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Mary E Russell - One of the best experts on this subject based on the ideXlab platform.
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echocardiography improves detection of Rejection after heterotopic mouse Cardiac transplantation
Journal of The American Society of Echocardiography, 2002Co-Authors: Marielle Scherrercrosbie, Troels Glysingjensen, Stefanie J Fry, Anneclaire Vancon, Silpa Gadiraju, Michael H Picard, Mary E RussellAbstract:Abstract Background: Current assessments of Cardiac Rejection in murine transplant models rely on subjective estimates of the force of the palpable heart beat that have limited sensitivity and precision. Methods: We used 2-dimensional echocardiography to evaluate changes in left ventricular posterior wall thickness (PWT) in a heterotopic Cardiac mouse transplant model of Rejection. Nine allografts and 6 isografts were imaged daily for 6 days and harvested. Thirteen allografts were imaged daily and harvested at day 3. Results: Intraobserver variability on PWT was 0.003 ± 0.09 mm, interobserver variability 0.09 ± 0.11 mm. Allograft PWT increased after transplantation (0.74 ± 0.02 mm to 1.28 ± 0.05 mm at day 5, P P P Conclusion: Two-dimensional echocardiography allows the noninvasive detection and follow-up of Cardiac Rejection after transplantation. It eliminates the subjectivity of palpation and provides quantitative and reliable indices of Rejection. (J Am Soc Echocardiogr 2002;15:1315-20.)
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exacerbated transplant arteriosclerosis in inducible nitric oxide deficient mice
Circulation, 1998Co-Authors: Jorg Koglin, Troels Glysingjensen, John S Mudgett, Mary E RussellAbstract:Background—Inducible NO synthase (NOS2, or iNOS) is upregulated in grafts with transplant arteriosclerosis. However, the functional role of NOS2 in the pathogenesis of transplant arteriosclerosis remains unclear. NOS2 may regulate lesion development by modulating the early alloimmune response and/or late myointimal thickening. Methods and Results—To determine whether NOS2-mediated pathways protect against or promote transplant arteriosclerosis, we used NOS2-deficient mice as recipients in our vascularized chronic Cardiac Rejection model. The severity of vascular thickening in 55-day grafts placed into NOS2 −/− recipients (n=13) was compared with that in wild-type recipients (n=15). Computer-assisted analysis of all elastin-stained vessels (n=283) showed significantly increased luminal occlusion (77.1±9.4% versus 40.8±13.6%, P<.0001) and intima/media ratios in allografts from NOS2 −/− recipients (1.9±1.3 versus 0.4±0.3, P=.0002). To elucidate potential mechanisms, we studied NOS2 effects on T-cell differen...
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chronic Cardiac Rejection in the lew to f344 rat model blockade of cd28 b7 costimulation by ctla4ig modulates t cell and macrophage activation and attenuates arteriosclerosis
Journal of Clinical Investigation, 1996Co-Authors: Mary E Russell, Troels Glysingjensen, Wayne W Hancock, Enver Akalin, Africa F Wallace, Theresa A Willett, Mohamed H SayeghAbstract:CTLA4Ig, a fusion protein that blocks CD28-B7 costimulation, was studied in a LEW to F344 rat model of chronic Cardiac Rejection. In rats treated with a single dose of CTLA4Ig (0.5 mg intraperitoneally) 2 d after transplantation, allografts survived significantly longer ( > 70 d in 64%) than in untreated controls or rats treated with control Ig (all rejected within 25 d). Only 25% of grafts from rats treated with a single, high dose of cyclosporine A (25 mg/kg, 2 d after transplantation) survived longer than 70 d. Reverse transcriptase PCR and immunostaining analyses of tissue from 75-d, CTLA4Ig-treated allografts showed reduced expression of the T cell factor IFN-gamma and macrophage activation factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as well as TGF-beta. Grafts from longterm survivors ( > 120 d) treated with CTLA4Ig showed significant reductions in the frequency and severity of arteriosclerosis in comparison with cyclosporine A-treated rats. Thus, T cell activation is a proximal event in the cascade that culminates in the arteriosclerosis of chronic Rejection. Strategies for blocking T cell costimulation may help prevent chronic Rejection in clinical transplantation.
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upregulation and modulation of inducible nitric oxide synthase in rat Cardiac allografts with chronic Rejection and transplant arteriosclerosis
Circulation, 1995Co-Authors: Mary E Russell, Lauri R Wyner, Africa F Wallace, John B Newell, Morris J KarnovskyAbstract:Background The Lewis-F344 rat Cardiac transplantation model produces Cardiac allografts with chronic Rejection characterized by arteriosclerotic lesions composed of macrophages and smooth muscle cells. Modulation of the inflammatory response with a diet deficient in essential fatty acids protects against the development of intimal thickening. Little is known about the components of the inflammatory response mediating this process. The cytokine-inducible isoform of nitric oxide synthase (iNOS) regulates the high-output nitric oxide pathway that confers activation properties to macrophages and regulates vasomotion, monocyte adherence, and smooth muscle cell proliferation in the vasculature. The purpose of the present study was to determine whether the iNOS pathway was upregulated during the course of chronic Cardiac Rejection. Methods and Results We studied iNOS mRNA and protein expression patterns in a series of Lewis-F344 Cardiac allografts with early and late chronic Rejection and after modulation of the inflammatory response (in an effort to attenuate arteriosclerosis). Relative gene transcript levels were measured with a 32P-dCTP reverse-transcriptase polymerase chain reaction assay designed to amplify iNOS mRNA. The distribution of the iNOS gene product was examined by immunocytochemistry with a polyclonal antibody against iNOS. NOS transcript levels increased significantly in Cardiac allografts (days 7, 14, 28, and 75) compared with paired host hearts (exposed to the same circulation) and syngrafts ( P <.003). Immunostaining localized the iNOS antigen within subpopulations of mononuclear inflammatory cells in Cardiac allografts—presumably, activated macrophages. The number of iNOS-positive mononuclear cells was 25-fold higher in Cardiac allografts compared with paired host hearts and syngrafts ( P <.009). In Cardiac allografts of 75 days or older, there also was striking iNOS staining within some medial and intimal smooth muscle cells in various vessels. Modulation of the inflammatory response (with a diet deficient in essential fatty acids) produced significant decreases in the intimal thickening score and in the percentage of diseased vessels in 28-day Cardiac allografts compared with allografts from rats fed a control diet. There was a correlate decrease in iNOS transcript levels and in the number of iNOS-positive mononuclear cells in the 28-day Cardiac allografts from rats fed the essential fatty acid-deficient diet. Conclusions The early and persistent upregulation of iNOS in chronic Cardiac Rejection and the coincident reduction in arteriosclerosis and downregulation of iNOS suggest that this inducible regulator may contribute to the inflammatory response mediating transplant arteriosclerosis.
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cloning and characterization of allograft inflammatory factor 1 a novel macrophage factor identified in rat Cardiac allografts with chronic Rejection
Journal of Clinical Investigation, 1995Co-Authors: Ulrike Utans, Robert J Arceci, Yukari Yamashita, Mary E RussellAbstract:The development of arteriosclerotic lesions in the Lewis to F344 rat model of chronic Cardiac Rejection is characterized by macrophage adhesion to the vessel lumen and macrophage infiltration in the neointima prior to smooth muscle cell accumulation. We report the cloning and characterization of allograft inflammatory factor-1 (AIF-1), a novel cDNA that is expressed early and persistently in chronically rejecting Cardiac allografts but is absent in Cardiac syngrafts and host hearts. The full-length cDNA codes for a hydrophilic polypeptide of 17 kD that contains a 12-amino acid region similar to an EF-hand (calcium-binding) domain. In Cardiac allografts AIF-1 transcripts and protein localized to infiltrating mononuclear cells. Analysis of isolated cell populations confirmed that AIF-1 was selectively expressed in macrophages and neutrophils and demonstrated that AIF-1 transcripts could be upregulated by sixfold after stimulation with the T cell-derived cytokine IFN-gamma. Treatment with a diet deficient in essential fatty acids (which attenuates arteriosclerosis) or CTLA-4 Ig (which blocks lymphocyte activation) significantly decreased AIF-1 transcript levels. Upregulation of AIF-1 in the setting of T cell activation suggests that it may play a role in macrophage activation and function.
Bruce M Mcmanus - One of the best experts on this subject based on the ideXlab platform.
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exosomal mir 142 3p is increased during Cardiac allograft Rejection and augments vascular permeability through down regulation of endothelial rab11fip2 expression
Cardiovascular Research, 2017Co-Authors: Ihdina Sukma Dewi, Selvi Celik, Anna Karlsson, Zsuzsanna Hollander, Karen K Lam, Janet Wilson Mcmanus, Scott J Tebbutt, Paul Keown, Robert Mcmaster, Bruce M McmanusAbstract:AIMS: Exosome-mediated microRNA transfer is a recently discovered mode of cell-to-cell communication, in which microRNAs act as paracrine molecules, exerting their regulatory effects in recipient cells. T cells and endothelial cells are two main players in the mechanism of acute cellular Cardiac Rejection. The aim of this study was to investigate the role of exosomal microRNAs in the crosstalk between T cells and endothelial cells and its implications for the molecular mechanisms that drive acute cellular Rejection in heart transplantation.METHODS AND RESULTS: Exosomes isolated from serum samples of heart transplant patients with and without acute Cardiac allograft Rejection were profiled and showed enrichment of miR-142-3p, miR-92a-3p, miR-339-3p and miR-21-5p. Treatment of endothelial cells with the respected serum exosomes resulted the increased of miR-142-3p level in endothelial cells. Using T cells isolated from healthy donors and activated with either anti-CD3/CD28 antibody or IL-2/PHA, we could show that miR-142-3p is released from activated cells, is contained in exosomes and can be transferred to human vascular endothelial cells in vitro. Transcriptome analysis of endothelial cells treated with activated T cell supernatant with or without exosomes was used to identify mRNA targets of transferred miR-142-3-p. Overexpression of miR-142-3p in endothelial cells resulted in a significant down-regulation of RAB11FIP2, and interaction of miR-142-3p with its predicted target site was confirmed with a reporter assay. Moreover, treatment of endothelial cells with serum exosomes from heart transplant patients with acute cellular Rejection resulted in down-regulation of RAB11FIP2 expression and increase in vascular endothelial permeability.CONCLUSION: We have identified a novel mechanism whereby miR-142-3p, a microRNA enriched in exosomes during acute cellular Rejection, is transferred to endothelial cells and compromises endothelial barrier function via down-regulation of RAB11FIP2. This study sheds new light on the interaction between host immune system and Cardiac allograft endothelium during acute cellular Rejection. (Less)
Morris J Karnovsky - One of the best experts on this subject based on the ideXlab platform.
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upregulation and modulation of inducible nitric oxide synthase in rat Cardiac allografts with chronic Rejection and transplant arteriosclerosis
Circulation, 1995Co-Authors: Mary E Russell, Lauri R Wyner, Africa F Wallace, John B Newell, Morris J KarnovskyAbstract:Background The Lewis-F344 rat Cardiac transplantation model produces Cardiac allografts with chronic Rejection characterized by arteriosclerotic lesions composed of macrophages and smooth muscle cells. Modulation of the inflammatory response with a diet deficient in essential fatty acids protects against the development of intimal thickening. Little is known about the components of the inflammatory response mediating this process. The cytokine-inducible isoform of nitric oxide synthase (iNOS) regulates the high-output nitric oxide pathway that confers activation properties to macrophages and regulates vasomotion, monocyte adherence, and smooth muscle cell proliferation in the vasculature. The purpose of the present study was to determine whether the iNOS pathway was upregulated during the course of chronic Cardiac Rejection. Methods and Results We studied iNOS mRNA and protein expression patterns in a series of Lewis-F344 Cardiac allografts with early and late chronic Rejection and after modulation of the inflammatory response (in an effort to attenuate arteriosclerosis). Relative gene transcript levels were measured with a 32P-dCTP reverse-transcriptase polymerase chain reaction assay designed to amplify iNOS mRNA. The distribution of the iNOS gene product was examined by immunocytochemistry with a polyclonal antibody against iNOS. NOS transcript levels increased significantly in Cardiac allografts (days 7, 14, 28, and 75) compared with paired host hearts (exposed to the same circulation) and syngrafts ( P <.003). Immunostaining localized the iNOS antigen within subpopulations of mononuclear inflammatory cells in Cardiac allografts—presumably, activated macrophages. The number of iNOS-positive mononuclear cells was 25-fold higher in Cardiac allografts compared with paired host hearts and syngrafts ( P <.009). In Cardiac allografts of 75 days or older, there also was striking iNOS staining within some medial and intimal smooth muscle cells in various vessels. Modulation of the inflammatory response (with a diet deficient in essential fatty acids) produced significant decreases in the intimal thickening score and in the percentage of diseased vessels in 28-day Cardiac allografts compared with allografts from rats fed a control diet. There was a correlate decrease in iNOS transcript levels and in the number of iNOS-positive mononuclear cells in the 28-day Cardiac allografts from rats fed the essential fatty acid-deficient diet. Conclusions The early and persistent upregulation of iNOS in chronic Cardiac Rejection and the coincident reduction in arteriosclerosis and downregulation of iNOS suggest that this inducible regulator may contribute to the inflammatory response mediating transplant arteriosclerosis.
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chronic Cardiac Rejection identification of five upregulated genes in transplanted hearts by differential mrna display
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Ulrike Utans, Peng Liang, Lauri R Wyner, Morris J Karnovsky, Mary E RussellAbstract:Abstract Transplant arteriosclerosis, the major manifestation of chronic Rejection, develops after allogeneic (Lewis to F344) but not syngeneic (Lewis to Lewis) rat Cardiac transplantation. To identify transcriptionally regulated mediators associated with chronic Cardiac Rejection, we adapted the differential mRNA display technique for in vivo transplant specimens. Gene transcript patterns in four allogeneic hearts showing early signs of chronic Rejection were compared with those in two syngeneic hearts exposed to the same surgical procedure but histologically normal. Twelve differentially expressed cDNA bands were identified. We improved the probability of isolating one or more allograft-specific cDNAs from a single display band by first using recovered and reamplified PCR products as probes in RNA blot analysis. cDNA fragments cloned from individual bands were then used in a second RNA blot analysis, which allowed for the correlation of specific mRNA transcripts with cDNA clones. Five cDNA clones produced time-dependent, allograft-specific hybridization. Sequence analysis demonstrated that two of these cDNAs corresponded to unknown genes, whereas the other three represented known genes not previously associated with chronic Rejection. The latter group included the macrophage lectin specific for galactose/N-acetylgalactosamine (a cell-surface receptor), the nuclear P1 gene (a homologue of a yeast replication protein), and a ubiquitin-like gene. Our application of the differential display technique allowed the direct identification of potential mediators under in vivo conditions that preserve the environment of the disease process--including infiltrating cell populations critical to the inflammatory response.
Ihdina Sukma Dewi - One of the best experts on this subject based on the ideXlab platform.
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exosomal mir 142 3p is increased during Cardiac allograft Rejection and augments vascular permeability through down regulation of endothelial rab11fip2 expression
Cardiovascular Research, 2017Co-Authors: Ihdina Sukma Dewi, Selvi Celik, Anna Karlsson, Zsuzsanna Hollander, Karen K Lam, Janet Wilson Mcmanus, Scott J Tebbutt, Paul Keown, Robert Mcmaster, Bruce M McmanusAbstract:AIMS: Exosome-mediated microRNA transfer is a recently discovered mode of cell-to-cell communication, in which microRNAs act as paracrine molecules, exerting their regulatory effects in recipient cells. T cells and endothelial cells are two main players in the mechanism of acute cellular Cardiac Rejection. The aim of this study was to investigate the role of exosomal microRNAs in the crosstalk between T cells and endothelial cells and its implications for the molecular mechanisms that drive acute cellular Rejection in heart transplantation.METHODS AND RESULTS: Exosomes isolated from serum samples of heart transplant patients with and without acute Cardiac allograft Rejection were profiled and showed enrichment of miR-142-3p, miR-92a-3p, miR-339-3p and miR-21-5p. Treatment of endothelial cells with the respected serum exosomes resulted the increased of miR-142-3p level in endothelial cells. Using T cells isolated from healthy donors and activated with either anti-CD3/CD28 antibody or IL-2/PHA, we could show that miR-142-3p is released from activated cells, is contained in exosomes and can be transferred to human vascular endothelial cells in vitro. Transcriptome analysis of endothelial cells treated with activated T cell supernatant with or without exosomes was used to identify mRNA targets of transferred miR-142-3-p. Overexpression of miR-142-3p in endothelial cells resulted in a significant down-regulation of RAB11FIP2, and interaction of miR-142-3p with its predicted target site was confirmed with a reporter assay. Moreover, treatment of endothelial cells with serum exosomes from heart transplant patients with acute cellular Rejection resulted in down-regulation of RAB11FIP2 expression and increase in vascular endothelial permeability.CONCLUSION: We have identified a novel mechanism whereby miR-142-3p, a microRNA enriched in exosomes during acute cellular Rejection, is transferred to endothelial cells and compromises endothelial barrier function via down-regulation of RAB11FIP2. This study sheds new light on the interaction between host immune system and Cardiac allograft endothelium during acute cellular Rejection. (Less)
Troels Glysingjensen - One of the best experts on this subject based on the ideXlab platform.
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echocardiography improves detection of Rejection after heterotopic mouse Cardiac transplantation
Journal of The American Society of Echocardiography, 2002Co-Authors: Marielle Scherrercrosbie, Troels Glysingjensen, Stefanie J Fry, Anneclaire Vancon, Silpa Gadiraju, Michael H Picard, Mary E RussellAbstract:Abstract Background: Current assessments of Cardiac Rejection in murine transplant models rely on subjective estimates of the force of the palpable heart beat that have limited sensitivity and precision. Methods: We used 2-dimensional echocardiography to evaluate changes in left ventricular posterior wall thickness (PWT) in a heterotopic Cardiac mouse transplant model of Rejection. Nine allografts and 6 isografts were imaged daily for 6 days and harvested. Thirteen allografts were imaged daily and harvested at day 3. Results: Intraobserver variability on PWT was 0.003 ± 0.09 mm, interobserver variability 0.09 ± 0.11 mm. Allograft PWT increased after transplantation (0.74 ± 0.02 mm to 1.28 ± 0.05 mm at day 5, P P P Conclusion: Two-dimensional echocardiography allows the noninvasive detection and follow-up of Cardiac Rejection after transplantation. It eliminates the subjectivity of palpation and provides quantitative and reliable indices of Rejection. (J Am Soc Echocardiogr 2002;15:1315-20.)
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exacerbated transplant arteriosclerosis in inducible nitric oxide deficient mice
Circulation, 1998Co-Authors: Jorg Koglin, Troels Glysingjensen, John S Mudgett, Mary E RussellAbstract:Background—Inducible NO synthase (NOS2, or iNOS) is upregulated in grafts with transplant arteriosclerosis. However, the functional role of NOS2 in the pathogenesis of transplant arteriosclerosis remains unclear. NOS2 may regulate lesion development by modulating the early alloimmune response and/or late myointimal thickening. Methods and Results—To determine whether NOS2-mediated pathways protect against or promote transplant arteriosclerosis, we used NOS2-deficient mice as recipients in our vascularized chronic Cardiac Rejection model. The severity of vascular thickening in 55-day grafts placed into NOS2 −/− recipients (n=13) was compared with that in wild-type recipients (n=15). Computer-assisted analysis of all elastin-stained vessels (n=283) showed significantly increased luminal occlusion (77.1±9.4% versus 40.8±13.6%, P<.0001) and intima/media ratios in allografts from NOS2 −/− recipients (1.9±1.3 versus 0.4±0.3, P=.0002). To elucidate potential mechanisms, we studied NOS2 effects on T-cell differen...
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chronic Cardiac Rejection in the lew to f344 rat model blockade of cd28 b7 costimulation by ctla4ig modulates t cell and macrophage activation and attenuates arteriosclerosis
Journal of Clinical Investigation, 1996Co-Authors: Mary E Russell, Troels Glysingjensen, Wayne W Hancock, Enver Akalin, Africa F Wallace, Theresa A Willett, Mohamed H SayeghAbstract:CTLA4Ig, a fusion protein that blocks CD28-B7 costimulation, was studied in a LEW to F344 rat model of chronic Cardiac Rejection. In rats treated with a single dose of CTLA4Ig (0.5 mg intraperitoneally) 2 d after transplantation, allografts survived significantly longer ( > 70 d in 64%) than in untreated controls or rats treated with control Ig (all rejected within 25 d). Only 25% of grafts from rats treated with a single, high dose of cyclosporine A (25 mg/kg, 2 d after transplantation) survived longer than 70 d. Reverse transcriptase PCR and immunostaining analyses of tissue from 75-d, CTLA4Ig-treated allografts showed reduced expression of the T cell factor IFN-gamma and macrophage activation factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as well as TGF-beta. Grafts from longterm survivors ( > 120 d) treated with CTLA4Ig showed significant reductions in the frequency and severity of arteriosclerosis in comparison with cyclosporine A-treated rats. Thus, T cell activation is a proximal event in the cascade that culminates in the arteriosclerosis of chronic Rejection. Strategies for blocking T cell costimulation may help prevent chronic Rejection in clinical transplantation.