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Maxime Breban - One of the best experts on this subject based on the ideXlab platform.

  • Tolerogenic XCR1+ dendritic cell population is dysregulated in HLA-B27 Transgenic Rat model of spondyloarthritis.
    Arthritis Research & Therapy, 2019
    Co-Authors: Kétia Ermoza, Simon Glatigny, Nadège Jah, Vânia Camilo, Hendrick Mambu Mambueni, Gilles Chiocchia, Luiza M. Araujo, Maxime Breban
    Abstract:

    Spondyloarthritis (SpA) is a chronic inflammatory disease affecting primarily axial and peripheral joints and sometimes also extra-articular organs, such as the gut. Rats Transgenic for HLA-B27 and human β2-microglobulin (B27-Tg Rat) develop clinical manifestations resembling human disease. In this model, it has been shown that CD103+ conventional dendritic cells (cDCs) exhibited altered functions, likely promoting SpA development. CD4− cDC subpopulation expressing XCR1, a chemokine receptor involved in their migRation, have been described to be tolerogenic in steady state. Thus, in this study, we wished to examine the fate of XCR1+ cDCs in this animal model of SpA. cDC populations were isolated from the spleen, mesenteric lymph nodes (MLN), and colonic lamina propria from B27-TG and control nonTransgenic (NTG) and/or HLA-B7 Transgenic Rats after collagenase digestion and density gradient and characterized with flow cytometry or real-time PCR. MigRation of cDCs from intestinal mucosa to MLN was assessed, using TLR-7 stimulation with Resiquimod. We observed a reduced frequency of cCD4− DCs in B27-Tg Rats, as compared to control Rats. Furthermore, such decrease was not due to excessive death of CD4− cDCs in B27-Tg Rats. Interestingly, we observed a decrease frequency of the XCR1+ subpopulation among CD4− cDCs in the spleen, MLN, and lamina propria from B27-Tg Rats. Finally, after TLR-7 stimulation, the migRation of XCR1+ cDCs to MLN was proportionally reduced in B27-Tg Rats. Our results demonstRate for the first time a decreased proportion of the tolerogenic XCR1+ cDC subpopulation in SpA target organs in B27-Tg Rat, which may affect the maintenance of self-tolerance and control of inflammation.

  • Additional file 4: of Tolerogenic XCR1+ dendritic cell population is dysregulated in HLA-B27 Transgenic Rat model of spondyloarthritis
    2019
    Co-Authors: Kétia Ermoza, Simon Glatigny, Nadège Jah, Vânia Camilo, Hendrick Mambu Mambueni, Luiza Araujo, Gilles Chiocchia, Maxime Breban
    Abstract:

    Figure S4. The whole population of CD103+ cDCs is increased but not the CD4+ cDCs, in B27-Tg Rat colonic lamina propria. Mononuclear cells were isolated form the colonic lamina propria and stained with anti-CD103 and anti-CD45 mAbs. The graphs show the frequency (A) and absolute number (B) of CD103+ cDCs among CD45RC− cDCs in NTG and B27-Tg Rats. The graphs show the frequency (C) and absolute number (D) of CD4+ cDCs among CD103 + cDCs in NTG and B27-Tg Rats. This experiment was repeated 7–8 times. Bars show the mean ± SEM. Data were analyzed by unpaired Student’s t test. (PDF 66 kb

  • Tolerogenic XCR1+ dendritic cell population is dysregulated in HLA-B27 Transgenic Rat model of spondyloarthritis
    BMC, 2019
    Co-Authors: Kétia Ermoza, Simon Glatigny, Nadège Jah, Vânia Camilo, Hendrick Mambu Mambueni, Gilles Chiocchia, Luiza M. Araujo, Maxime Breban
    Abstract:

    Abstract Background Spondyloarthritis (SpA) is a chronic inflammatory disease affecting primarily axial and peripheral joints and sometimes also extra-articular organs, such as the gut. Rats Transgenic for HLA-B27 and human β2-microglobulin (B27-Tg Rat) develop clinical manifestations resembling human disease. In this model, it has been shown that CD103+ conventional dendritic cells (cDCs) exhibited altered functions, likely promoting SpA development. CD4− cDC subpopulation expressing XCR1, a chemokine receptor involved in their migRation, have been described to be tolerogenic in steady state. Thus, in this study, we wished to examine the fate of XCR1+ cDCs in this animal model of SpA. Methods cDC populations were isolated from the spleen, mesenteric lymph nodes (MLN), and colonic lamina propria from B27-TG and control nonTransgenic (NTG) and/or HLA-B7 Transgenic Rats after collagenase digestion and density gradient and characterized with flow cytometry or real-time PCR. MigRation of cDCs from intestinal mucosa to MLN was assessed, using TLR-7 stimulation with Resiquimod. Results We observed a reduced frequency of cCD4− DCs in B27-Tg Rats, as compared to control Rats. Furthermore, such decrease was not due to excessive death of CD4− cDCs in B27-Tg Rats. Interestingly, we observed a decrease frequency of the XCR1+ subpopulation among CD4− cDCs in the spleen, MLN, and lamina propria from B27-Tg Rats. Finally, after TLR-7 stimulation, the migRation of XCR1+ cDCs to MLN was proportionally reduced in B27-Tg Rats. Conclusion Our results demonstRate for the first time a decreased proportion of the tolerogenic XCR1+ cDC subpopulation in SpA target organs in B27-Tg Rat, which may affect the maintenance of self-tolerance and control of inflammation

  • The HLA-B27 Transgenic Rat, a model of spondyloarthritis, has decreased bone mineral density and increased RANKL to osteoprotegerin mRNA Ratio.
    The Journal of Rheumatology, 2009
    Co-Authors: Martina Rauner, Simon Glatigny, Maxime Breban, Daniela Stupphann, Martin Haas, Ingrid Fert, Wolfgang Sipos, Peter Pietschmann
    Abstract:

    Objective. Bone metabolism in spondyloarthritis (SpA) is not well elucidated. We investigated alteRations in bone in the HLA-B27 Transgenic Rat, a model of SpA. Methods. Femur, tibia, and lumbar vertebral bodies of disease-prone HLA-B27 Transgenic, healthy HLA-B7 Transgenic, and nonTransgenic control Rats were used for bone histomorphometric and dual energy x-ray absorptiometry (DEXA) analysis. Serum levels of type I collagen C-telopeptides (CTX), N-terminal propeptide of type I procollagen (P1NP), and osteocalcin, as well as receptor activator of nuclear factor-κ B ligand (RANKL) and osteoprotegerin (OPG), were measured. RNA was isolated from the bone tissue of the femura to analyze gene expression of RANKL, OPG, and osteocalcin. Results. Histomorphometric analysis indicated a significant decrease in bone volume as well as trabecular number and thickness in the HLA-B27 Rats. Trabecular sepaRation was increased. Numbers of osteoblasts, osteoclasts, and osteoid volume were not altered significantly. The decrease in bone mineral density was confirmed using DEXA. Levels of RANKL mRNA were significantly increased in the bone tissue of HLA-B27 Transgenic Rats, resulting in an increased RANKL to OPG Ratio. Osteocalcin mRNA expression was also significantly elevated in bone of HLA-B27 Rats. Serum levels of CTX, RANKL, OPG, P1NP, and osteocalcin did not differ significantly. Conclusion. Our data indicate that, similarly to SpA in humans, HLA-B27 Transgenic Rats show a reduced bone mass, and suggest an involvement of the RANKL/OPG system in the mechanism of bone loss in this disease. This model may be adequate to study osteoporosis in SpA.

  • AlteRation of antigen‐independent immunologic synapse formation between dendritic cells from HLA–B27–Transgenic Rats and CD4+ T cells: Selective impairment of costimulatory molecule engagement by mature HLA–B27
    Arthritis & Rheumatism, 2007
    Co-Authors: Cécile Hacquard-bouder, Ingrid Fert, Claudine André, Maria-sole Chimenti, Benoît Giquel, Emmanuel Donnadieu, Alain Schmitt, Maxime Breban
    Abstract:

    Objective To investigate the molecular mechanism responsible for the reduced capacity of dendritic cells (DCs) from HLA–B27–Transgenic Rats to form conjugates with naive T cells. Methods We monitored interactions between DCs derived from HLA–B27–Transgenic, HLA–B7–Transgenic control, and nonTransgenic Rats and naive CD4+ T cells. Chemoattraction was studied in Transwell assays, and the formation of an immunologic synapse was examined by videomicroscopy and electron microscopy. Involvement of specific molecules in the defective interaction was examined in antibody-blocking assays. Results T cells migRated normally toward B27 DCs, but upon contact, the frequency of T cells undergoing a Ca2+ response was decreased, indicating impaired immunologic synapse formation. The immunologic synapse formed between B27 DCs and T cells appeared to be normal, as assessed by electron microscopy and by the Ca2+ response. Blocking lymphocyte function−associated antigen 1 on T cells or blocking activated leukocyte cell adhesion molecules on DCs inhibited an equivalent proportion of conjugates from forming between B27 or control DCs and T cells, whereas blocking CD86 on DCs and blocking CD28, CD2, or CD4 on T cells inhibited a greater number of conjugates from forming with control DCs, indicating specific involvement of costimulatory molecules in the reduced formation of conjugates with B27 DCs. Mature B27 molecules on the DC surface were responsible for this decreased formation of conjugates. Conclusion In the HLA–B27–Transgenic Rat model of spondylarthropathy, mature B27 molecules expressed by DCs impair the formation of an antigen-independent immunologic synapse with naive CD4+ T cells by interfering with the engagement of costimulatory molecules. This phenomenon could potentially affect the production and/or maintenance of regulatory T cells and contribute to the expansion of pathogenic CD4+ T cells.

James C Keith - One of the best experts on this subject based on the ideXlab platform.

  • A monoclonal antibody against kininogen reduces inflammation in the HLA-B27 Transgenic Rat
    Arthritis Research & Therapy, 2005
    Co-Authors: James C Keith, Leo M Albert, Yelena Leathurby, Irma M Sainz, Irma Isordia-salas, Robin A Pixley, Robert W Colman
    Abstract:

    The human leukocyte antigen B27 (HLA-B27) Transgenic Rat is a model of human inflammatory bowel disease, rheumatoid arthritis and psoriasis. Studies of chronic inflammation in other Rat models have demonstRated activation of the kallikrein–kinin system as well as modulation by a plasma kallikrein inhibitor initiated before the onset of clinicopathologic changes or a deficiency in high-molecular-mass kininogen. Here we study the effects of monoclonal antibody C11C1, an antibody against high-molecular-mass kininogen that inhibits the binding of high-molecular-mass kininogen to leukocytes and endothelial cells in the HLA-B27 Rat, which was administered after the onset of the inflammatory changes. Thrice-weekly intraperitoneal injections of monoclonal antibody C11C1 or isotype IgG_1 were given to male 23-week-old Rats for 16 days. Stool character as a measure of intestinal inflammation, and the rear limbs for clinical signs of arthritis (tarsal joint swelling and erythema) were scored daily. The animals were killed and the histology sections were assigned a numerical score for colonic inflammation, synovitis, and cartilage damage. AdministRation of monoclonal C11C1 rapidly decreased the clinical scores of pre-existing inflammatory bowel disease ( P < 0.005) and arthritis ( P < 0.001). Histological analyses confirmed significant reductions in colonic lesions ( P = 0.004) and synovitis ( P = 0.009). Decreased concentRations of plasma prekallikrein and high-molecular-mass kininogen were found, providing evidence of activation of the kallikrein–kinin system. The levels of these biomarkers were reversed by monoclonal antibody C11C1, which may have therapeutic potential in human inflammatory bowel disease and arthritis.

  • The utility of pathway selective estrogen receptor ligands that inhibit nuclear factor-κB transcriptional activity in models of rheumatoid arthritis
    Arthritis Research & Therapy, 2005
    Co-Authors: James C Keith, Leo M Albert, Yelena Leathurby, Max Follettie, Lisa Borges-marcucci, Christopher C Chadwick, Robert J Steffan, Lili Wang, Douglas C Harnish
    Abstract:

    Rheumatoid arthritis (RA) is a chronic inflammatory disease that produces synovial prolifeRation and joint erosions. The pathologic lesions of RA are driven through the production of inflammatory mediators in the synovium mediated, in part, by the transcription factor NF-κB. We have identified a non-steroidal estrogen receptor ligand, WAY-169916, that selectively inhibits NF-κB transcriptional activity but is devoid of conventional estrogenic activity. The activity of WAY-169916 was monitored in two models of arthritis, the HLA-B27 Transgenic Rat and the Lewis Rat adjuvant-induced model, after daily oral administRation. In both models, a near complete reversal in hindpaw scores was observed as well as marked improvements in the histological scores. In the Lewis Rat adjuvant model, WAY-169916 markedly suppresses the adjuvant induction of three serum acute phase proteins: haptoglobin, α1-acid glycoprotein (α1-AGP), and C-reactive protein (CRP). Gene expression experiments also demonstRate a global suppression of adjuvant-induced gene expression in the spleen, liver, and popliteal lymph nodes. Finally, WAY-169916 was effective in suppressing tumor necrosis factor-α-mediated inflammatory gene expression in fibroblast-like synoviocytes isolated from patients with RA. Together, these data suggest the utility of WAY-169916, and other compounds in its class, in treating RA through global suppression of inflammation via selective blockade of NF-κB transcriptional activity.

  • Identification of pathway-selective estrogen receptor ligands that inhibit NF-κB transcriptional activity
    Proceedings of the National Academy of Sciences, 2005
    Co-Authors: Christopher C Chadwick, Leo M Albert, Yelena Leathurby, Lisa Borges-marcucci, James C Keith, Amy Eckert, Susan Chippari, Edward Martin Matelan, Heather A. Harris, Ramesh A. Bhat
    Abstract:

    Inflammation is now recognized as a key component in a number of diseases such as atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease. The transcription factor NF-κB has been shown to be involved in both the early and late stages of the inflammatory-prolifeRative process. In this report, we describe the identification of the pathway-selective estrogen receptor (ER) ligand, WAY-169916, that inhibits NF-κB transcriptional activity but is devoid of conventional estrogenic activity. This pathway-selective ligand does not promote the classic actions of estrogens such as stimulation of uterine prolifeRation or ER-mediated gene expression, but is a potent antiinflammatory agent, as demonstRated in the HLA-B27 Transgenic Rat model of inflammatory bowel disease. Our results indicate the potential utility of pathway-selective ER ligands such as WAY-169916 in the treatment of chronic inflammatory diseases.

  • A Monoclonal Antibody to High Molecular Weight Kininogen Reduces Inflammation in the HLA-B27 Transgenic Rat Model of Inflammatory Bowel Disease and Arthritis.
    Blood, 2004
    Co-Authors: Robin A Pixley, James C Keith, Irma M Sainz, Irma Isordia-salas, Yelena Leatherby, Leo Massillamone Albert, Robert W Colman
    Abstract:

    The HLA-B27 Rat is a well-characterized model of human bowel disease, rheumatoid arthritis and psoriasis. Previous studies of chronic inflammation in other Rat models of inflammatory disease have demonstRated activation of the kallilrein-kinin system (KKS) as well as modulation by a kallikrein inhibitor and HK deficiency. The effects of C11C1, a monoclonal antibody acting to inhibit cellular binding of high molecular weight kininogen (HK), were studied in the HLA-B27 Transgenic Rat. Thrice weekly intraperitoneal injections of C11C1 (1.9 mg/kg) or IgG1 (6mg/kg) were given to male HLA-B27 Transgenic Rats for 3 weeks, beginning when the Rats were 23 weeks old. Stool character was scored daily as a measure of intestinal inflammation, and the rear limbs were scored daily for clinical signs of arthritis, tarsal joint swelling and erythema. At the end of the experiment the animals were euthanized, and the colon and tarsal joint histologic lesions were examined. The histology sections were assigned a numerical score for colonic inflammation, synovitis, and cartilage damage. Activation of KKS was assessed by assays of plasma prekallikrein, HK, factor XI, and factor XII. AdministRation of the monoclonal antibody directed against HK rapidly decreased the clinical scores of inflammatory bowel disease from 3.0 ± 0 to 1.2 ± 0.2 (p

  • Beneficial effects of estrogen treatment in the HLA-B27 Transgenic Rat model of inflammatory bowel disease
    American Journal of Physiology-Gastrointestinal and Liver Physiology, 2004
    Co-Authors: Douglas C Harnish, Leo M Albert, Yelena Leathurby, Amy Eckert, Agnes Ciarletta, Marion Kasaian, James C Keith
    Abstract:

    A well-established model of bowel inflammation is the HLA-B27 Transgenic Rat that exhibits a spontaneous disease phenotype resulting in chronic diarrhea caused by immune cell activation. Estrogens ...

Leo M Albert - One of the best experts on this subject based on the ideXlab platform.

  • A monoclonal antibody against kininogen reduces inflammation in the HLA-B27 Transgenic Rat
    Arthritis Research & Therapy, 2005
    Co-Authors: James C Keith, Leo M Albert, Yelena Leathurby, Irma M Sainz, Irma Isordia-salas, Robin A Pixley, Robert W Colman
    Abstract:

    The human leukocyte antigen B27 (HLA-B27) Transgenic Rat is a model of human inflammatory bowel disease, rheumatoid arthritis and psoriasis. Studies of chronic inflammation in other Rat models have demonstRated activation of the kallikrein–kinin system as well as modulation by a plasma kallikrein inhibitor initiated before the onset of clinicopathologic changes or a deficiency in high-molecular-mass kininogen. Here we study the effects of monoclonal antibody C11C1, an antibody against high-molecular-mass kininogen that inhibits the binding of high-molecular-mass kininogen to leukocytes and endothelial cells in the HLA-B27 Rat, which was administered after the onset of the inflammatory changes. Thrice-weekly intraperitoneal injections of monoclonal antibody C11C1 or isotype IgG_1 were given to male 23-week-old Rats for 16 days. Stool character as a measure of intestinal inflammation, and the rear limbs for clinical signs of arthritis (tarsal joint swelling and erythema) were scored daily. The animals were killed and the histology sections were assigned a numerical score for colonic inflammation, synovitis, and cartilage damage. AdministRation of monoclonal C11C1 rapidly decreased the clinical scores of pre-existing inflammatory bowel disease ( P < 0.005) and arthritis ( P < 0.001). Histological analyses confirmed significant reductions in colonic lesions ( P = 0.004) and synovitis ( P = 0.009). Decreased concentRations of plasma prekallikrein and high-molecular-mass kininogen were found, providing evidence of activation of the kallikrein–kinin system. The levels of these biomarkers were reversed by monoclonal antibody C11C1, which may have therapeutic potential in human inflammatory bowel disease and arthritis.

  • The utility of pathway selective estrogen receptor ligands that inhibit nuclear factor-κB transcriptional activity in models of rheumatoid arthritis
    Arthritis Research & Therapy, 2005
    Co-Authors: James C Keith, Leo M Albert, Yelena Leathurby, Max Follettie, Lisa Borges-marcucci, Christopher C Chadwick, Robert J Steffan, Lili Wang, Douglas C Harnish
    Abstract:

    Rheumatoid arthritis (RA) is a chronic inflammatory disease that produces synovial prolifeRation and joint erosions. The pathologic lesions of RA are driven through the production of inflammatory mediators in the synovium mediated, in part, by the transcription factor NF-κB. We have identified a non-steroidal estrogen receptor ligand, WAY-169916, that selectively inhibits NF-κB transcriptional activity but is devoid of conventional estrogenic activity. The activity of WAY-169916 was monitored in two models of arthritis, the HLA-B27 Transgenic Rat and the Lewis Rat adjuvant-induced model, after daily oral administRation. In both models, a near complete reversal in hindpaw scores was observed as well as marked improvements in the histological scores. In the Lewis Rat adjuvant model, WAY-169916 markedly suppresses the adjuvant induction of three serum acute phase proteins: haptoglobin, α1-acid glycoprotein (α1-AGP), and C-reactive protein (CRP). Gene expression experiments also demonstRate a global suppression of adjuvant-induced gene expression in the spleen, liver, and popliteal lymph nodes. Finally, WAY-169916 was effective in suppressing tumor necrosis factor-α-mediated inflammatory gene expression in fibroblast-like synoviocytes isolated from patients with RA. Together, these data suggest the utility of WAY-169916, and other compounds in its class, in treating RA through global suppression of inflammation via selective blockade of NF-κB transcriptional activity.

  • Identification of pathway-selective estrogen receptor ligands that inhibit NF-κB transcriptional activity
    Proceedings of the National Academy of Sciences, 2005
    Co-Authors: Christopher C Chadwick, Leo M Albert, Yelena Leathurby, Lisa Borges-marcucci, James C Keith, Amy Eckert, Susan Chippari, Edward Martin Matelan, Heather A. Harris, Ramesh A. Bhat
    Abstract:

    Inflammation is now recognized as a key component in a number of diseases such as atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease. The transcription factor NF-κB has been shown to be involved in both the early and late stages of the inflammatory-prolifeRative process. In this report, we describe the identification of the pathway-selective estrogen receptor (ER) ligand, WAY-169916, that inhibits NF-κB transcriptional activity but is devoid of conventional estrogenic activity. This pathway-selective ligand does not promote the classic actions of estrogens such as stimulation of uterine prolifeRation or ER-mediated gene expression, but is a potent antiinflammatory agent, as demonstRated in the HLA-B27 Transgenic Rat model of inflammatory bowel disease. Our results indicate the potential utility of pathway-selective ER ligands such as WAY-169916 in the treatment of chronic inflammatory diseases.

  • Beneficial effects of estrogen treatment in the HLA-B27 Transgenic Rat model of inflammatory bowel disease
    American Journal of Physiology-Gastrointestinal and Liver Physiology, 2004
    Co-Authors: Douglas C Harnish, Leo M Albert, Yelena Leathurby, Amy Eckert, Agnes Ciarletta, Marion Kasaian, James C Keith
    Abstract:

    A well-established model of bowel inflammation is the HLA-B27 Transgenic Rat that exhibits a spontaneous disease phenotype resulting in chronic diarrhea caused by immune cell activation. Estrogens ...

  • Evaluation of an Estrogen Receptor-β Agonist in Animal Models of Human Disease
    Endocrinology, 2003
    Co-Authors: Heather A. Harris, Leo M Albert, Yelena Leathurby, Michael S. Malamas, Richard Eric Mewshaw, Chris P. Miller, Yogendra P. Kharode, James Marzolf, Barry S. Komm, Richard C. Winneker
    Abstract:

    The discovery of a second estrogen receptor (ER), called ERβ, in 1996 sparked intense interest within the scientific community to discover its role in mediating estrogen action. However, despite more than 6 yr of research into the function of this receptor, its physiological role in mediating estrogen action remains unclear and controversial. We have developed a series of highly selective agonists for ERβ and have characterized their activity in several clinically relevant rodent models of human disease. The activity of one such compound, ERB-041, is reported here. We conclude from these studies that ERβ does not mediate the bone-sparing activity of estrogen on the Rat skeleton and that it does not affect ovulation or ovariectomy-induced weight gain. In addition, these compounds are nonuterotrophic and nonmammotrophic. However, ERB-041 has a dramatic beneficial effect in the HLA-B27 Transgenic Rat model of inflammatory bowel disease and the Lewis Rat adjuvant-induced arthritis model. Daily oral doses as l...

Yelena Leathurby - One of the best experts on this subject based on the ideXlab platform.

  • A monoclonal antibody against kininogen reduces inflammation in the HLA-B27 Transgenic Rat
    Arthritis Research & Therapy, 2005
    Co-Authors: James C Keith, Leo M Albert, Yelena Leathurby, Irma M Sainz, Irma Isordia-salas, Robin A Pixley, Robert W Colman
    Abstract:

    The human leukocyte antigen B27 (HLA-B27) Transgenic Rat is a model of human inflammatory bowel disease, rheumatoid arthritis and psoriasis. Studies of chronic inflammation in other Rat models have demonstRated activation of the kallikrein–kinin system as well as modulation by a plasma kallikrein inhibitor initiated before the onset of clinicopathologic changes or a deficiency in high-molecular-mass kininogen. Here we study the effects of monoclonal antibody C11C1, an antibody against high-molecular-mass kininogen that inhibits the binding of high-molecular-mass kininogen to leukocytes and endothelial cells in the HLA-B27 Rat, which was administered after the onset of the inflammatory changes. Thrice-weekly intraperitoneal injections of monoclonal antibody C11C1 or isotype IgG_1 were given to male 23-week-old Rats for 16 days. Stool character as a measure of intestinal inflammation, and the rear limbs for clinical signs of arthritis (tarsal joint swelling and erythema) were scored daily. The animals were killed and the histology sections were assigned a numerical score for colonic inflammation, synovitis, and cartilage damage. AdministRation of monoclonal C11C1 rapidly decreased the clinical scores of pre-existing inflammatory bowel disease ( P < 0.005) and arthritis ( P < 0.001). Histological analyses confirmed significant reductions in colonic lesions ( P = 0.004) and synovitis ( P = 0.009). Decreased concentRations of plasma prekallikrein and high-molecular-mass kininogen were found, providing evidence of activation of the kallikrein–kinin system. The levels of these biomarkers were reversed by monoclonal antibody C11C1, which may have therapeutic potential in human inflammatory bowel disease and arthritis.

  • The utility of pathway selective estrogen receptor ligands that inhibit nuclear factor-κB transcriptional activity in models of rheumatoid arthritis
    Arthritis Research & Therapy, 2005
    Co-Authors: James C Keith, Leo M Albert, Yelena Leathurby, Max Follettie, Lisa Borges-marcucci, Christopher C Chadwick, Robert J Steffan, Lili Wang, Douglas C Harnish
    Abstract:

    Rheumatoid arthritis (RA) is a chronic inflammatory disease that produces synovial prolifeRation and joint erosions. The pathologic lesions of RA are driven through the production of inflammatory mediators in the synovium mediated, in part, by the transcription factor NF-κB. We have identified a non-steroidal estrogen receptor ligand, WAY-169916, that selectively inhibits NF-κB transcriptional activity but is devoid of conventional estrogenic activity. The activity of WAY-169916 was monitored in two models of arthritis, the HLA-B27 Transgenic Rat and the Lewis Rat adjuvant-induced model, after daily oral administRation. In both models, a near complete reversal in hindpaw scores was observed as well as marked improvements in the histological scores. In the Lewis Rat adjuvant model, WAY-169916 markedly suppresses the adjuvant induction of three serum acute phase proteins: haptoglobin, α1-acid glycoprotein (α1-AGP), and C-reactive protein (CRP). Gene expression experiments also demonstRate a global suppression of adjuvant-induced gene expression in the spleen, liver, and popliteal lymph nodes. Finally, WAY-169916 was effective in suppressing tumor necrosis factor-α-mediated inflammatory gene expression in fibroblast-like synoviocytes isolated from patients with RA. Together, these data suggest the utility of WAY-169916, and other compounds in its class, in treating RA through global suppression of inflammation via selective blockade of NF-κB transcriptional activity.

  • Identification of pathway-selective estrogen receptor ligands that inhibit NF-κB transcriptional activity
    Proceedings of the National Academy of Sciences, 2005
    Co-Authors: Christopher C Chadwick, Leo M Albert, Yelena Leathurby, Lisa Borges-marcucci, James C Keith, Amy Eckert, Susan Chippari, Edward Martin Matelan, Heather A. Harris, Ramesh A. Bhat
    Abstract:

    Inflammation is now recognized as a key component in a number of diseases such as atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease. The transcription factor NF-κB has been shown to be involved in both the early and late stages of the inflammatory-prolifeRative process. In this report, we describe the identification of the pathway-selective estrogen receptor (ER) ligand, WAY-169916, that inhibits NF-κB transcriptional activity but is devoid of conventional estrogenic activity. This pathway-selective ligand does not promote the classic actions of estrogens such as stimulation of uterine prolifeRation or ER-mediated gene expression, but is a potent antiinflammatory agent, as demonstRated in the HLA-B27 Transgenic Rat model of inflammatory bowel disease. Our results indicate the potential utility of pathway-selective ER ligands such as WAY-169916 in the treatment of chronic inflammatory diseases.

  • Beneficial effects of estrogen treatment in the HLA-B27 Transgenic Rat model of inflammatory bowel disease
    American Journal of Physiology-Gastrointestinal and Liver Physiology, 2004
    Co-Authors: Douglas C Harnish, Leo M Albert, Yelena Leathurby, Amy Eckert, Agnes Ciarletta, Marion Kasaian, James C Keith
    Abstract:

    A well-established model of bowel inflammation is the HLA-B27 Transgenic Rat that exhibits a spontaneous disease phenotype resulting in chronic diarrhea caused by immune cell activation. Estrogens ...

  • Evaluation of an Estrogen Receptor-β Agonist in Animal Models of Human Disease
    Endocrinology, 2003
    Co-Authors: Heather A. Harris, Leo M Albert, Yelena Leathurby, Michael S. Malamas, Richard Eric Mewshaw, Chris P. Miller, Yogendra P. Kharode, James Marzolf, Barry S. Komm, Richard C. Winneker
    Abstract:

    The discovery of a second estrogen receptor (ER), called ERβ, in 1996 sparked intense interest within the scientific community to discover its role in mediating estrogen action. However, despite more than 6 yr of research into the function of this receptor, its physiological role in mediating estrogen action remains unclear and controversial. We have developed a series of highly selective agonists for ERβ and have characterized their activity in several clinically relevant rodent models of human disease. The activity of one such compound, ERB-041, is reported here. We conclude from these studies that ERβ does not mediate the bone-sparing activity of estrogen on the Rat skeleton and that it does not affect ovulation or ovariectomy-induced weight gain. In addition, these compounds are nonuterotrophic and nonmammotrophic. However, ERB-041 has a dramatic beneficial effect in the HLA-B27 Transgenic Rat model of inflammatory bowel disease and the Lewis Rat adjuvant-induced arthritis model. Daily oral doses as l...

Robert W Colman - One of the best experts on this subject based on the ideXlab platform.

  • A monoclonal antibody against kininogen reduces inflammation in the HLA-B27 Transgenic Rat
    Arthritis Research & Therapy, 2005
    Co-Authors: James C Keith, Leo M Albert, Yelena Leathurby, Irma M Sainz, Irma Isordia-salas, Robin A Pixley, Robert W Colman
    Abstract:

    The human leukocyte antigen B27 (HLA-B27) Transgenic Rat is a model of human inflammatory bowel disease, rheumatoid arthritis and psoriasis. Studies of chronic inflammation in other Rat models have demonstRated activation of the kallikrein–kinin system as well as modulation by a plasma kallikrein inhibitor initiated before the onset of clinicopathologic changes or a deficiency in high-molecular-mass kininogen. Here we study the effects of monoclonal antibody C11C1, an antibody against high-molecular-mass kininogen that inhibits the binding of high-molecular-mass kininogen to leukocytes and endothelial cells in the HLA-B27 Rat, which was administered after the onset of the inflammatory changes. Thrice-weekly intraperitoneal injections of monoclonal antibody C11C1 or isotype IgG_1 were given to male 23-week-old Rats for 16 days. Stool character as a measure of intestinal inflammation, and the rear limbs for clinical signs of arthritis (tarsal joint swelling and erythema) were scored daily. The animals were killed and the histology sections were assigned a numerical score for colonic inflammation, synovitis, and cartilage damage. AdministRation of monoclonal C11C1 rapidly decreased the clinical scores of pre-existing inflammatory bowel disease ( P < 0.005) and arthritis ( P < 0.001). Histological analyses confirmed significant reductions in colonic lesions ( P = 0.004) and synovitis ( P = 0.009). Decreased concentRations of plasma prekallikrein and high-molecular-mass kininogen were found, providing evidence of activation of the kallikrein–kinin system. The levels of these biomarkers were reversed by monoclonal antibody C11C1, which may have therapeutic potential in human inflammatory bowel disease and arthritis.

  • A Monoclonal Antibody to High Molecular Weight Kininogen Reduces Inflammation in the HLA-B27 Transgenic Rat Model of Inflammatory Bowel Disease and Arthritis.
    Blood, 2004
    Co-Authors: Robin A Pixley, James C Keith, Irma M Sainz, Irma Isordia-salas, Yelena Leatherby, Leo Massillamone Albert, Robert W Colman
    Abstract:

    The HLA-B27 Rat is a well-characterized model of human bowel disease, rheumatoid arthritis and psoriasis. Previous studies of chronic inflammation in other Rat models of inflammatory disease have demonstRated activation of the kallilrein-kinin system (KKS) as well as modulation by a kallikrein inhibitor and HK deficiency. The effects of C11C1, a monoclonal antibody acting to inhibit cellular binding of high molecular weight kininogen (HK), were studied in the HLA-B27 Transgenic Rat. Thrice weekly intraperitoneal injections of C11C1 (1.9 mg/kg) or IgG1 (6mg/kg) were given to male HLA-B27 Transgenic Rats for 3 weeks, beginning when the Rats were 23 weeks old. Stool character was scored daily as a measure of intestinal inflammation, and the rear limbs were scored daily for clinical signs of arthritis, tarsal joint swelling and erythema. At the end of the experiment the animals were euthanized, and the colon and tarsal joint histologic lesions were examined. The histology sections were assigned a numerical score for colonic inflammation, synovitis, and cartilage damage. Activation of KKS was assessed by assays of plasma prekallikrein, HK, factor XI, and factor XII. AdministRation of the monoclonal antibody directed against HK rapidly decreased the clinical scores of inflammatory bowel disease from 3.0 ± 0 to 1.2 ± 0.2 (p