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Salomon Amar - One of the best experts on this subject based on the ideXlab platform.

  • reduction of articular and systemic inflammation by kava 241 in a porphyromonas gingivalis induced arthritis murine model
    Infection and Immunity, 2018
    Co-Authors: Jian You, Olivier Huck, Xianxian Han, Bin Cai, James S Panek, Salomon Amar
    Abstract:

    Rheumatoid arthritis (RA) is an inflammatory disease that has been linked to several risk factors, including periodontitis. Identification of new anti-inflammatory compounds to treat arthritis is needed. We had previously demonstrated the beneficial effect of Kava-241, a kavain-derived compound, in the management of Porphyromonas gingivalis-induced periodontitis. The present study evaluated systemic and articular effects of Kava-241 in an infective arthritis murine model triggered by P. gingivalis bacterial inoculation and primed with a Collagen Antibody cocktail (CIA) to induce joint inflammation and tissular destruction. Clinical inflammation score and radiological analyses of the paws were performed continuously, while histological assessment was obtained at sacrifice. Mice exposed to P. gingivalis and a CIA cocktail and treated concomitantly with Kava-241 exhibited a reduced clinical inflammatory score and a decreased number of inflammatory cells and osteoclasts within joint. Kava-241 treatment also decreased significantly tumor necrosis factor alpha (TNF-α) in serum from mice injected with a Toll-like receptor 2 or 4 (TLR-2/4) ligand, P. gingivalis-lipopolysaccharide (LPS). Finally, bone marrow-derived macrophages infected with P. gingivalis and exposed to Kava-241 displayed reduced TLR-2/4, reduced mitogen-activated protein kinase (MAPK)-related signal elements, and reduced LPS-induced TNF-α factor (LITAF), all explaining the observed reduction of TNF-α secretion. Taken together, these results emphasized the novel properties of Kava-241 in the management of inflammatory conditions, especially TNF-α-related diseases such as infective RA.

  • kavain involvement in lps induced signaling pathways
    Journal of Cellular Biochemistry, 2016
    Co-Authors: Xiaoren Tang, Salomon Amar
    Abstract:

    : Kavain, a compound extracted from the Kava plant, Piper methysticum, is found to be involved in TNF-α expression in human and mouse cells via regulation of transcriptional factors such as NF-kB and LITAF. LITAF is known to activate the transcription of more than 20 cytokines that are involved in a variety of cellular processes and is associated with many inflammatory diseases, including angiogenesis, cancer, arthritis, and more. The modulation of LITAF is expected to positively affect cytokine-mediated diseases. Thus, intensive efforts have been deployed in search of LITAF inhibitors. In this work, we found that, in vitro, Kavain reduced LPS- induced TNF-α secretion in mouse macrophages, mouse bone marrow macrophages (BMM), and human peripheral blood mononuclear cells (HPBMC). We also found that Kavain treatment in RAW264.7 cells deactivated MyD88 and Akt, inhibited LITAF, and reduced the production of TNF-α, IL-27, and MIG in response to LPS. Similarly, it had a significant in vivo anti-inflammatory effect on wild-type (WT) mice that developed Collagen Antibody Induced Arthritis (CAIA). Overall, MyD88 was found to be an important mediator of the LPS-induced inflammatory response that can be distinguished from the NF-κB pathway. We also found that MyD88 is involved in the pathway linking LPS/LITAF to TNF-α. Therefore, given that Kavain modulates LPS-induced signaling pathways leading to cytokine expression, therapeutic interventions involving Kavain in inflammatory diseases are warranted. J. Cell. Biochem. 117: 2272-2280, 2016. © 2016 Wiley Periodicals, Inc.

  • kavain inhibition of lps induced tnf α via erk litaf
    Toxicology Research, 2016
    Co-Authors: Xiaoren Tang, Salomon Amar
    Abstract:

    Kavain, an extract from the shrub Piper methysticum, was recently reported to modulate TNF-α expression in both human and mouse cells via regulation of LPS-Induced TNF-Alpha Factor (LITAF). The purpose of the present study was to define the molecular pathway(s) associated with Kavain′s effects on TNF modulation. In vitro studies using WT mouse primary macrophages showed that Kavain significantly reduced E. coli LPS-induced TNF-α production but this effect was almost abrogated in LITAF−/− and ERK2−/− cells. Therefore we reintroduced the ERK2 gene in ERK2−/− cells and partially restored E. coli LPS-induced LITAF-mediated TNF-α production. The translocation of LITAF into to nucleus was found to be dependent on ERK2 S206 residue. Kavain inhibits LITAF/TNF-α expression via dephosphorylation of ERK2 in response to E. coli LPS. Finally, in vivo, Kavain had a significant anti-inflammatory effect on wild type mice that developed Collagen Antibody Induced Arthritis (CAIA), but only a minor effect in ERK2−/− mice also affected by CAIA. Based on these findings, we concluded that ERK2 may be the kinase upstream for LITAF being a crucial factor for Kavain-mediated regulation of LPS-induced TNF-α.

  • kavain inhibition of lps induced tnf α via erk litaf
    Toxicology Research, 2016
    Co-Authors: Xiaoren Tang, Salomon Amar
    Abstract:

    Kavain, an extract from the shrub Piper Methysticum, was recently reported to modulate TNF-α expression in both human and mouse cells via regulation of LPS-Induced TNF-Alpha Factor (LITAF). The purpose of the present study was to define the molecular pathway(s) associated with Kavain effects on TNF modulation. In vitro studies using WT mouse primary macrophages showed that Kavain significantly reduced E.coli LPS-induced TNF-α production but this effect was almost abrogated in LITAF-/- and ERK2-/- cells. Therefore we reintroduced the ERK2 gene in ERK2-/- cells and partially restored E.coli LPS-induced LITAF-mediated TNF-α production. The translocation of LITAF into to nucleus was found to be dependent on ERK2 S206 residue. Kavain inhibits LITAF/TNF-α expression via dephosphorylation of ERK2 in response to E.coli LPS. Finally, in vivo, Kavain had a significant anti-inflammatory effect on wild type mice that developed Collagen Antibody Induced Arthritis (CAIA), but only a minor effect in ERK2-/- mice also affected by CAIA. Based on these findings, we concluded that ERK2 may be the kinase upstream of LITAF with its Serine residue 206 being crucial for the regulation of LPS-induced TNF-α.

  • whole body deletion of lps induced tnf α factor litaf markedly improves experimental endotoxic shock and inflammatory arthritis
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Jamie Cassidy Merrill, Susan E. Leeman, Jian You, Cara Constable, Salomon Amar
    Abstract:

    LPS-induced TNF-α factor (LITAF) mediates cytokine expression in response to endotoxin challenge. Previously, we reported that macrophage-specific LITAF-deficient (macLITAF−/−) mice exposed to LPS have a delayed onset in the serum levels of proinflammatory cytokines and prolonged persistence of anti-inflammatory cytokines, but only partial protection from endotoxic shock. We postulated that greater protection might be achieved if LITAF were deleted from all LITAF-producing cells, including macrophages. Using a Cre-loxP system, we engineered a tamoxifen-induced recombination mouse [tamLITAF(i)−/−] that resulted in whole-body LITAF deficiency. Our findings demonstrate that (i) tamLITAF(i)−/− mice are more resistant to systemic Escherichia coli LPS-induced lethality than our previous macLITAF−/− mice, providing evidence that LITAF-producing cells other than LysMCre-positive cells play an important role in mediating endotoxic shock; (ii) tamLITAF(i)−/− mice show a similar pattern of cytokine expression with decreased proinflammatory and prolonged anti-inflammatory mediators compared with WT mice; and (iii) tamLITAF(i)−/− mice, compared with WT mice, display a significant reduction in bone resorption and inflammation associated with a local chronic inflammatory disease—namely, Collagen Antibody-induced arthritis. Our findings offer a unique model to study the role of LITAF in systemic and chronic local inflammatory processes, and pave the way for anti-LITAF therapeutic approaches for the treatment of TNF-mediated inflammatory diseases.

Rikard Holmdahl - One of the best experts on this subject based on the ideXlab platform.

  • Collagen Antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency.
    Arthritis & Rheumatism, 2012
    Co-Authors: Jie Su, Katalin Sandor, Nilesh M. Agalave, Azar Baharpoor, Kutty Selva Nandakumar, Johanna Lundberg, Rikard Holmdahl, Simone Codeluppi, Camilla I Svensson
    Abstract:

    Objective Pain is one of the most debilitating symptoms reported by rheumatoid arthritis (RA) patients. While the Collagen Antibody–induced arthritis (CAIA) model is used for studying the effector phase of RA pathologic progression, it has not been evaluated as a model for studies of pain. Thus, this study was undertaken to examine pain-like behavior induced by antiCollagen antibodies and to assess the effect of currently prescribed analgesics for RA. In addition, the involvement of spinal glia in Antibody-induced pain was explored. Methods CAIA was induced in mice by intravenous injection of a Collagen Antibody cocktail, followed by intraperitoneal injection of lipopolysaccharide. Disease severity was assessed by visual and histologic examination. Pain-like behavior and the antinociceptive effect of diclofenac, buprenorphine, gabapentin, pentoxifylline, and JNK-interacting protein 1 were examined in mechanical stimulation experiments. Spinal astrocyte and microglia reactivity were investigated by real-time polymerase chain reaction and immunohistochemistry. Results Following the induction of CAIA, mice developed transient joint inflammation. In contrast, pain-like behavior was observed prior to, and outlasted, the visual signs of arthritis. Whereas gabapentin and buprenorphine attenuated mechanical hypersensitivity during both the inflammatory and postinflammatory phases of arthritis, diclofenac was antinociceptive only during the inflammatory phase. Spinal astrocytes and microglia displayed time-dependent signs of activation, and inhibition of glial activity reversed CAIA-induced mechanical hypersensitivity. Conclusion CAIA represents a multifaceted model for studies exploring the mechanisms of pain induced by inflammation in the articular joint. Our findings of a time-dependent prostaglandin and spinal glial contribution to Antibody-induced pain highlight the importance of using appropriate disease models to assess joint-related pain.

  • enhancement of Antibody induced arthritis via toll like receptor 2 stimulation is regulated by granulocyte reactive oxygen species
    American Journal of Pathology, 2012
    Co-Authors: Tiina Kelkka, Kutty Selva Nandakumar, Malin Hultqvist, Rikard Holmdahl
    Abstract:

    The suppressive role of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) complex-derived reactive oxygen species (ROS) in adaptive immunity-driven arthritis models is well established. In this study, we aimed to investigate the role of NOX2 complex-derived ROS in a model of innate immunity-driven arthritis and to identify the ROS-regulated innate receptors that control arthritis. We used Collagen Antibody-induced arthritis (CAIA), which is a T and B lymphocyte-independent model of the effector phase of arthritis and is induced by well-defined monoclonal arthritogenic antibodies and enhanced by injection of lipopolysaccharide (LPS). CAIA was induced in both wild-type and Ncf1 mutant mice that lack phagocyte oxidative burst, and stimulated with LPS and other agents to activate innate immune responses. We found that both LPS and lipomannan enhanced CAIA more potently in the presence of functional phagocyte ROS production than in its absence. The ROS-dependent enhancement of CAIA was regulated by TLR2, but not by TLR4 stimulation, and was driven by granulocytes, whereas macrophages did not contribute to the phenotype. In addition, we report that Collagen-induced arthritis was not affected by the functionality of the TLR4. We report that TLR2 signaling as an important ROS-regulated proinflammatory pathway leads to severe neutrophil-dependent inflammation in murine CAIA and conclude that the TLR2 pathway is modulated by phagocyte ROS to stimulate the development of arthritis.

  • a recombinant vaccine effectively induces c5a specific neutralizing antibodies and prevents arthritis
    PLOS ONE, 2010
    Co-Authors: Kutty Selva Nandakumar, Rikard Holmdahl, Asa Jansson, Bingze Xu, Niclas Rydell, Anna M Blom
    Abstract:

    OBJECTIVES: To develop and validate a recombinant vaccine to attenuate inflammation in arthritis by sustained neutralization of the anaphylatoxin C5a. METHODS: We constructed and expressed fusion protein of C5a and maltose binding protein. Efficacy of specific C5a neutralization was tested using the fusion protein as vaccine in three different arthritis mouse models: Collagen induced arthritis (CIA), chronic relapsing CIA and Collagen Antibody induced arthritis (CAIA). Levels of anti-C5a antibodies and anti-Collagen type II were measured by ELISA. C5a neutralization assay was done using a rat basophilic leukemia cell-line transfected with the human C5aR. Complement activity was determined using a hemolytic assay and joint morphology was assessed by histology. RESULTS: Vaccination of mice with MBP-C5a led to significant reduction of arthritis incidence and severity but not anti-Collagen Antibody synthesis. Histology of the MBP-C5a and control (MBP or PBS) vaccinated mice paws confirmed the vaccination effect. Sera from the vaccinated mice developed C5a-specific neutralizing antibodies, however C5 activation and formation of the membrane attack complex by C5b were not significantly altered. CONCLUSIONS: Exploitation of host immune response to generate sustained C5a neutralizing antibodies without significantly compromising C5/C5b activity is a useful strategy for developing an effective vaccine for Antibody mediated and C5a dependent inflammatory diseases. Further developing of such a therapeutic vaccine would be more optimal and cost effective to attenuate inflammation without affecting host immunity.

  • blocking of experimental arthritis by cleavage of igg antibodies in vivo
    Arthritis & Rheumatism, 2007
    Co-Authors: Kutty Selva Nandakumar, Lars Bjorck, Bjorn P Johansson, Rikard Holmdahl
    Abstract:

    Objective. To investigate whether IgG-degrading enzyme of Streptococcus pyogenes (IdeS), a bacterial cysteine endopeptidase that cleaves human IgG in the hinge region, can be used for blocking the development of arthritis. Methods. Recombinant IdeS was purified and tested for specificity against mouse IgG. IdeS was injected intravenously into mice with Collagen Antibody-induced arthritis (CAIA), Collagen-induced arthritis (CIA), or relapsing CIA, and its effects on arthritis development and severity were assessed. Results. IdeS efficiently cleaved mouse IgG2a/c and IgG3 in vitro. Even at low dosage (10 mu g), IdeS specifically cleaved IgG2a in vivo without any apparent side effects. IdeS treatment efficiently blocked CAIA induced by IgG2a antibodies. No effect was observed when arthritis was induced with IgG2b anti-type 11 Collagen antibodies; since IdeS does not cleave IgG2b, this indicated that IgG cleavage was the mechanism of action. IdeS treatment reduced the severity of arthritis if administered within 24 hours after the onset of clinical arthritis, but did not block ongoing severe arthritis. IdeS treatment also significantly prevented an Antibody-induced relapse in mice that had chronic arthritis, and delayed the onset and reduced the severity of arthritis in classic CIA. Conclusion. IdeS has therapeutic potential in IgG Antibody-mediated autoimmune arthritis, representing a new and unique means of blocking pathogenic antibodies. (Less)

  • macrophages suppress t cell responses and arthritis development in mice by producing reactive oxygen species
    Journal of Clinical Investigation, 2007
    Co-Authors: Kyra A Gelderman, Kutty Selva Nandakumar, Malin Hultqvist, Angela Pizzolla, Ming Zhao, Ragnar Mattsson, Rikard Holmdahl
    Abstract:

    Reduced capacity to produce ROS increases the severity of T cell-dependent arthritis in both mice and rats with polymorphisms in neutrophil cytosolic factor 1 (Ncf1) (p47phox). Since T cells cannot exert oxidative burst, we hypothesized that T cell responsiveness is downregulated by ROS produced by APCs. Macrophages have the highest burst capacity among APCs, so to study the effect of macrophage ROS on T cell activation, we developed transgenic mice expressing functional Ncf1 restricted to macrophages. Macrophage-restricted expression of functional Ncf1 restored arthritis resistance to the level of that of wild-type mice in a Collagen-induced arthritis model but not in a T cell-independent anti-Collagen Antibody-induced arthritis model. T cell activation was downregulated and skewed toward Th2 in transgenic mice. In vitro, IL-2 production and T cell proliferation were suppressed by macrophage ROS, irrespective of T cell origin. IFN-gamma production, however, was independent of macrophage ROS but dependent on T cell origin. These effects were antigen dependent but not restricted to Collagen type II. In conclusion, macrophage-derived ROS play a role in T cell selection, maturation, and differentiation, and also a suppressive role in T cell activation, and thereby mediate protection against autoimmune diseases like arthritis.

Youngro Byun - One of the best experts on this subject based on the ideXlab platform.

  • orally active desulfated low molecular weight heparin and deoxycholic acid conjugate 6ods lhbd suppresses neovascularization and bone destruction in arthritis
    Journal of Controlled Release, 2012
    Co-Authors: Seung Rim Hwang, Taslim A Alhilal, Ok Cheol Jeon, Jin Hee Kang, Youngtae Chang, Young Mo Kang, Victor C Yang, Youngro Byun
    Abstract:

    Abstract The regulation of angiogenesis is an interesting area to consider for novel therapeutic approaches to rheumatoid arthritis (RA). Chemically modified heparins have been developed as possible candidates for angiogenesis inhibitor; however, they have a major clinical drawback in exhibiting poor oral bioavailability. Here, orally absorbable O -desulfated low molecular weight heparin (ODS-LMWH) derivatives were newly synthesized by conjugating 2- O - or 6- O -desulfated LMWH with deoxycholic acid (DOCA) or bis DOCA (a dimer of DOCA), and their physicochemical properties, antiangiogenic potency and pharmacokinetic profiles were assessed. After selecting the best candidate among those derivatives, its therapeutic efficacy on arthritis was investigated in a murine Collagen Antibody-induced arthritis (CAIA) model. ODS-LMWH derivatives significantly inhibited the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs) and basic fibroblast growth factor (bFGF)-induced angiogenesis in the Matrigel plug assay. Among all the compounds, 6ODS-LHbD showed the highest oral bioavailability in rats (19.3%). In the CAIA mouse model, 6ODS-LHbD (10 mg/kg, p.o., S.I.D.) significantly inhibited neovascularization in the joint, the increase of hind-paw thickness, and the structural damage in the bone. Therefore, 6ODS-LHbD would be a promising candidate for an orally active drug for the treatment of RA.

Victor C Yang - One of the best experts on this subject based on the ideXlab platform.

  • orally active desulfated low molecular weight heparin and deoxycholic acid conjugate 6ods lhbd suppresses neovascularization and bone destruction in arthritis
    Journal of Controlled Release, 2012
    Co-Authors: Seung Rim Hwang, Taslim A Alhilal, Ok Cheol Jeon, Jin Hee Kang, Youngtae Chang, Young Mo Kang, Victor C Yang, Youngro Byun
    Abstract:

    Abstract The regulation of angiogenesis is an interesting area to consider for novel therapeutic approaches to rheumatoid arthritis (RA). Chemically modified heparins have been developed as possible candidates for angiogenesis inhibitor; however, they have a major clinical drawback in exhibiting poor oral bioavailability. Here, orally absorbable O -desulfated low molecular weight heparin (ODS-LMWH) derivatives were newly synthesized by conjugating 2- O - or 6- O -desulfated LMWH with deoxycholic acid (DOCA) or bis DOCA (a dimer of DOCA), and their physicochemical properties, antiangiogenic potency and pharmacokinetic profiles were assessed. After selecting the best candidate among those derivatives, its therapeutic efficacy on arthritis was investigated in a murine Collagen Antibody-induced arthritis (CAIA) model. ODS-LMWH derivatives significantly inhibited the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs) and basic fibroblast growth factor (bFGF)-induced angiogenesis in the Matrigel plug assay. Among all the compounds, 6ODS-LHbD showed the highest oral bioavailability in rats (19.3%). In the CAIA mouse model, 6ODS-LHbD (10 mg/kg, p.o., S.I.D.) significantly inhibited neovascularization in the joint, the increase of hind-paw thickness, and the structural damage in the bone. Therefore, 6ODS-LHbD would be a promising candidate for an orally active drug for the treatment of RA.

Kutty Selva Nandakumar - One of the best experts on this subject based on the ideXlab platform.

  • Collagen Antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency.
    Arthritis & Rheumatism, 2012
    Co-Authors: Jie Su, Katalin Sandor, Nilesh M. Agalave, Azar Baharpoor, Kutty Selva Nandakumar, Johanna Lundberg, Rikard Holmdahl, Simone Codeluppi, Camilla I Svensson
    Abstract:

    Objective Pain is one of the most debilitating symptoms reported by rheumatoid arthritis (RA) patients. While the Collagen Antibody–induced arthritis (CAIA) model is used for studying the effector phase of RA pathologic progression, it has not been evaluated as a model for studies of pain. Thus, this study was undertaken to examine pain-like behavior induced by antiCollagen antibodies and to assess the effect of currently prescribed analgesics for RA. In addition, the involvement of spinal glia in Antibody-induced pain was explored. Methods CAIA was induced in mice by intravenous injection of a Collagen Antibody cocktail, followed by intraperitoneal injection of lipopolysaccharide. Disease severity was assessed by visual and histologic examination. Pain-like behavior and the antinociceptive effect of diclofenac, buprenorphine, gabapentin, pentoxifylline, and JNK-interacting protein 1 were examined in mechanical stimulation experiments. Spinal astrocyte and microglia reactivity were investigated by real-time polymerase chain reaction and immunohistochemistry. Results Following the induction of CAIA, mice developed transient joint inflammation. In contrast, pain-like behavior was observed prior to, and outlasted, the visual signs of arthritis. Whereas gabapentin and buprenorphine attenuated mechanical hypersensitivity during both the inflammatory and postinflammatory phases of arthritis, diclofenac was antinociceptive only during the inflammatory phase. Spinal astrocytes and microglia displayed time-dependent signs of activation, and inhibition of glial activity reversed CAIA-induced mechanical hypersensitivity. Conclusion CAIA represents a multifaceted model for studies exploring the mechanisms of pain induced by inflammation in the articular joint. Our findings of a time-dependent prostaglandin and spinal glial contribution to Antibody-induced pain highlight the importance of using appropriate disease models to assess joint-related pain.

  • enhancement of Antibody induced arthritis via toll like receptor 2 stimulation is regulated by granulocyte reactive oxygen species
    American Journal of Pathology, 2012
    Co-Authors: Tiina Kelkka, Kutty Selva Nandakumar, Malin Hultqvist, Rikard Holmdahl
    Abstract:

    The suppressive role of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) complex-derived reactive oxygen species (ROS) in adaptive immunity-driven arthritis models is well established. In this study, we aimed to investigate the role of NOX2 complex-derived ROS in a model of innate immunity-driven arthritis and to identify the ROS-regulated innate receptors that control arthritis. We used Collagen Antibody-induced arthritis (CAIA), which is a T and B lymphocyte-independent model of the effector phase of arthritis and is induced by well-defined monoclonal arthritogenic antibodies and enhanced by injection of lipopolysaccharide (LPS). CAIA was induced in both wild-type and Ncf1 mutant mice that lack phagocyte oxidative burst, and stimulated with LPS and other agents to activate innate immune responses. We found that both LPS and lipomannan enhanced CAIA more potently in the presence of functional phagocyte ROS production than in its absence. The ROS-dependent enhancement of CAIA was regulated by TLR2, but not by TLR4 stimulation, and was driven by granulocytes, whereas macrophages did not contribute to the phenotype. In addition, we report that Collagen-induced arthritis was not affected by the functionality of the TLR4. We report that TLR2 signaling as an important ROS-regulated proinflammatory pathway leads to severe neutrophil-dependent inflammation in murine CAIA and conclude that the TLR2 pathway is modulated by phagocyte ROS to stimulate the development of arthritis.

  • a recombinant vaccine effectively induces c5a specific neutralizing antibodies and prevents arthritis
    PLOS ONE, 2010
    Co-Authors: Kutty Selva Nandakumar, Rikard Holmdahl, Asa Jansson, Bingze Xu, Niclas Rydell, Anna M Blom
    Abstract:

    OBJECTIVES: To develop and validate a recombinant vaccine to attenuate inflammation in arthritis by sustained neutralization of the anaphylatoxin C5a. METHODS: We constructed and expressed fusion protein of C5a and maltose binding protein. Efficacy of specific C5a neutralization was tested using the fusion protein as vaccine in three different arthritis mouse models: Collagen induced arthritis (CIA), chronic relapsing CIA and Collagen Antibody induced arthritis (CAIA). Levels of anti-C5a antibodies and anti-Collagen type II were measured by ELISA. C5a neutralization assay was done using a rat basophilic leukemia cell-line transfected with the human C5aR. Complement activity was determined using a hemolytic assay and joint morphology was assessed by histology. RESULTS: Vaccination of mice with MBP-C5a led to significant reduction of arthritis incidence and severity but not anti-Collagen Antibody synthesis. Histology of the MBP-C5a and control (MBP or PBS) vaccinated mice paws confirmed the vaccination effect. Sera from the vaccinated mice developed C5a-specific neutralizing antibodies, however C5 activation and formation of the membrane attack complex by C5b were not significantly altered. CONCLUSIONS: Exploitation of host immune response to generate sustained C5a neutralizing antibodies without significantly compromising C5/C5b activity is a useful strategy for developing an effective vaccine for Antibody mediated and C5a dependent inflammatory diseases. Further developing of such a therapeutic vaccine would be more optimal and cost effective to attenuate inflammation without affecting host immunity.

  • Rabeximod reduces arthritis severity in mice by decreasing activation of inflammatory cells.
    'BMJ', 2010
    Co-Authors: Hultqvist Malin, Kutty Selva Nandakumar, Björklund Ulf, Holmdahl Rikard
    Abstract:

    OBJECTIVES: /st> The novel small molecule 9-chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo[2,3-b] quinoxaline (Rabeximod) reduces severity of arthritis in rodent models of rheumatoid arthritis (RA) and multiple sclerosis (MS). This study aimed to investigate the cellular target in vivo. METHODS: /st> Collagen Antibody-induced arthritis (CAIA) is induced by monoclonal Collagen type II antibodies and enhanced by lipopolysaccharide. It was investigated how and when Rabeximod operates on inflammatory cells after stimulation of either Toll-like receptor (TLR)4 (lipopolysaccharide) or TLR2 (lipomannan) in mice lacking functional signalling through TLR4 due to a spontaneous deletion of the Tlr4 gene. RESULTS: /st> Rabeximod efficiently prevented arthritis during the time window when TLR2 or TLR4 ligands activate inflammatory macrophages. The effect operated downstream of TLR activation as Rabeximod was highly therapeutic in CAIA enhanced through TLR2 stimuli in TLR4 deficient mice. In addition, it was found that the arthritis ameliorating effect of Rabeximod was time dependent, since inhibition of tumour necrosis factor alpha production from macrophages in vitro was more pronounced if administered close to stimulation. CONCLUSIONS: /st> Rabeximod suppresses arthritis by preventing activation of inflammatory cells, most likely macrophages, in a time dependent fashion, downstream of TLR2 and TLR4 stimulation

  • blocking of experimental arthritis by cleavage of igg antibodies in vivo
    Arthritis & Rheumatism, 2007
    Co-Authors: Kutty Selva Nandakumar, Lars Bjorck, Bjorn P Johansson, Rikard Holmdahl
    Abstract:

    Objective. To investigate whether IgG-degrading enzyme of Streptococcus pyogenes (IdeS), a bacterial cysteine endopeptidase that cleaves human IgG in the hinge region, can be used for blocking the development of arthritis. Methods. Recombinant IdeS was purified and tested for specificity against mouse IgG. IdeS was injected intravenously into mice with Collagen Antibody-induced arthritis (CAIA), Collagen-induced arthritis (CIA), or relapsing CIA, and its effects on arthritis development and severity were assessed. Results. IdeS efficiently cleaved mouse IgG2a/c and IgG3 in vitro. Even at low dosage (10 mu g), IdeS specifically cleaved IgG2a in vivo without any apparent side effects. IdeS treatment efficiently blocked CAIA induced by IgG2a antibodies. No effect was observed when arthritis was induced with IgG2b anti-type 11 Collagen antibodies; since IdeS does not cleave IgG2b, this indicated that IgG cleavage was the mechanism of action. IdeS treatment reduced the severity of arthritis if administered within 24 hours after the onset of clinical arthritis, but did not block ongoing severe arthritis. IdeS treatment also significantly prevented an Antibody-induced relapse in mice that had chronic arthritis, and delayed the onset and reduced the severity of arthritis in classic CIA. Conclusion. IdeS has therapeutic potential in IgG Antibody-mediated autoimmune arthritis, representing a new and unique means of blocking pathogenic antibodies. (Less)