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Aaron R Bolduc - One of the best experts on this subject based on the ideXlab platform.
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the indoleamine 2 3 dioxygenase pathway controls Complement dependent enhancement of chemo radiation therapy against murine glioblastoma
Journal for ImmunoTherapy of Cancer, 2014Co-Authors: Minghui Li, Aaron R Bolduc, Nasrul Hoda, Denise N Gamble, Sarahbianca Dolisca, Kelly Hoang, Claire N Ashley, David Mccall, Amyn M RojianiAbstract:Background Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immune-suppressive properties that is commonly exploited by tumors to evade immune destruction. Anti-tumor T cell responses can be initiated in solid tumors, but are immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO. In addition to these known effects on the adaptive immune system, we previously showed widespread, T cell-dependent Complement Deposition during allogeneic fetal rejection upon maternal treatment with IDO-blockade. We hypothesized that IDO protects glioblastoma from the full effects of chemo-radiation therapy by preventing vascular activation and Complement-dependent tumor destruction.
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the indoleamine 2 3 dioxygenase pathway controls Complement dependent enhancement of chemo radiation therapy against murine glioblastoma
Journal for ImmunoTherapy of Cancer, 2014Co-Authors: Aaron R Bolduc, Nasrul Hoda, Denise N Gamble, Sarahbianca Dolisca, Kelly Hoang, Claire N Ashley, David Mccall, Amyn M Rojiani, Bernard L MariaAbstract:Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immune-suppressive properties that is commonly exploited by tumors to evade immune destruction. Anti-tumor T cell responses can be initiated in solid tumors, but are immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO. In addition to these known effects on the adaptive immune system, we previously showed widespread, T cell-dependent Complement Deposition during allogeneic fetal rejection upon maternal treatment with IDO-blockade. We hypothesized that IDO protects glioblastoma from the full effects of chemo-radiation therapy by preventing vascular activation and Complement-dependent tumor destruction. To test this hypothesis, we utilized a syngeneic orthotopic glioblastoma model in which GL261 glioblastoma tumor cells were stereotactically implanted into the right frontal lobes of syngeneic mice. These mice were treated with IDO-blocking drugs in combination with chemotherapy and radiation therapy. Pharmacologic inhibition of IDO synergized with chemo-radiation therapy to prolong survival in mice bearing intracranial glioblastoma tumors. We now show that pharmacologic or genetic inhibition of IDO allowed chemo-radiation to trigger widespread Complement Deposition at sites of tumor growth. Chemotherapy treatment alone resulted in collections of perivascular leukocytes within tumors, but no Complement Deposition. Adding IDO-blockade led to upregulation of VCAM-1 on vascular endothelium within the tumor microenvironment, and further adding radiation in the presence of IDO-blockade led to widespread Deposition of Complement. Mice genetically deficient in Complement component C3 lost all of the synergistic effects of IDO-blockade on chemo-radiation-induced survival. Together these findings identify a novel mechanistic link between IDO and Complement, and implicate Complement as a major downstream effector mechanism for the beneficial effect of IDO-blockade after chemo-radiation therapy. We speculate that this represents a fundamental pathway by which the tumor regulates intratumoral vascular activation and protects itself from immune-mediated tumor destruction.
Nobuhiro Yuki - One of the best experts on this subject based on the ideXlab platform.
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Polyclonal IgM and IgA block in vitro Complement Deposition mediated by anti-ganglioside antibodies in autoimmune neuropathies
International immunopharmacology, 2016Co-Authors: Makoto Sudo, Yoshiki Yamaguchi, Peter J. Späth, Kazuki Miyaji, Kana Morita-matsumoto, Nobuhiro YukiAbstract:Intravenous immunoglobulin (IVIG), consisting of IgG, is the first-line treatment for Guillain-Barre syndrome and multifocal motor neuropathy. IgG, but neither IgM nor IgA, has been demonstrated in vitro to inhibit Complement Deposition mediated by anti-ganglioside autoantibodies in sera from patients with both conditions. The objective of this study is to investigate the in vitro effectiveness of IgM and IgA in inhibiting Complement Deposition to ganglioside/anti-ganglioside antibody complexes. Serum samples were obtained from patients with multifocal motor neuropathy associated with anti-GM1 IgM antibodies, Guillain-Barre syndrome associated with anti-GM1 IgG antibodies and Miller Fisher syndrome associated with anti-GQ1b IgG antibodies. Inhibition of Complement Deposition using different immunoglobulin preparations was measured by enzyme-linked immunosorbent assay. IgM/A-enriched IVIG and immunoglobulin isotypes (polyclonal IgM and IgA) showed higher potential in inhibiting Complement Deposition than standard IVIG. Although the safety concerns about the use of IgM and IgA for an immunotherapy still remain, IgM and IgA may serve as an alternative immunotherapy in those anti-ganglioside antibody-mediated neuropathies.
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different ivig glycoforms affect in vitro inhibition of anti ganglioside antibody mediated Complement Deposition
PLOS ONE, 2014Co-Authors: Makoto Sudo, Yoshiki Yamaguchi, Benjamin K. Ong, Nortina Shahrizaila, Peter J. Späth, Kana Matsumotomorita, Nobuhiro YukiAbstract:Intravenous immunoglobulin (IVIG) is the first line treatment for Guillain–Barre syndrome and multifocal motor neuropathy, which are caused by anti-ganglioside antibody-mediated Complement-dependent cytotoxicity. IVIG has many potential mechanisms of action, and sialylation of the IgG Fc portion reportedly has an anti-inflammatory effect in antibody-dependent cell-mediated cytotoxicity models. We investigated the effects of different IVIG glycoforms on the inhibition of antibody-mediated Complement-dependent cytotoxicity. Deglycosylated, degalactosylated, galactosylated and sialylated IgG were prepared from IVIG following treatment with glycosidases and glycosyltransferases. Sera from patients with Guillain–Barre syndrome, Miller Fisher syndrome and multifocal motor neuropathy associated with anti-ganglioside antibodies were used. Inhibition of Complement Deposition subsequent to IgG or IgM autoantibody binding to ganglioside, GM1 or GQ1b was assessed on microtiter plates. Sialylated and galactosylated IVIGs more effectively inhibited C3 Deposition than original IVIG or enzyme-treated IVIGs (agalactosylated and deglycosylated IVIGs). Therefore, sialylated and galactosylated IVIGs may be more effective than conventional IVIG in the treatment of Complement-dependent autoimmune diseases.
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Different IVIG Glycoforms Affect In Vitro Inhibition of Anti-Ganglioside Antibody-Mediated Complement Deposition
2014Co-Authors: Makoto Sudo, Yoshiki Yamaguchi, Peter J. Späth, Kana Matsumoto-morita, Benjamin K. Ong, Nortina Shahrizaila, Nobuhiro YukiAbstract:Intravenous immunoglobulin (IVIG) is the first line treatment for Guillain–Barre ́ syndrome and multifocal motor neuropathy, which are caused by anti-ganglioside antibody-mediated Complement-dependent cytotoxicity. IVIG has many potential mechanisms of action, and sialylation of the IgG Fc portion reportedly has an anti-inflammatory effect in antibody-dependent cell-mediated cytotoxicity models. We investigated the effects of different IVIG glycoforms on the inhibition of antibody-mediated Complement-dependent cytotoxicity. Deglycosylated, degalactosylated, galactosylated and sialylated IgG were prepared from IVIG following treatment with glycosidases and glycosyltransferases. Sera from patients with Guillain–Barre ́ syndrome, Miller Fisher syndrome and multifocal motor neuropathy associated with anti-ganglioside antibodies were used. Inhibition of Complement Deposition subsequent to IgG or IgM autoantibody binding to ganglioside, GM1 or GQ1b was assessed on microtiter plates. Sialylated and galactosylated IVIGs more effectively inhibited C3 Deposition than original IVIG or enzyme-treated IVIGs (agalactosylated and deglycosylated IVIGs). Therefore, sialylated and galactosylated IVIGs may be more effective than conventional IVIG in the treatment of Complement-dependen
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Different IVIG Glycoforms Affect In Vitro Inhibition of Anti-Ganglioside Antibody-Mediated Complement Deposition
2014Co-Authors: Makoto Sudo, Yoshiki Yamaguchi, Kana Matsumoto-morita, Benjamin K. Ong, Nortina Shahrizaila, Peter J. Späth, Nobuhiro YukiAbstract:Intravenous immunoglobulin (IVIG) is the first line treatment for Guillain–Barré syndrome and multifocal motor neuropathy, which are caused by anti-ganglioside antibody-mediated Complement-dependent cytotoxicity. IVIG has many potential mechanisms of action, and sialylation of the IgG Fc portion reportedly has an anti-inflammatory effect in antibody-dependent cell-mediated cytotoxicity models. We investigated the effects of different IVIG glycoforms on the inhibition of antibody-mediated Complement-dependent cytotoxicity. Deglycosylated, degalactosylated, galactosylated and sialylated IgG were prepared from IVIG following treatment with glycosidases and glycosyltransferases. Sera from patients with Guillain–Barré syndrome, Miller Fisher syndrome and multifocal motor neuropathy associated with anti-ganglioside antibodies were used. Inhibition of Complement Deposition subsequent to IgG or IgM autoantibody binding to ganglioside, GM1 or GQ1b was assessed on microtiter plates. Sialylated and galactosylated IVIGs more effectively inhibited C3 Deposition than original IVIG or enzyme-treated IVIGs (agalactosylated and deglycosylated IVIGs). Therefore, sialylated and galactosylated IVIGs may be more effective than conventional IVIG in the treatment of Complement-dependent autoimmune diseases.
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ivig blocks Complement Deposition mediated by anti gm1 antibodies in multifocal motor neuropathy
Journal of Neurology Neurosurgery and Psychiatry, 2011Co-Authors: Nobuhiro Yuki, H. Watanabe, P. J. SpÄthAbstract:Background The pathogenesis of multifocal motor neuropathy (MMN) has yet to be established. MMN patients often carry anti-GM1 IgM antibodies, suggesting an autoimmune process involving Complement. Intravenous immunoglobulin (IVIG) is the first line treatment, but its action mechanism is unknown. Objective To test whether anti-GM1 IgM antibodies in MMN sera activate Complement, inducing and propagating the disease and whether IVIG inhibits Complement activation, resulting in clinical improvement. Methods Sera with anti-GM1 IgM but not IgG or IgA reactivity were obtained from 13 patients with MMN. We tested whether their anti-GM1 IgM antibodies produced Complement component deposits on GM1-coated microtiter plates and whether IVIG blocks such Deposition. Results C1q, C4b, C3b and C5b-9 were deposited on GM1-coated wells. Their Depositions were highly correlated with anti-GM1 IgM antibody titre. IVIG reduced the Deposition of these Complement components dose-dependently. Conclusions Anti-GM1 IgM antibodies bound to GM1 and activated Complement in vitro. The results together with earlier data from our group suggest that IgM-induced, Complement-mediated injury occurs at the nodes of Ranvier in peripheral motor nerves and generates conduction block and muscle weakness. In vitro IVIG inhibited this type of Complement activation, suggesting that in vivo, the resulting reduction in membrane attack complex-mediated damage leads to improved muscle strength.
Amyn M Rojiani - One of the best experts on this subject based on the ideXlab platform.
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the indoleamine 2 3 dioxygenase pathway controls Complement dependent enhancement of chemo radiation therapy against murine glioblastoma
Journal for ImmunoTherapy of Cancer, 2014Co-Authors: Minghui Li, Aaron R Bolduc, Nasrul Hoda, Denise N Gamble, Sarahbianca Dolisca, Kelly Hoang, Claire N Ashley, David Mccall, Amyn M RojianiAbstract:Background Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immune-suppressive properties that is commonly exploited by tumors to evade immune destruction. Anti-tumor T cell responses can be initiated in solid tumors, but are immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO. In addition to these known effects on the adaptive immune system, we previously showed widespread, T cell-dependent Complement Deposition during allogeneic fetal rejection upon maternal treatment with IDO-blockade. We hypothesized that IDO protects glioblastoma from the full effects of chemo-radiation therapy by preventing vascular activation and Complement-dependent tumor destruction.
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the indoleamine 2 3 dioxygenase pathway controls Complement dependent enhancement of chemo radiation therapy against murine glioblastoma
Journal for ImmunoTherapy of Cancer, 2014Co-Authors: Aaron R Bolduc, Nasrul Hoda, Denise N Gamble, Sarahbianca Dolisca, Kelly Hoang, Claire N Ashley, David Mccall, Amyn M Rojiani, Bernard L MariaAbstract:Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immune-suppressive properties that is commonly exploited by tumors to evade immune destruction. Anti-tumor T cell responses can be initiated in solid tumors, but are immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO. In addition to these known effects on the adaptive immune system, we previously showed widespread, T cell-dependent Complement Deposition during allogeneic fetal rejection upon maternal treatment with IDO-blockade. We hypothesized that IDO protects glioblastoma from the full effects of chemo-radiation therapy by preventing vascular activation and Complement-dependent tumor destruction. To test this hypothesis, we utilized a syngeneic orthotopic glioblastoma model in which GL261 glioblastoma tumor cells were stereotactically implanted into the right frontal lobes of syngeneic mice. These mice were treated with IDO-blocking drugs in combination with chemotherapy and radiation therapy. Pharmacologic inhibition of IDO synergized with chemo-radiation therapy to prolong survival in mice bearing intracranial glioblastoma tumors. We now show that pharmacologic or genetic inhibition of IDO allowed chemo-radiation to trigger widespread Complement Deposition at sites of tumor growth. Chemotherapy treatment alone resulted in collections of perivascular leukocytes within tumors, but no Complement Deposition. Adding IDO-blockade led to upregulation of VCAM-1 on vascular endothelium within the tumor microenvironment, and further adding radiation in the presence of IDO-blockade led to widespread Deposition of Complement. Mice genetically deficient in Complement component C3 lost all of the synergistic effects of IDO-blockade on chemo-radiation-induced survival. Together these findings identify a novel mechanistic link between IDO and Complement, and implicate Complement as a major downstream effector mechanism for the beneficial effect of IDO-blockade after chemo-radiation therapy. We speculate that this represents a fundamental pathway by which the tumor regulates intratumoral vascular activation and protects itself from immune-mediated tumor destruction.
Katsumi Eguchi - One of the best experts on this subject based on the ideXlab platform.
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acetylcholine receptors loss and postsynaptic damage in musk antibody positive myasthenia gravis
Annals of Neurology, 2005Co-Authors: Hirokazu Shiraishi, Masakatsu Motomura, Toshiro Yoshimura, Takayasu Fukudome, Taku Fukuda, Yoko Nakao, Mitsuhiro Tsujihata, Angela Vincent, Katsumi EguchiAbstract:Muscle-specific tyrosine kinase (MuSK) antibodies are found in some patients with "seronegative" myasthenia gravis (MG), but how they cause myasthenic symptoms is not clear. We visualized acetylcholine receptors (AChRs) and Complement component 3 (C3) in muscle biopsies from 10 Japanese MG patients with MuSK antibodies, compared with 42 with AChR antibodies. The AChR density was not significantly decreased in MuSK antibody (Ab)-positive end-plates compared with AChR antibody-positive end-plates, and C3 was detected in only two of eight MuSK Ab-positive patients. MuSK antibodies do not appear to cause substantial AChR loss, Complement Deposition, or morphological damage. Effects on MuSK function need to be explored.
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acetylcholine receptors loss and postsynaptic damage in musk antibody positive myasthenia gravis
Annals of Neurology, 2005Co-Authors: Hirokazu Shiraishi, Masakatsu Motomura, Toshiro Yoshimura, Takayasu Fukudome, Taku Fukuda, Yoko Nakao, Mitsuhiro Tsujihata, Angela Vincent, Katsumi EguchiAbstract:Muscle-specific tyrosine kinase (MuSK) antibodies are found in some patients with “seronegative” myasthenia gravis (MG), but how they cause myasthenic symptoms is not clear. We visualized acetylcholine receptors (AChRs) and Complement component 3 (C3) in muscle biopsies from 10 Japanese MG patients with MuSK antibodies, compared with 42 with AChR antibodies. The AChR density was not significantly decreased in MuSK antibody (Ab)–positive end-plates compared with AChR antibody–positive end-plates, and C3 was detected in only two of eight MuSK Ab–positive patients. MuSK antibodies do not appear to cause substantial AChR loss, Complement Deposition, or morphological damage. Effects on MuSK function need to be explored. Ann Neurol 2005;57:289–293
Jeremy Dufloo - One of the best experts on this subject based on the ideXlab platform.
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anti hiv 1 antibodies trigger non lytic Complement Deposition on infected cells
EMBO Reports, 2020Co-Authors: Jeremy Dufloo, Florence Guivelbenhassine, Julian Buchrieser, Valerie Lorin, Ludivine GrzelakAbstract:The effect of anti-HIV-1 antibodies on Complement activation at the surface of infected cells remains partly understood. Here, we show that a subset of anti-Envelope (Env) broadly neutralizing antibodies (bNAbs), targeting the CD4 binding site and the V3 loop, triggers C3 Deposition and Complement-dependent cytotoxicity (CDC) on Raji cells engineered to express high surface levels of HIV-1 Env. Primary CD4 T cells infected with laboratory-adapted or primary HIV-1 strains and treated with bNAbs are susceptible to C3 Deposition but not to rapid CDC. The cellular protein CD59 and viral proteins Vpu and Nef protect infected cells from CDC mediated by bNAbs or by polyclonal IgGs from HIV-positive individuals. However, Complement Deposition accelerates the disappearance of infected cells within a few days of culture. Altogether, our results uncover the contribution of Complement to the antiviral activity of anti-HIV-1 bNAbs.