillamine pretreatment completely prevented all clinical signs of autoimmunity normally observed in 60-80% of Rats treated with high dose (20 mg/day) D-penicillamine. We demonstRated that this tolerance is immune-mediated; tolerance to D-penicillamine is long lasting, we can adoptively transfer splenocytes from tolerant Rats into slightly irradiated naive syngeneic recipients, and Rats exposed to low dose D-penicillamine produce tolerogenic cytokines [Masson, M. J., and Uetrecht, J. P. (2004) Tolerance induced by low dose D-penicillamine in the Brown Norway Rat model of drug-induced autoimmunity is immune-mediated. Chem. Res. Toxicol. 17, 82-94]. The aim of this study was to provide further understanding of the cells that are responsible for transferring tolerance and to assess the presence of regulatory T cells in the spleen of tolerant animals. We cotransferred T cells or splenocytes depleted of T cells from tolerant BN Rats with splenocytes from naive BN Rats into lightly irradiated syngeneic recipients. We found that neither tolerant splenocyte subpopulation could completely prevent clinical signs of autoimmunity. These results demonstRate that immune tolerance to D-penicillamine-induced autoimmunity may require both antigen presenting cells and T cells.

  • Tolerance induced by low dose D-penicillamine in the Brown Norway Rat model of drug-induced autoimmunity is immune-mediated.
    Chemical research in toxicology, 2004
    Co-Authors: Mary Jane Masson, Jack Uetrecht
    Abstract:

    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.

Ching-yuang Lin - One of the best experts on this subject based on the ideXlab platform.

Related terms

Brown Norway Rat - 15 days free trial to Access Experts & Abstracts