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Article ; Online: HuM195 and its single-chain variable fragment increase Aβ phagocytosis in microglia via elimination of CD33 inhibitory signaling.

Wong, Eitan / Malviya, Manish / Jain, Tanya / Liao, George P / Kehs, Zoe / Chang, Jerry C / Studer, Lorenz / Scheinberg, David A / Li, Yue-Ming

Molecular psychiatry

2024

Abstract: CD33 is a transmembrane receptor expressed on cells of myeloid lineage and regulates innate immunity. CD33 is a risk factor for Alzheimer's disease (AD) and targeting CD33 has been a promising strategy drug development. However, the mechanism of CD33's ... ...

Abstract	CD33 is a transmembrane receptor expressed on cells of myeloid lineage and regulates innate immunity. CD33 is a risk factor for Alzheimer's disease (AD) and targeting CD33 has been a promising strategy drug development. However, the mechanism of CD33's action is poorly understood. Here we investigate the mechanism of anti-CD33 antibody HuM195 (Lintuzumab) and its single-chain variable fragment (scFv) and examine their therapeutic potential. Treatment with HuM195 full-length antibody or its scFv increased phagocytosis of β-amyloid 42 (Aβ42) in human microglia and monocytes. This activation of phagocytosis was driven by internalization and degradation of CD33, thereby downregulating its inhibitory signal. HumM195 transiently induced CD33 phosphorylation and its signaling via receptor dimerization. However, this signaling decayed with degradation of CD33. scFv binding to CD33 leads to a degradation of CD33 without detection of the CD33 dimerization and signaling. Moreover, we found that treatments with either HuM195 or scFv promotes the secretion of IL33, a cytokine implicated in microglia reprogramming. Importantly, recombinant IL33 potentiates the uptake of Aβ42 in monocytes. Collectively, our findings provide unanticipated mechanistic insight into the role of CD33 signaling in both monocytes and microglia and define a molecular basis for the development of CD33-based therapy of AD.
Language	English
Publishing date	2024-02-21
Publishing country	England
Document type	Journal Article
ZDB-ID	1330655-8
ISSN	1476-5578 ; 1359-4184
ISSN (online)	1476-5578
ISSN	1359-4184
DOI	10.1038/s41380-024-02474-z
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Book ; Online ; Thesis: Autoimmune encephalitis: Analysis of the intrathecal plasma cell repertoire and expression of patient derived antineuronal antibodies in recombinant form

Malviya, Manish [Verfasser]

2017

Author's details	Manish Malviya
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	English
Publisher	Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf
Publishing place	Düsseldorf
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Challenges and solutions for therapeutic TCR-based agents.

Malviya, Manish / Aretz, Zita E H / Molvi, Zaki / Lee, Jayop / Pierre, Stephanie / Wallisch, Patrick / Dao, Tao / Scheinberg, David A

Immunological reviews

2023 Volume 320, Issue 1, Page(s) 58–82

Abstract: Recent development of methods to discover and engineer therapeutic T-cell receptors (TCRs) or antibody mimics of TCRs, and to understand their immunology and pharmacology, lag two decades behind therapeutic antibodies. Yet we have every expectation that ... ...

Abstract	Recent development of methods to discover and engineer therapeutic T-cell receptors (TCRs) or antibody mimics of TCRs, and to understand their immunology and pharmacology, lag two decades behind therapeutic antibodies. Yet we have every expectation that TCR-based agents will be similarly important contributors to the treatment of a variety of medical conditions, especially cancers. TCR engineered cells, soluble TCRs and their derivatives, TCR-mimic antibodies, and TCR-based CAR T cells promise the possibility of highly specific drugs that can expand the scope of immunologic agents to recognize intracellular targets, including mutated proteins and undruggable transcription factors, not accessible by traditional antibodies. Hurdles exist regarding discovery, specificity, pharmacokinetics, and best modality of use that will need to be overcome before the full potential of TCR-based agents is achieved. HLA restriction may limit each agent to patient subpopulations and off-target reactivities remain important barriers to widespread development and use of these new agents. In this review we discuss the unique opportunities for these new classes of drugs, describe their unique antigenic targets, compare them to traditional antibody therapeutics and CAR T cells, and review the various obstacles that must be overcome before full application of these drugs can be realized.
MeSH term(s)	Humans ; Receptors, Antigen, T-Cell/metabolism ; Neoplasms/therapy ; Antibodies
Chemical Substances	Receptors, Antigen, T-Cell ; Antibodies
Language	English
Publishing date	2023-07-16
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.13233
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Article ; Online: Challenges and solutions for therapeutic TCR‐based agents

Malviya, Manish / Aretz, Zita E. H. / Molvi, Zaki / Lee, Jayop / Pierre, Stephanie / Wallisch, Patrick / Dao, Tao / Scheinberg, David A.

Immunological Reviews. 2023 Nov., v. 320, no. 1 p.58-82

2023

Abstract: Recent development of methods to discover and engineer therapeutic T‐cell receptors (TCRs) or antibody mimics of TCRs, and to understand their immunology and pharmacology, lag two decades behind therapeutic antibodies. Yet we have every expectation that ... ...

Abstract	Recent development of methods to discover and engineer therapeutic T‐cell receptors (TCRs) or antibody mimics of TCRs, and to understand their immunology and pharmacology, lag two decades behind therapeutic antibodies. Yet we have every expectation that TCR‐based agents will be similarly important contributors to the treatment of a variety of medical conditions, especially cancers. TCR engineered cells, soluble TCRs and their derivatives, TCR‐mimic antibodies, and TCR‐based CAR T cells promise the possibility of highly specific drugs that can expand the scope of immunologic agents to recognize intracellular targets, including mutated proteins and undruggable transcription factors, not accessible by traditional antibodies. Hurdles exist regarding discovery, specificity, pharmacokinetics, and best modality of use that will need to be overcome before the full potential of TCR‐based agents is achieved. HLA restriction may limit each agent to patient subpopulations and off‐target reactivities remain important barriers to widespread development and use of these new agents. In this review we discuss the unique opportunities for these new classes of drugs, describe their unique antigenic targets, compare them to traditional antibody therapeutics and CAR T cells, and review the various obstacles that must be overcome before full application of these drugs can be realized.
Keywords	T-lymphocytes ; antibodies ; patients ; pharmacokinetics ; therapeutics
Language	English
Dates of publication	2023-11
Size	p. 58-82.
Publishing place	John Wiley & Sons, Ltd
Document type	Article ; Online
Note	REVIEW
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.13233
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Treatment of experimental autoimmune encephalomyelitis with engineered bi-specific Foxp3+ regulatory CD4+ T cells.

Malviya, Manish / Saoudi, Abdelhadi / Bauer, Jan / Fillatreau, Simon / Liblau, Roland

Journal of autoimmunity

2020 Volume 108, Page(s) 102401

Abstract: The use of autoantigen-specific regulatory T cells (Tregs) as a cellular therapy for autoimmune diseases is appealing. However, it is challenging to isolate and expand large quantity of Tregs expressing disease-relevant T-cell receptors (TCR). To ... ...

Abstract	The use of autoantigen-specific regulatory T cells (Tregs) as a cellular therapy for autoimmune diseases is appealing. However, it is challenging to isolate and expand large quantity of Tregs expressing disease-relevant T-cell receptors (TCR). To overcome this problem, we used an approach aiming at redirecting the specificity of polyclonal Tregs through autoreactive TCR gene transfer technology. In this study, we examined whether Tregs engineered through retroviral transduction to express a TCR cross-reactive to two CNS autoantigens, myelin oligodendrocyte glycoprotein (MOG) and neurofilament-medium (NF-M), had a superior protective efficacy compared with Tregs expressing a MOG mono-specific TCR. We observed that engineered Tregs (engTregs) exhibited in vitro regulatory effects related to the antigenic specificity of the introduced TCR, and commensurate in potency with the avidity of the transduced TCR. In experimental autoimmune encephalomyelitis (EAE), adoptively transferred engTregs proliferated, and migrated to the CNS, while retaining FoxP3 expression. EngTregs expressing MOG/NF-M cross-reactive TCR had superior protective properties over engTregs expressing MOG-specific TCR in MOG-induced EAE. Remarkably, MOG/NF-M bi-specific TCR-engTregs also improved recovery from EAE induced by an unrelated CNS autoantigen, proteolipid protein (PLP). This study underlines the benefit of using TCRs cross-reacting towards multiple autoantigens, compared with mono-reactive TCR, for the generation of engTregs affording protection from autoimmune disease in adoptive cell therapy.
MeSH term(s)	Animals ; Autoantigens/immunology ; Cross Reactions/immunology ; Disease Models, Animal ; Encephalomyelitis, Autoimmune, Experimental/etiology ; Encephalomyelitis, Autoimmune, Experimental/metabolism ; Encephalomyelitis, Autoimmune, Experimental/therapy ; Forkhead Transcription Factors/antagonists & inhibitors ; Forkhead Transcription Factors/metabolism ; Genetic Engineering/methods ; Immunotherapy, Adoptive/methods ; Mice ; Myelin-Oligodendrocyte Glycoprotein/immunology ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/immunology ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/immunology ; T-Lymphocytes, Regulatory/drug effects ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; Treatment Outcome
Chemical Substances	Autoantigens ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; Myelin-Oligodendrocyte Glycoprotein ; Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen
Language	English
Publishing date	2020-01-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639452-8
ISSN	1095-9157 ; 0896-8411
ISSN (online)	1095-9157
ISSN	0896-8411
DOI	10.1016/j.jaut.2020.102401
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Article: Dual targeting ovarian cancer by Muc16 CAR-T cells secreting a bispecific T cell engager antibody for an intracellular tumor antigen WT1.

Mun, Sung Soo / Peraro, Leila / Meyerberg, Jeremy / Korontsvit, Tatyana / Malviya, Manish / Gardner, Thomas / Kyi, Chrisann / O'Cearbhaill, Roisin E / Liu, Cheng / Dao, Tao / Scheinberg, David A

Research square

2023

Abstract: Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single antigens is limited by the heterogeneous target antigen expression in epithelial ovarian ... ...

Abstract	Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single antigens is limited by the heterogeneous target antigen expression in epithelial ovarian tumors. To overcome this limitation, we describe an engineered cell with both dual targeting and orthogonal cytotoxic modalities directed against two tumor antigens that are highly expressed on ovarian cancer cells: cell surface Muc16 and intracellular WT1. Muc16-specific CAR-T cells (4H11) were engineered to secrete a bispecific T cell engager (BiTE) constructed from a TCR mimic antibody (ESK1) reactive with the WT1-derived epitope RMFPNAPYL (RMF) presented by HLA-A2 molecules. The secreted ESK1 BiTE recruited and redirected other T cells to WT1 on the tumor cells. We show that ESK1 BiTE-secreting 4H11 CAR-T cells exhibited enhanced anticancer activity against cancer cells with low Muc16 expression, compared to 4H11 CAR-T cells alone, both in vitro and in mouse tumor models. Dual orthogonal cytotoxic modalities with different specificities targeting both surface and intracellular tumor-associated antigens present a promising strategy to overcome resistance to CAR-T cell therapy in epithelial ovarian cancer and other cancers.
Language	English
Publishing date	2023-05-08
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-2887299/v1
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Article ; Online: Dual targeting ovarian cancer by Muc16 CAR T cells secreting a bispecific T cell engager antibody for an intracellular tumor antigen WT1.

Mun, Sung Soo / Meyerberg, Jeremy / Peraro, Leila / Korontsvit, Tatyana / Gardner, Thomas / Malviya, Manish / Kyi, Chrisann / O'Cearbhaill, Roisin E / Liu, Cheng / Dao, Tao / Scheinberg, David A

Cancer immunology, immunotherapy : CII

2023 Volume 72, Issue 11, Page(s) 3773–3786

Abstract	Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single antigens is limited by the heterogeneous target antigen expression in epithelial ovarian tumors. To overcome this limitation, we describe an engineered cell with both dual targeting and orthogonal cytotoxic modalities directed against two tumor antigens that are highly expressed on ovarian cancer cells: cell surface Muc16 and intracellular WT1. Muc16-specific CAR T cells (4H11) were engineered to secrete a bispecific T cell engager (BiTE) constructed from a TCR mimic antibody (ESK1) reactive with the WT1-derived epitope RMFPNAPYL (RMF) presented by HLA-A2 molecules. The secreted ESK1 BiTE recruited and redirected other T cells to WT1 on the tumor cells. We show that ESK1 BiTE-secreting 4H11 CAR T cells exhibited enhanced anticancer activity against cancer cells with low Muc16 expression, compared to 4H11 CAR T cells alone, both in vitro and in mouse tumor models. Dual orthogonal cytotoxic modalities with different specificities targeting both surface and intracellular tumor-associated antigens present a promising strategy to overcome resistance to CAR T cell therapy in epithelial ovarian cancer and other cancers.
MeSH term(s)	Humans ; Mice ; Female ; Animals ; Carcinoma, Ovarian Epithelial/therapy ; Receptors, Chimeric Antigen ; Ovarian Neoplasms/therapy ; Antigens, Neoplasm ; T-Lymphocytes ; WT1 Proteins
Chemical Substances	Receptors, Chimeric Antigen ; Antigens, Neoplasm ; WT1 protein, human ; WT1 Proteins ; WT1 protein, mouse
Language	English
Publishing date	2023-08-27
Publishing country	Germany
Document type	Journal Article
ZDB-ID	195342-4
ISSN	1432-0851 ; 0340-7004
ISSN (online)	1432-0851
ISSN	0340-7004
DOI	10.1007/s00262-023-03529-w
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Article ; Online: In vivo effect of antidepressants on [3H]paroxetine binding to serotonin transporters in rat brain.

Nadgir, Subhash M / Malviya, Manish

Neurochemical research

2008 Volume 33, Issue 11, Page(s) 2250–2256

Abstract: Amine transporters are major target for development of various pharmacological agents to treat behavioral disorders. Serotonin transporters (SERT) have been implicated in the etiology of depression and drugs acting on SERT can be effective in treating ... ...

Abstract	Amine transporters are major target for development of various pharmacological agents to treat behavioral disorders. Serotonin transporters (SERT) have been implicated in the etiology of depression and drugs acting on SERT can be effective in treating depression. The aim of the present study was to study the in vivo effect of various antidepressants on [(3)H]paroxetine binding to SERT in regions of rat brain. Rats were treated with tricyclic antidepressant (TCAs) such as amitriptyline (AMI), serotonin/norepinephrine reuptake inhibitor (SNRIs) such as clomipramine (CMI), and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (FLX) and citalopram (CIT) (10 mg/kg body wt.) for 30 days. Density of SERT was measured in cortex and hippocampus using [(3)H]paroxetine (0.03-1.0 nM) in presence and absence of 10 muM fluoxetine as displacer. It was observed that the density of cortical SERT was significantly decreased with CMI (68%, P < 0.0001), FLX (67%, P < 0.0001), CIT (54%, P < 0.0001), and AMI (52%, P < 0.0001) treatment, when compared to the density of 120.7 +/- 4.0 fmol/mg protein in control rats, without altering the affinity (Kd) of [(3)H]paroxetine to the transporters. The density of SERT in hippocampus was also significantly decreased with FLX (65%, P < 0.0001), CMI (54%, P < 0.0001), CIT (52%, P < 0.0001) and AMI (46%, P < 0.0001) treatment, when compared to the density of 74.0 +/- 2.6 fmol/mg protein in control rats, without altering the affinity of [(3)H]paroxetine to the transporters. Displacement study showed high affinity for CMI > CIT > FLX. The results suggest that chronic antidepressant treatment significantly down-regulates both cortical and hippocampal SERT in rat brain and SSRIs have high affinity for SERT than TCAs.
MeSH term(s)	Animals ; Antidepressive Agents, Second-Generation/pharmacology ; Brain/drug effects ; Brain/metabolism ; Imipramine/metabolism ; Male ; Paroxetine/metabolism ; Radioligand Assay ; Rats ; Rats, Sprague-Dawley ; Serotonin Plasma Membrane Transport Proteins/metabolism ; Serotonin Uptake Inhibitors/pharmacology ; Tritium
Chemical Substances	Antidepressive Agents, Second-Generation ; Serotonin Plasma Membrane Transport Proteins ; Serotonin Uptake Inhibitors ; Tritium (10028-17-8) ; Paroxetine (41VRH5220H) ; Imipramine (OGG85SX4E4)
Language	English
Publishing date	2008-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	199335-5
ISSN	1573-6903 ; 0364-3190
ISSN (online)	1573-6903
ISSN	0364-3190
DOI	10.1007/s11064-008-9703-z
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Zs.A 1368: Show issues

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Article: Targeted Cellular Micropharmacies: Cells Engineered for Localized Drug Delivery.

Gardner, Thomas J / Bourne, Christopher M / Dacek, Megan M / Kurtz, Keifer / Malviya, Manish / Peraro, Leila / Silberman, Pedro C / Vogt, Kristen C / Unti, Mildred J / Brentjens, Renier / Scheinberg, David

Cancers

2020 Volume 12, Issue 8

Abstract: The recent emergence of engineered cellular therapies, such as Chimeric antigen receptor (CAR) CAR T and T cell receptor (TCR) engineered T cells, has shown great promise in the treatment of various cancers. These agents aggregate and expand ... ...

Abstract	The recent emergence of engineered cellular therapies, such as Chimeric antigen receptor (CAR) CAR T and T cell receptor (TCR) engineered T cells, has shown great promise in the treatment of various cancers. These agents aggregate and expand exponentially at the tumor site, resulting in potent immune activation and tumor clearance. Moreover, the ability to elaborate these cells with therapeutic agents, such as antibodies, enzymes, and immunostimulatory molecules, presents an unprecedented opportunity to specifically modulate the tumor microenvironment through cell-mediated drug delivery. This unique pharmacology, combined with significant advances in synthetic biology and cell engineering, has established a new paradigm for cells as vectors for drug delivery. Targeted cellular micropharmacies (TCMs) are a revolutionary new class of living drugs, which we envision will play an important role in cancer medicine and beyond. Here, we review important advances and considerations underway in developing this promising advancement in biological therapeutics.
Keywords	covid19
Language	English
Publishing date	2020-08-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12082175
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Article: Dose-dependent inhibition of demyelination and microglia activation by IVIG.

Winter, Meike / Baksmeier, Christine / Steckel, Julia / Barman, Sumanta / Malviya, Manish / Harrer-Kuster, Melanie / Hartung, Hans-Peter / Goebels, Norbert

Annals of clinical and translational neurology

2016 Volume 3, Issue 11, Page(s) 828–843

Abstract: Objective: Intravenous immunoglobulin (IVIG) is an established treatment for numerous autoimmune conditions. Clinical trials of IVIG for multiple sclerosis, using diverse dose regimens, yielded controversial results. The aim of this study is to dissect ... ...

Abstract	Objective: Intravenous immunoglobulin (IVIG) is an established treatment for numerous autoimmune conditions. Clinical trials of IVIG for multiple sclerosis, using diverse dose regimens, yielded controversial results. The aim of this study is to dissect IVIG effector mechanisms on demyelination in an Methods: Using organotypic cerebellar slice cultures (OSC) from transgenic mice expressing green fluorescent protein (GFP) in oligodendrocytes/myelin, we induced extensive immune-mediated demyelination and oligodendrocyte loss with an antibody specific for myelin oligodendrocyte glycoprotein (MOG) and complement. Protective IVIG effects were assessed by live imaging of GFP expression, confocal microscopy, immunohistochemistry, gene expression analysis and flow cytometry. Results: IVIG protected OSC from demyelination in a dose-dependent manner, which was at least partly attributed to interference with complement-mediated oligodendroglia damage, while binding of the anti-MOG antibody was not prevented. Staining with anti-CD68 antibodies and flow cytometry confirmed that IVIG prevented microglia activation and oligodendrocyte death, respectively. Equimolar IVIG-derived Fab fragments or monoclonal IgG did not protect OSC, while Fc fragments derived from a polyclonal mixture of human IgG were at least as potent as intact IVIG. Interpretation: Both intact IVIG and Fc fragments exert a dose-dependent protective effect on antibody-mediated CNS demyelination and microglia activation by interfering with the complement cascade and, presumably, interacting with local immune cells. Although this experimental model lacks blood-brain barrier and peripheral immune components, our findings warrant further studies on optimal dose finding and alternative modes of application to enhance local IVIG concentrations at the site of tissue damage.
Language	English
Publishing date	2016-09-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2740696-9
ISSN	2328-9503
ISSN	2328-9503
DOI	10.1002/acn3.326
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