37 results on '"Herbert P.M. Brok"'
Search Results
2. Induction of Progressive Demyelinating Autoimmune Encephalomyelitis in Common Marmoset Monkeys Using MOG(34-56) Peptide in Incomplete Freund Adjuvant
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Linda van Straalen, Jeffrey J. Bajramovic, Bert A. 't Hart, Nicole Heijmans, Yolanda S. Kap, Jan Bauer, Jon D. Laman, Nikki van Driel, Herbert P.M. Brok, S. Anwar Jagessar, Erwin L. A. Blezer, and Immunology
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Encephalomyelitis ,T-Lymphocytes ,Freund's Adjuvant ,Demyelinating Autoimmune Diseases, CNS ,Pathology and Forensic Medicine ,Myelin oligodendrocyte glycoprotein ,Cellular and Molecular Neuroscience ,Myelin ,Immune system ,Antigen ,Antigens, CD ,biology.animal ,medicine ,Animals ,Calgranulin B ,Humans ,Myelin Proteolipid Protein ,Autoantibodies ,Cell Line, Transformed ,Glycoproteins ,Autoimmune disease ,biology ,Experimental autoimmune encephalomyelitis ,Marmoset ,Brain ,Callithrix ,General Medicine ,medicine.disease ,Flow Cytometry ,Magnetic Resonance Imaging ,Immunity, Innate ,Peptide Fragments ,Disease Models, Animal ,medicine.anatomical_structure ,Neurology ,Spinal Cord ,Immunology ,biology.protein ,Leukocytes, Mononuclear ,Cytokines ,Myelin-Oligodendrocyte Glycoprotein ,Neurology (clinical) - Abstract
Experimental autoimmune encephalomyelitis in the neotropical primate common marmoset (Callithrix jacchus) is a relevant autoimmune animal model of multiple sclerosis. T cells specific for peptide 34 to 56 of myelin/oligodendrocyte glycoprotein (MOG(34-56)) have a central pathogenic role in this model. The aim of this study was to assess the requirement for innate immune stimulation for activation of this core pathogenic autoimmune mechanism. Marmoset monkeys were sensitized against synthetic MOG(34-56) peptide alone or in combination with the nonencephalitogenic peptide MOG(74-96) formulated in incomplete Freund adjuvant, which lacks microbial components. Experimental autoimmune encephalomyelitis development was recorded by monitoring neurological signs, brain magnetic resonance imaging, and longitudinal profiling of cellular and humoral immune parameters. All monkeys developed autoimmune inflammatory/demyelinating central nervous system disease characterized by massive brain and spinal cord demyelinating white matter lesions with activated macrophages and CD3(+) T cells. Immune profiling ex vivo demonstrated the activation of mainly CD3(+)CD4(+)/8(+)CD56(+) T cells against MOG(34-56). Upon ex vivo stimulation, these T cells produced more interleukin 17A compared with TH1 cytokines (e. g. interferon-gamma) and displayed peptide-specific cytolytic activity. These results indicate that the full spectrum of marmoset experimental autoimmune encephalomyelitis can be induced by sensitization against a single MOG peptide in incomplete Freund adjuvant lacking microbial compounds for innate immune activation and by eliciting antigen-specific T-cell cytolytic activity.
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- 2010
3. A Monoclonal Antibody Selection for Immunohistochemical Examination of Lymphoid Tissues From Non-human Primates
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Bert A. 't Hart, Nikki van Driel, Marie-José Melief, Herbert P.M. Brok, Marjan van Meurs, Gerrit Koopman, Jon D. Laman, Yolanda S. Kap, and Immunology
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Primates ,Histology ,medicine.drug_class ,Cross Reactions ,Monoclonal antibody ,Article ,SDG 3 - Good Health and Well-being ,biology.animal ,medicine ,Animals ,Humans ,Lymphocytes ,biology ,Antibodies, Monoclonal ,Marmoset ,Cell Differentiation ,Tamarin ,biology.organism_classification ,Immunohistochemistry ,Callithrix ,Virology ,Saguinus oedipus ,Rhesus macaque ,biology.protein ,Anatomy ,Antibody ,Biomarkers - Abstract
Non-human primates (NHPs) offer valuable animal models for basic research into human diseases and for the preclinical validation of new therapeutics. Detailed in situ examination of the involved cell types using immunohistochemistry is often hampered by the lack of cross-reactive antibodies (Abs). In the current study, we have tested a large panel of monoclonal antibodies raised against human leukocyte differentiation and activation markers for cross-reactivity on cryosections of lymphoid tissue from six NHP species. In total, we have tested 130 Abs against 69 antigens expressed in tissues from one great ape species (chimpanzee/Pan troglodytes), two Old World species (rhesus macaque/Macaca mulatta and cynomolgus macaque/Macaca fascicularis), and three New World species (common marmoset/Callithrix jacchus, cotton-top tamarin/Saguinus oedipus, and owl monkey/Aotus triviogatus). We have found a large panel of cross-reactive Abs: 93 of 102 (91%) in chimpanzee, 97 of 125 (78%) in rhesus macaque, 70 of 109 (64%) in cynomolgus macaque, 69 of 116 (60%) in common marmoset, 40 of 81 (49%) in cotton-top tamarin, and 35 of 80 (44%) in owl monkey. The availability of a reliable panel of cross-reactive markers is important to gaining further insight into immunological processes in disease-affected tissues from NHP species. (J Histochem Cytochem 57:1159-1167, 2009)
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- 2009
4. Engraftment of cutaneous fibroblasts within synovial membrane in a nonhuman primate: Short-term results
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Herbert P.M. Brok, Natacha Bessis, Tom W J Huizinga, Delphine Lemeiter, Marie-Christophe Boissier, Liliane Laroche, Catherine Fournier, and Bert A. 't Hart
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Metatarsophalangeal Joint ,musculoskeletal diseases ,Pathology ,medicine.medical_specialty ,Genetic enhancement ,Cell ,Arthritis ,CHO Cells ,Toe Joint ,Transfection ,Transplantation, Autologous ,Injections, Intra-Articular ,Metacarpophalangeal Joint ,Mice ,Cricetulus ,Rheumatology ,Synovectomy ,Cricetinae ,Finger Joint ,medicine ,Animals ,Humans ,Skin ,business.industry ,Chinese hamster ovary cell ,Graft Survival ,Genetic Therapy ,Fibroblasts ,medicine.disease ,Arthritis, Experimental ,Macaca mulatta ,Disease Models, Animal ,Treatment Outcome ,medicine.anatomical_structure ,Lac Operon ,Synovial membrane ,business ,Ex vivo ,Subcutaneous tissue - Abstract
Objectives Gene therapy using cells as vectors to achieve secretion of therapeutic proteins may hold promise in the treatment of chronic diseases. Cell-based gene therapy with xenogeneic cells secreting antiinflammatory cytokines (IL-4, IL-13, or IL-1 receptor type II) has been found effective in mice with collagen-induced arthritis (CIA), a model for human rheumatoid arthritis. Autologous cells engineered to produce antiinflammatory cytokines were also effective in the mouse CIA model. In all these experiments, the cells were grafted into the subcutaneous tissue of the back, resulting in systemic treatment. To evaluate the feasibility of cell-based gene therapy confined to the joints, we performed intraarticular injections of autologous cells in a rhesus monkey with CIA, a model more similar to human RA. Methods We prepared ex vivo cultures of skin fibroblasts from the animal then transfected the cells with a plasmid carrying the lacZ gene. We injected these marker cells into metacarpophalangeal, metatarsophalangeal, and interphalangeal joints. Results Kinetic evaluation of synovial tissue X-gal labeling, which reflected reported gene expression by skin fibroblasts present within the synovium, showed significant labeling by transfected cells up to 6 days after intraarticular injection. Xenogeneic fibroblasts (Chinese hamster ovary cells) injected intraarticularly were also detected within synovial specimens; however, labeling intensity was less marked than with autologous cells. Our findings establish the feasibility of skin fibroblast grafting into the synovium. Conclusion This preliminary study opens the door to studies of heterotopic autologous transfected cells for the treatment of CIA in monkeys by direct gene transfer within joints.
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- 2007
5. Greffe de fibroblastes cutanés au sein de la membrane synoviale chez le primate non-humain: étude à court-terme
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Natacha Bessis, Tom W J Huizinga, Herbert P.M. Brok, Liliane Laroche, Bert A. 't Hart, Marie-Christophe Boissier, Catherine Fournier, and Delphine Lemeiter
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Rheumatology - Abstract
Resume Objectifs La therapie genique par vecteurs cellulaires autorisant la secretion de proteines therapeutiques est prometteuse dans le traitement des maladies chroniques. Nous avons deja montre, dans l'arthrite au collagene (AEC) chez la souris, modele de polyarthrite rhumatoide (PR), qu'il etait possible de traiter la maladie par therapie cellulaire avec des cellules xenogeniques secretant des cytokines anti-inflammatoires (IL-4, IL-13 ou recepteur leurre de l'IL-1). De meme, des cellules syngeniques transfectees par des genes de cytokines anti-inflammatoires etaient aussi efficaces dans ce modele. Dans l'ensemble des experiences, les cellules etaient greffees dans le tissu sous-cutane du dos, soit un traitement par voie systemique et non locale. Dans le but d'evaluer la possibilite d'une therapie cellulaire intra-articulaire, nous avons realise des injections de cellules autologues au sein de l'articulation chez des singes rhesus developpant une AEC, modele ressemblant a la PR humaine. Methodes Nous avons realise des cultures ex vivo de fibroblastes de peau de singes rhesus, et les avons transfecte par un plasmide codant le gene lacZ. Ces cellules ont ensuite ete injectees dans les metacarpophalangiennes, les metatarsophalangiennes, et les interphalangiennes. Resultats L'evaluation de la cinetique d'expression de lacZ (marquage avec X-gal des fibroblastes cutanes presents dans la membrane synoviale) revelait une presence de la proteine transgenique jusqu'a six jours apres l'injection intra-articulaire. Des fibroblastes xenogeniques (d'ovaires de Hamster chinois) injectes dans l'articulation etaient aussi detectes dans les synoviales, mais le marquage etait moins intense qu'avec les cellules autologues. Conclusion Notre travail met en evidence la faisabilite d'une greffe autologue heterotopique de fibroblastes cutanes dans la synoviale dans le traitement local de l'AEC chez le singe.
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- 2007
6. The human CMV-UL86 peptide 981-1003 shares a crossreactive T-cell epitope with the encephalitogenic MOG peptide 34-56, but lacks the capacity to induce EAE in rhesus monkeys
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Avraham Ben-Nun, Leonie A. Boven, Sandra Amor, Liesbeth Celebi-Paul, Herbert P.M. Brok, Marjan van Meurs, Nicole Kerlero de Rosbo, Jan Bauer, Bert A. 't Hart, Yolanda S. Kap, Anwar Jagessar, Geoff Keir, Jeffrey J. Bajramovic, Jon D. Laman, Rogier Q. Hintzen, Pathology, Amsterdam Neuroscience - Neuroinfection & -inflammation, AII - Inflammatory diseases, Immunology, and Neurology
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CD4-Positive T-Lymphocytes ,Male ,Encephalomyelitis, Autoimmune, Experimental ,T cell ,Immunology ,Epitopes, T-Lymphocyte ,CD8-Positive T-Lymphocytes ,Cross Reactions ,Lymphocyte Activation ,Epitope ,Antibodies ,Monocytes ,Myelin oligodendrocyte glycoprotein ,Cell Line ,Polyethylene Glycols ,Myelin ,immune system diseases ,medicine ,Immunology and Allergy ,Animals ,Humans ,Cell Proliferation ,Glycoproteins ,Myelin-associated glycoprotein ,biology ,Experimental autoimmune encephalomyelitis ,Brain ,medicine.disease ,Virology ,Macaca mulatta ,Peptide Fragments ,Recombinant Proteins ,nervous system diseases ,Myelin-Associated Glycoprotein ,medicine.anatomical_structure ,Cholesterol ,Neurology ,nervous system ,Spinal Cord ,Acute disseminated encephalomyelitis ,biology.protein ,Capsid Proteins ,Female ,Myelin-Oligodendrocyte Glycoprotein ,Neurology (clinical) ,CD8 ,Myelin Proteins - Abstract
Rhesus monkeys immunized with MOG(34-56), a dominant T-cell epitope from myelin/oligodendrocyte glycoprotein, develop an acute neurological disease resembling acute disseminated encephalomyelitis (ADEM) in humans. The typical large demyelinated lesions and mononuclear infiltrates in the monkey brains are caused by MOG(34-56) T-cells. We show that MOG(34-56)-reactive CD4+ and CD8+ T-cells are induced in monkeys immunized with a peptide from the human CMV major capsid protein (UL86; 981-1003), that shares sequence similarity with MOG(34-56). Monkeys sensitized against the viral peptide and subsequently challenged with MOG(34-56) display histological signs of encephalitis, but do not show overt neurological signs.
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- 2007
7. Quantitative MRI-pathology correlations of brain white matter lesions developing in a non-human primate model of multiple sclerosis
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Klaas Nicolay, Herbert P.M. Brok, Erwin L. A. Blezer, Jan Bauer, and Bert A. 't Hart
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Pathology ,medicine.medical_specialty ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Biology ,medicine.disease ,Luxol fast blue stain ,Hyperintensity ,White matter ,Myelin ,medicine.anatomical_structure ,medicine ,Molecular Medicine ,Radiology, Nuclear Medicine and imaging ,Magnetization transfer ,Spectroscopy ,Ex vivo - Abstract
Experimental autoimmune encephalomyelitis (EAE) induced with recombinant human myelin/oligodendrocyte glycoprotein in the common marmoset is a useful preclinical model of multiple sclerosis in which white matter lesions can be well visualized with MRI. In this study we characterized lesion progression with quantitative in vivo MRI (4.7 T; T(1) relaxation time +/- Gd-DTPA; T(2) relaxation time; magnetization transfer ratio, MTR, imaging) and correlated end stage MRI presentation with quantitative ex vivo MRI (formaldehyde fixed brains; T(1) and T(2) relaxation times; MTR) and histology. The histopathological characterization included axonal density measurements and the numeric quantification of infiltrated macrophages expressing markers for early active [luxol fast blue (LFB) or migration inhibition factor-related protein-14 positive] or late active/inactive [periodic acid Schiff (PAS) positive] demyelinating lesion. MRI experiments were done every two weeks until the monkeys were sacrificed with severe EAE-related motor deficits. Compared with the normal appearing white matter, lesions showed an initial increase in T(1) relaxation times, leakage of Gd-DTPA and decrease in MTR values. The progressive enlargement of lesions was associated with stabilized T(1) values, while T(2) initially increased and stabilized thereafter and MTR remained decreased. Gd-DTPA leakage was highly variable throughout the experiment. MRI characteristics of the cortex and (normal appearing) white matter did not change during the experiment. We observed that in vivo MTR values correlated positively with the number of early active (LFB+) and negatively with late active (PAS+) macrophages. Ex vivo MTR and relaxation times correlated positively with the number of PAS-positive macrophages. None of the investigated MRI parameters correlated with axonal density.
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- 2006
8. Reactivation by exon shuffling of a conservedHLA-DR3-like pseudogene segment in a New World primate species
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Ronald E. Bontrop, Herbert P.M. Brok, Natasja G. de Groot, Marit K. H. van der Wiel, Gaby G. M. Doxiadis, Jon J. van Rood, Nel Otting, and Bert A. 't Hart
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Primates ,Genetics ,Multidisciplinary ,Sequence Homology, Amino Acid ,Transcription, Genetic ,biology ,Pseudogene ,Molecular Sequence Data ,Histocompatibility Antigens Class II ,Locus (genetics) ,Sequence alignment ,Exons ,Biological Sciences ,biology.organism_classification ,Exon shuffling ,Callithrix ,Exon ,HLA-DR3 Antigen ,Animals ,Amino Acid Sequence ,Sequence Alignment ,Gene ,Pseudogenes ,New World monkey - Abstract
The common marmoset (Callithrix jacchus), a New World monkey species with a limited MHC class II repertoire, is highly susceptible to certain bacterial infections. Genomic analysis of exon 2 sequences documented the existence of only oneDRBregion configuration harboring three loci. Two of these loci display moderate levels of allelic polymorphism, whereas the-DRB*W12gene appears to be monomorphic. This study shows that only theCaja-DRB*W16and-DRB*W12loci produce functional transcripts. TheCaja-DRB1*03locus is occupied by a pseudogene, given that most of the transcripts, if detected at all, show imperfections and are present at low levels. Moreover, two hybrid transcripts were identified that feature the evolutionarily conserved peptide-binding motif characteristic for theCaja-DRB1*03gene. Thus, the severely reduced MHC class II repertoire in common marmosets has been expanded by reactivation of a pseudogene segment as a result of exon shuffling.
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- 2006
9. Transfer of Central Nervous System Autoantigens and Presentation in Secondary Lymphoid Organs
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Jon D. Laman, Rogier Q. Hintzen, Bert A. 't Hart, Herbert P.M. Brok, Paul van der Valk, Marjan van Meurs, Leonie A. Boven, Rivka Ravid, Louis Boon, Susanne Rensing, Alex F. de Vos, and Center of Experimental and Molecular Medicine
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Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,T-Lymphocytes ,Encephalomyelitis ,Immunology ,Antigen presentation ,Antigen-Presenting Cells ,Epitopes, T-Lymphocyte ,Inguinal Canal ,Biology ,Autoantigens ,Myelin ,medicine ,Animals ,Humans ,Immunology and Allergy ,Cell Aggregation ,Antigen Presentation ,MHC class II ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Brain ,Callithrix ,Myelin Basic Protein ,Dendritic cell ,medicine.disease ,Macaca mulatta ,Macaca fascicularis ,Protein Transport ,Tolerance induction ,medicine.anatomical_structure ,Axilla ,biology.protein ,Lymph Nodes ,Biomarkers ,Neck ,Spleen - Abstract
Dendritic cells are thought to regulate tolerance induction vs immunization by transferring Ags and peripheral signals to draining lymph nodes (LN). However, whether myelin Ag transfer and presentation in LN occurs during demyelinating brain disease is unknown. In this study, we demonstrate redistribution of autoantigens from brain lesions to cervical LN in monkey experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS). Immunohistochemical analysis revealed significantly more cells containing myelin Ags in cervical LN of monkeys with EAE compared with those of healthy control monkeys. Myelin Ags were observed in cells expressing dendritic cell/macrophage-specific markers, MHC class II, and costimulatory molecules. Moreover, these cells were directly juxtaposed to T cells, suggesting that cognate interactions between myelin-containing APC and T cells are taking place in brain-draining LN. Indeed, myelin Ag-reactive T cells were observed in cervical LN from marmosets and rhesus monkeys. Importantly, these findings were paralleled by our findings in human tissue. We observed significantly more myelin Ag-containing cells in LN of individuals with MS compared with those of control individuals. These cells expressed APC markers, as observed in marmosets and rhesus monkeys. These findings suggest that during MS and EAE, modulation of T cell reactivity against brain-derived Ags also takes place in cervical LN and not necessarily inside the brain. A major implication is that novel therapeutic strategies may be targeted to peripheral events, thereby circumventing the blood-brain barrier.
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- 2002
10. Non-human primate models of multiple sclerosis
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Margreet Jonker, Sandra Amor, Herbert P.M. Brok, Erwin L. A. Blezer, R. E. Bontrop, Jon D. Laman, Bert A. 't Hart, and Jan Bauer
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education.field_of_study ,Multiple sclerosis ,Immunology ,Population ,Biology ,medicine.disease ,biology.organism_classification ,medicine.disease_cause ,Callithrix ,Myelin oligodendrocyte glycoprotein ,Autoimmunity ,Immune system ,Demyelinating disease ,medicine ,biology.protein ,Immunology and Allergy ,Experimental pathology ,education ,Neuroscience - Abstract
The phylogenetic proximity between non-human primate species and humans is reflected by a high degree of immunological similarity. Non-human primates therefore provide important experimental models for disorders in the human population that are caused by the immune system, such as autoimmune diseases. In this paper we describe non-human primate models of multiple sclerosis, a chronic inflammatory and demyelinating disease of the human central nervous system. While reviewing data from the literature and our own research we will discuss the unique role of such models in the research of basic disease mechanisms and the development of new therapies.
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- 2001
11. An extensive monoclonal antibody panel for the phenotyping of leukocyte subsets in the common marmoset and the cotton-top tamarin
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Gareth D. Griffiths, Herbert P.M. Brok, Leah Scott, Bert A. 't Hart, and Rebecca J. Hornby
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CD antigen ,biology ,medicine.drug_class ,Biophysics ,Marmoset ,Tamarin ,Cell Biology ,Hematology ,Monoclonal antibody ,biology.organism_classification ,Molecular biology ,Epitope ,Pathology and Forensic Medicine ,chemistry.chemical_compound ,Endocrinology ,Immune system ,chemistry ,Antigen ,biology.animal ,medicine ,Fluorescein isothiocyanate - Abstract
New World monkeys are valuable animal models to study human diseases. To determine the phenotype of cells involved in immune responses, we used flow cytometry to screen a large panel of anti-human monoclonal antibodies (mAb) for cross-reactivity with cells of the common marmoset and the cotton-top tamarin. Certain antigens (e.g., CD2, CD8, CD20) are well conserved. However, CD10, CD23, and CD33 showed a clear discrepancy in their reaction patterns in both species, indicating that significant differences on the epitope level occurred during evolution. Epstein-Barr virus-transformed B-cell lines were shown to be a valuable tool for screening B-cell-specific reagents. In some cases, fluorescein isothiocyanate (FITC) and phycoerythrin (PE) modification of mAbs had a negative effect on the binding capacity, which stressed the importance of choosing the right label. Despite the fact that some CD antigens were not detected, adequate numbers of cross-reactive mAbs were identified to perform extensive studies on immunological functions in both the common marmoset and the cotton-top tamarin.
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- 2001
12. The major histocompatibility complex influences the ethiopathogenesis of MS-like disease in primates at multiple levels
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Herbert P.M. Brok, Ronald E. Bontrop, Bert A. 't Hart, Sandra Amor, and Immunology
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Male ,MBP, myelin basic protein ,TCR, T-cell recptor ,T-Lymphocytes ,primates ,experimental autoimmune encephalomyelitis ,APC, antigen presenting cell ,Major Histocompatibility Complex ,Mice ,Risk Factors ,TMEV, Theiler’s murine encephalomyelitis virus ,Immunology and Allergy ,SFV, Semliki Forest Virus ,Myelin Sheath ,EAE, experimental autoimmune encephalomyelitis ,Genetics ,CLN, cervical lymph node ,Experimental autoimmune encephalomyelitis ,Brain ,General Medicine ,PLP, proteolipid protein ,Female ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,BBB, blood-brain barrier ,Immunology ,Antigen-Presenting Cells ,chemical and pharmacologic phenomena ,Human leukocyte antigen ,Biology ,CNS, central nervous system ,Major histocompatibility complex ,Article ,MS, multiple sclerosis ,Immune system ,medicine ,Animals ,Humans ,MHC, major histocompatibility complex ,MOG, myelin/oligodendrocyte glycoprotein ,Antigen-presenting cell ,Autoantibodies ,HLA, human leukocyte antigen ,Multiple sclerosis ,T-cell receptor ,medicine.disease ,Ig, immunoglobulin ,Histocompatibility ,Disease Models, Animal ,biology.protein - Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease primarily affecting the central nervous system. Of the many candidate polymorphic major histocompatibility complex (MHC) and non-MHC genes contributing to disease susceptibility, including those encoding effector (cytokines and chemokines) or receptor molecules within the immune system (MHC, TCR, Ig or FcR), human leukocyte antigen (HLA) class II genes have the most significant influence. In this article we put forward the hypothesis that the influence of HLA genes on the risk to develop MS is actually the sum of multiple antigen presenting cell (APC) and T-cell interactions involving HLA class I and class II molecules. This article will also discuss that, because of the genetic and immunologic similarity to humans, autoimmune models of MS in non-human primates are the experimental models “par excellence” to test this hypothesis.
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- 2001
13. Myelin/oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis in common marmosets : the encephalitogenic T cell epitope pMOG24-36 is presented by a monomorphic MHC class II molecule
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Herbert P.M. Brok, Antonio Uccelli, Natasja G. de Groot, Bert A. 't Hart, Nicole Kerlero de Rosbo, Elisabetta Capello, Ronald E. Bontrop, Avraham Ben-Nun, Luca Roccatagliata, Gianluigi Mancardi, Klaas Nicolay, Jon D. Laman, and Immunology
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Male ,Animals, Antigen Presentation, Autoantibodies ,biosynthesis, Callithrix, Cell Line, Encephalomyelitis ,Autoimmune ,Experimental ,etiology/immunology/pathology, Epitopes ,T-Lymphocyte ,immunology/metabolism, Female, Histocompatibility Antigens Class II ,immunology/metabolism, Humans, Immunization, Injections ,Intradermal, Lymphocyte Activation, Male, Myelin Basic Proteins ,administration /&/ dosage/immunology, Myelin Proteins, Myelin-Associated Glycoprotein ,administration /&/ dosage/immunology, Peptide Fragments ,immunology/metabolism, T-Lymphocyte Subsets ,immunology ,Epitopes, T-Lymphocyte ,Lymphocyte Activation ,Epitope ,Myelin ,Epitopes ,Myelin Basic Proteins ,T-Lymphocyte Subsets ,immune system diseases ,Immunology and Allergy ,Encephalomyelitis ,Antigen Presentation ,Callithrix ,Myelin-Associated Glycoprotein ,medicine.anatomical_structure ,Female ,Myelin Proteins ,Encephalomyelitis, Autoimmune, Experimental ,Injections, Intradermal ,T cell ,Biology ,Myelin oligodendrocyte glycoprotein ,Cell Line ,Injections ,immunology/metabolism ,administration /&/ dosage/immunology ,Intradermal ,medicine ,Animals ,Humans ,Autoantibodies ,etiology/immunology/pathology ,Multiple sclerosis ,Histocompatibility Antigens Class II ,Myelin Basic Protein ,medicine.disease ,biology.organism_classification ,Virology ,Oligodendrocyte ,Peptide Fragments ,Myelin basic protein ,nervous system diseases ,nervous system ,Immunology ,biology.protein ,Myelin-Oligodendrocyte Glycoprotein ,Immunization ,biosynthesis - Abstract
Immunization of common marmosets (Callithrix jacchus) with a single dose of human myelin in CFA, without administration of Bordetella pertussis, induces a form of autoimmune encephalomyelitis (EAE) resembling in its clinical and pathological expression multiple sclerosis in humans. The EAE incidence in our outbred marmoset colony is 100%. This study was undertaken to assess the genetic and immunological basis of the high EAE susceptibility. To this end, we determined the separate contributions of immune reactions to myelin/oligodendrocyte glycoprotein (MOG) and myelin basic protein to the EAE induction. Essentially all pathological features of myelin-induced EAE were also found in animals immunized with MOG in CFA, whereas in animals immunized with myelin basic protein in CFA clinical and pathological signs of EAE were lacking. The epitope recognition by anti-MOG Abs and T cells were assessed. Evidence is provided that the initiation of EAE is based on T and B cell activation by the encephalitogenic phMOG14–36 peptide in the context of monomorphic Caja-DRB*W1201 molecules.
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- 2000
14. Preclinical models of multiple sclerosis in nonhuman primates
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S. Anwar Jagessar, Herbert P.M. Brok, Yolanda S. Kap, and Bert A. 't Hart
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business.industry ,Multiple sclerosis ,Immunology ,Experimental autoimmune encephalomyelitis ,medicine ,MEDLINE ,Immunology and Allergy ,medicine.disease ,medicine.disease_cause ,business ,Neuroscience ,Autoimmunity - Abstract
Biotechnology has enabled the development of specifically acting therapies for immune-mediated inflammatory disorders (IMIDs) based on biological molecules. The high species specificity precludes safety and effectivity testing in lower species (mice and rats), thus creating a need for valid experimental models in nonhuman primates (NHPs). Here, we review the creation of relevant NHP model(s) for multiple sclerosis (MS), an IMID of the human CNS. We will also discuss how the model(s) can help in the translation of a scientific principle developed in lower species into a therapy for MS.
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- 2010
15. Oligodendrocyte-specific protein is encephalitogenic in rhesus macaques and induces specific demyelination of the optic nerve
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Ivanela Kondova, Herbert P.M. Brok, Jeffrey J. Bajramovic, Sandra Amor, Boudewijn Ouwerling, S. Anwar Jagessar, Avraham Ben-Nun, Jan Bauer, Bert A. 't Hart, Linda van Straalen, and Pathology
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Central Nervous System ,Pathology ,medicine.medical_specialty ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,T-Lymphocytes ,Molecular Sequence Data ,Immunology ,Central nervous system ,Epitopes, T-Lymphocyte ,Nerve Tissue Proteins ,Biology ,Blindness ,Lymphocyte Activation ,medicine.disease_cause ,Epitope ,Autoimmunity ,Myelin ,medicine ,Animals ,Humans ,Immunology and Allergy ,Optic neuritis ,Amino Acid Sequence ,Sequence Homology, Amino Acid ,Multiple sclerosis ,Vaccination ,Optic Nerve ,medicine.disease ,Macaca mulatta ,Peptide Fragments ,Recombinant Proteins ,medicine.anatomical_structure ,Neuroimmunology ,Antibody Formation ,Claudins ,Leukocytes, Mononuclear ,Optic nerve ,Cytokines ,Epitopes, B-Lymphocyte ,Female ,Spleen ,Demyelinating Diseases - Abstract
Oligodendrocyte-specific protein (OSP) is a candidate autoantigen in the development of multiple sclerosis (MS). We evaluated the potential of OSP to induce EAE in rhesus monkeys, an out bred animal model for MS that is immunologically close to humans. Since OSP is a four-membrane spanning protein with highly hydrophobic regions, we synthesized recombinant proteins encompassing only the hydrophilic regions of human OSP (soluble (s)hOSP). Immunization with shOSP proteins induced clinical signs and histological features of optic neuritis in four out of ten rhesus monkeys. The development of clinical disease was associated with the presence of a strong cellular proliferative response to the immunizing shOSP protein. Analysis of the cellular responses in combination with neuropathological observations also indicates an important role for neutrophils in the disease process. Interestingly, all immunized monkeys developed antibody responses to OSP peptide 103-123, a B cell epitope previously identified in MS patients. These responses did not correlate with the development of clinical disease, but may have relevance as a biomarker for immunoreactivity towards OSP in myelin disorders. Our data demonstrate that in rhesus monkeys immune responses directed at OSP are encephalitogenic, leading to inflammatory responses throughout the central nervous system and to selective demyelination of the optic nerve.
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- 2008
16. Fast progression of recombinant human myelin/oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis in marmosets is associated with the activation of MOG34-56-specific cytotoxic T cells
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Herbert P.M. Brok, Jon D. Laman, Rogier Q. Hintzen, Erwin L. A. Blezer, Jan Bauer, Gustav J. Strijkers, Yolanda S. Kap, Bert A. 't Hart, E. J. Remarque, Paul Smith, S. Anwar Jagessar, and Other departments
- Subjects
Male ,Encephalomyelitis, Autoimmune, Experimental ,T cell ,Encephalomyelitis ,Immunology ,Autoimmunity ,Lymphocyte Activation ,Myelin oligodendrocyte glycoprotein ,Myelin ,immune system diseases ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Humans ,Autoantibodies ,Glycoproteins ,biology ,Experimental autoimmune encephalomyelitis ,Brain ,hemic and immune systems ,Callithrix ,medicine.disease ,Oligodendrocyte ,Peptide Fragments ,Recombinant Proteins ,nervous system diseases ,Myelin-Associated Glycoprotein ,medicine.anatomical_structure ,nervous system ,biology.protein ,Disease Progression ,Female ,Myelin-Oligodendrocyte Glycoprotein ,CD8 ,Myelin Proteins ,T-Lymphocytes, Cytotoxic - Abstract
The recombinant human (rh) myelin/oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) model in the common marmoset is characterized by 100% disease incidence, a chronic disease course, and a variable time interval between immunization and neurological impairment. We investigated whether monkeys with fast and slow disease progression display different anti-MOG T or B cell responses and analyzed the underlying pathogenic mechanism(s). The results show that fast progressor monkeys display a significantly wider specificity diversification of anti-MOG T cells at necropsy than slow progressors, especially against MOG34–56 and MOG74–96. MOG34–56 emerged as a critical encephalitogenic peptide, inducing severe neurological disease and multiple lesions with inflammation, demyelination, and axonal injury in the CNS. Although EAE was not observed in MOG74–96-immunized monkeys, weak T cell responses against MOG34–56 and low grade CNS pathology were detected. When these cases received a booster immunization with MOG34–56 in IFA, full-blown EAE developed. MOG34–56-reactive T cells expressed CD3, CD4, or CD8 and CD56, but not CD16. Moreover, MOG34–56-specific T cell lines displayed specific cytotoxic activity against peptide-pulsed B cell lines. The phenotype and cytotoxic activity suggest that these cells are NK-CTL. These results support the concept that cytotoxic cells may play a role in the pathogenesis of multiple sclerosis.
- Published
- 2008
17. Suppression of ongoing disease in a nonhuman primate model of multiple sclerosis by a human-anti-human IL-12p40 antibody
- Author
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Herbert P.M. Brok, E. J. Remarque, Jan Bauer, Bert A. 't Hart, Jacqueline Benson, Erwin L. A. Blezer, George Treacy, Jon D. Laman, Rogier Q. Hintzen, Sandra Amor, Pathology, Amsterdam Neuroscience - Neuroinfection & -inflammation, and AII - Inflammatory diseases
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,Encephalomyelitis ,Immunology ,Drug Evaluation, Preclinical ,Inflammation ,medicine ,Animals ,Humans ,Immunology and Allergy ,biology ,medicine.diagnostic_test ,Interleukin-12 Subunit p40 ,business.industry ,Multiple sclerosis ,Antibodies, Monoclonal ,Brain ,Callithrix ,Magnetic resonance imaging ,medicine.disease ,biology.organism_classification ,Interleukin-12 ,Magnetic Resonance Imaging ,Disease Models, Animal ,Protein Subunits ,Disease Progression ,Interleukin 12 ,biology.protein ,Experimental pathology ,Antibody ,medicine.symptom ,business - Abstract
IL-12p40 is a shared subunit of two cytokines with overlapping activities in the induction of autoreactive Th1 cells and therefore a potential target of therapy in Th1-mediated diseases. We have examined whether ongoing disease in a nonhuman primate model of multiple sclerosis (MS) can be suppressed with a new human IgG1κ Ab against human IL-12p40. Lesions developing in the brain white matter were visualized and characterized with standard magnetic resonance imaging techniques. To reflect the treatment of MS patients, treatment with the Ab was initiated after active brain white matter lesions were detected in T2-weighted images. In placebo-treated control monkeys we observed the expected progressive increase in the total T2 lesion volume and markedly increased T2 relaxation times, a magnetic resonance imaging marker of inflammation. In contrast, in monkeys treated with anti-IL-12p40 Ab, changes in the total T2 lesion volume and T2 relaxation times were significantly suppressed. Moreover, the time interval to serious neurological deficit was delayed from 31 ± 10 to 64 ± 20 days (odds ratio, 0.312). These results, in a disease model with high similarity to MS, are important for ongoing and planned trials of therapies that target IL-12 and/or IL-23.
- Published
- 2005
18. Severe T-cell depletion from the PALS leads to altered spleen composition in common marmosets with experimental autoimmune encephalomyelitis (EAE)
- Author
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Louis Boon, Bert A. 't Hart, Jon D. Laman, Rogier Q. Hintzen, Eric Claassen, Debby van Riel, Herbert P.M. Brok, Marjan van Meurs, Alex F. de Vos, Center of Experimental and Molecular Medicine, Amsterdam institute for Infection and Immunity, Science and Society, Immunology, Virology, and Neurology
- Subjects
Male ,Pathology ,Sialic Acid Binding Ig-like Lectin 1 ,Encephalomyelitis ,T-Lymphocytes ,Autoimmunity ,Lymphocyte Activation ,Immunologic ,Receptors ,Immunology and Allergy ,Lymphocytes ,Receptors, Immunologic ,Myelin Sheath ,Microscopy ,Membrane Glycoproteins ,biology ,Experimental autoimmune encephalomyelitis ,Nuclear Proteins ,Callithrix ,Immunohistochemistry ,Lymphoid organ ,CD ,medicine.anatomical_structure ,Lymphatic system ,Neurology ,Red pulp ,Female ,medicine.medical_specialty ,Encephalomyelitis, Autoimmune, Experimental ,Immunology ,Acid Phosphatase ,Plasma Cells ,Spleen ,Electron ,Lymphocyte Depletion ,Myelin oligodendrocyte glycoprotein ,Multiple sclerosis ,Experimental ,Immune system ,Microscopy, Electron, Transmission ,SDG 3 - Good Health and Well-being ,Antigens, CD ,Lymphopenia ,medicine ,Journal Article ,Transmission ,Animals ,Humans ,Comparative Study ,Antigens ,Animal ,Macrophages ,Germinal center ,medicine.disease ,Non-human primate ,Disease Models, Animal ,ran GTP-Binding Protein ,Immunoglobulin M ,Immunoglobulin G ,Disease Models ,biology.protein ,Neurology (clinical) ,Autoimmune - Abstract
Recent data suggest that the spleen is a crucial component of the immune system in the development of experimental autoimmune encephalomyelitis (EAE) in marmoset monkeys. Using immunohistochemistry, we investigated changes in the distribution of leukocytes in the spleen associated with clinical symptoms of EAE. Animals without EAE displayed well-developed T- and B-cell areas, germinal centers and red pulp. In contrast, a marked depletion of periarteriolar T cells with preservation of other elements was found in animals with clinical EAE. These findings suggest that immune responses within the spleen are impaired during a paralysing inflammatory process in the central nervous system.
- Published
- 2005
19. Decay-accelerating factor (CD55) is expressed by neurons in response to chronic but not acute autoimmune central nervous system inflammation associated with complement activation
- Author
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Herbert P.M. Brok, James Neal, B. Paul Morgan, Marjan van Meurs, Philippe Gasque, Bert A. 't Hart, Claire L. Harris, Nader Omidvar, Alexandra Chatagner, Johan Van Beek, and Jon D. Laman
- Subjects
Encephalomyelitis, Autoimmune, Experimental ,Glycosylphosphatidylinositols ,Complement receptor 1 ,Immunology ,Apoptosis ,CD59 Antigens ,Complement receptor ,Complement Hemolytic Activity Assay ,Cell Line ,Membrane Cofactor Protein ,Classical complement pathway ,Membrane Microdomains ,Antigens, CD ,Cell Movement ,Cell Line, Tumor ,Immunology and Allergy ,Animals ,Humans ,Complement Pathway, Classical ,Complement C1q ,Decay-accelerating factor ,Neurons ,Membrane Glycoproteins ,biology ,CD55 Antigens ,CD46 ,Brain ,Callithrix ,U937 Cells ,Opsonin Proteins ,Axons ,Cell biology ,Complement system ,Macaca fascicularis ,nervous system ,Acute Disease ,Chronic Disease ,Receptors, Complement 3b ,biology.gene ,K562 Cells ,Complement component 5a ,Signal Transduction - Abstract
There is compelling evidence that a unique innate immune response in the CNS plays a critical role in host defense and clearance of toxic cell debris. Although complement has been implicated in neuronal impairment, axonal loss, and demyelination, some preliminary evidence suggests that the initial insult consequently activates surrounding cells to signal neuroprotective activities. Using two different models of experimental autoimmune encephalomyelitis, we herein demonstrate selective C1q complement activation on neuron cell bodies and axons. Interestingly, in brains with chronic but not acute experimental autoimmune encephalomyelitis, C3b opsonization of neuronal cell bodies and axons was consistently associated with robust neuronal expression of one of the most effective complement regulators, decay-accelerating factor (CD55). In contrast, levels of other complement inhibitors, complement receptor 1 (CD35), membrane cofactor protein (CD46), and CD59 were largely unaffected on neurons and reactive glial cells in both conditions. In vitro, we found that proinflammatory stimuli (cytokines and sublytic doses of complement) failed to up-regulate CD55 expression on cultured IMR32 neuronal cells. Interestingly, overexpression of GPI-anchored CD55 on IMR32 was capable of modulating raft-associated protein kinase activities without affecting MAPK activities and neuronal apoptosis. Critically, ectopic expression of decay-accelerating factor conferred strong protection of neurons against complement attack (opsonization and lysis). We conclude that increased CD55 expression by neurons may represent a key protective signaling mechanism mobilized by brain cells to withstand complement activation and to survive within an inflammatory site.
- Published
- 2005
20. Treatment with chimeric anti-human CD40 antibody suppresses MRI-detectable inflammation and enlargement of pre-existing brain lesions in common marmosets affected by MOG-induced EAE
- Author
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Jon D. Laman, Mark de Boer, Louis Boon, Erwin L. A. Blezer, Herbert P.M. Brok, Jan Bauer, Bert A. 't Hart, Immunology, University of Groningen, Molecular Neuroscience and Ageing Research (MOLAR), and Translational Immunology Groningen (TRIGR)
- Subjects
Male ,Pathology ,MONOCLONAL-ANTIBODY ,Encephalomyelitis ,Anti-Inflammatory Agents ,non-human primate ,EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS ,CD40 ,Immunology and Allergy ,CD154 ,biology ,EAE ,Experimental autoimmune encephalomyelitis ,Marmoset ,Brain ,Callithrix ,CALLITHRIX-JACCHUS ,Magnetic Resonance Imaging ,Myelin-Associated Glycoprotein ,Neurology ,EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS ,B-CELLS ,medicine.symptom ,Immunosuppressive Agents ,Myelin Proteins ,medicine.medical_specialty ,Encephalomyelitis, Autoimmune, Experimental ,Recombinant Fusion Proteins ,Immunology ,Inflammation ,Myelin oligodendrocyte glycoprotein ,biology.animal ,medicine ,PROTEOLIPID PROTEIN ,Animals ,CD40 Antigens ,antibody therapy ,Autoantibodies ,MULTIPLE-SCLEROSIS LESIONS ,NONHUMAN PRIMATE ,medicine.disease ,biology.organism_classification ,Hyperintensity ,biology.protein ,Myelin-Oligodendrocyte Glycoprotein ,Neurology (clinical) ,LIGAND ,CELL RESPONSES - Abstract
Common marmosets, a Neotropical monkey species, are protected against clinical and neuropathological consequences of experimentally induced autoimmune encephalomyelitis (EAE) by prophylactic treatment with ch5D12, a humanized antagonist antibody against human CD40. In the current study we have tested whether ch5D12 acts therapeutically against the enlargement and inflammatory activity of existing (brain) white matter lesions using serial magnetic resonance imaging (MRI). The results show in all PBS treated monkeys (n=4) a rapid enlargement of T2 lesions together with an increment of the T2 signal intensity due to inflammatory edema. Treatment with ch5D12 delayed the enlargement of T2 lesions in 2 out of 3 tested monkeys while in 3 out of 3 monkeys the T2 signal increment of lesions was suppressed. In conjunction with previously published data on the clinical benefit of anti-CD40 treatment in the marmoset EAE model, the current findings support antibody-mediated blockade of CD40 interaction with its ligand CD154 as a potential treatment of MS. (C) 2005 Elsevier B.V. All rights reserved.
- Published
- 2005
21. Non-invasive measurement of brain damage in a primate model of multiple sclerosis
- Author
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Jan Bauer, Bert A. 't Hart, Jack T. W. E. Vogels, Erwin L. A. Blezer, Herbert P.M. Brok, TNO Voeding, and Immunology
- Subjects
CD4-Positive T-Lymphocytes ,Pathology ,positron emission tomography ,Magnetic Resonance Spectroscopy ,urinalysis ,X ray analysis ,multiple sclerosis ,proton nuclear magnetic resonance ,Mice ,allergic encephalomyelitis ,Myelin Basic Proteins ,Callithrix jacchus ,Biology Health ,immunopathology ,nuclear magnetic resonance imaging ,medicine.diagnostic_test ,Experimental autoimmune encephalomyelitis ,Marmoset ,Brain ,marmosets ,Callithrix ,neurologic disease ,Magnetic Resonance Imaging ,myelin ,Myelin-Associated Glycoprotein ,medicine.anatomical_structure ,chemometric analysis ,Molecular Medicine ,Biological Markers ,demyelination ,medicine.symptom ,non invasive measurement ,white matter ,Myelin Proteins ,Primates ,medicine.medical_specialty ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,diagnostic imaging ,Genes, MHC Class II ,review ,Rodentia ,Brain damage ,Neuropathology ,Biology ,White matter ,Th2 Cells ,Antigens, CD ,biology.animal ,medicine ,Animals, Outbred Strains ,Animalia ,Animals ,Humans ,human ,Molecular Biology ,Analytical research ,nuclear magnetic resonance spectroscopy ,marmoset ,neuropathology ,nonhuman ,Multiple sclerosis ,pattern recognition ,Magnetic resonance imaging ,Myelin Basic Protein ,medicine.disease ,biology.organism_classification ,brain injury ,Radiography ,Disease Models, Animal ,Chronic Disease ,Myelin-Oligodendrocyte Glycoprotein ,Biomarkers ,Demyelinating Diseases ,T-Lymphocytes, Cytotoxic - Abstract
Early recognition of whether a product has potential as a new therapy for treating multiple sclerosis (MS) relies upon the quality of the animal models used in the preclinical trials. The promising effects of new treatments in rodent models of experimental autoimmune encephalomyelitis (EAE) have rarely been reproduced in patients suffering from MS. EAE in outbred marmoset monkeys, Callithrix jacchus, is a valid new model, and might provide an experimental link between EAE in rodent models and human MS. Using magnetic resonance imaging techniques similar to those used in patients suffering from MS pathological abnormalities in the brain, white matter of the animal can be visualized and quantified. Moreover, NMR spectroscopy, in combination with pattern recognition, offers an advanced uroscopic technique for the identification of biomarkers of inflammatory demyelination.
- Published
- 2004
22. 1H-NMR spectroscopy combined with pattern recognition analysis reveals characteristic chemical patterns in urines of MS patients and non-human primates with MS-like disease
- Author
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Herbert P.M. Brok, Gerwin K. Spijksma, Bert A. 't Hart, Jan van der Greef, Jack T. W. E. Vogels, and Chris H. Polman
- Subjects
Male ,Encephalomyelitis, Autoimmune, Experimental ,Magnetic Resonance Spectroscopy ,Multiple Sclerosis ,Time Factors ,Urinalysis ,Urine ,Biology ,Tritium ,Pattern Recognition, Automated ,Myelin ,Species Specificity ,medicine ,Animals ,Humans ,Glycoproteins ,medicine.diagnostic_test ,business.industry ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Pattern recognition ,Callithrix ,Nuclear magnetic resonance spectroscopy ,medicine.disease ,biology.organism_classification ,Disease Models, Animal ,medicine.anatomical_structure ,Neurology ,Multivariate Analysis ,Proton NMR ,Female ,Immunization ,Neurology (clinical) ,Artificial intelligence ,business ,Myelin Proteins - Abstract
Proton nuclear magnetic resonance (1H-NMR) spectroscopy in combination with pattern recognition techniques were used to investigate the composition of organic compounds in urines from patients with multiple sclerosis (MS), patients with other neurological diseases (OND) and healthy controls (H). Using a valid animal model of MS, namely the common marmoset (Callithrix jacchus) model of experimental autoimmune encephalomyelitis (EAE), the relation of disease progression and alteration of the urine composition was investigated. Urine samples were collected during different stages of EAE, either induced with whole human myelin or with the myelin protein MOG in complete adjuvant. The urine samples were analysed with 1H-NMR spectroscopy allowing simultaneous detection of an array of compounds. Spectral differences between urines from EAE-affected and healthy monkeys were assessed with multivariate analysis. Evidence is provided that development of EAE is associated with changes in the chemical composition of the urine, in particular of compounds with NMR peaks in the region of the spectrum between 0.5 and 3.50 ppm. In addition, we found preliminary evidence for differences between urines from MS, OND and H groups. © 2003 Elsevier Science B.V. All rights reserved. Chemicals/CAS: tritium, 10028-17-8; Glycoproteins; Myelin Proteins; Tritium, 10028-17-8
- Published
- 2003
23. Prevention of experimental autoimmune encephalomyelitis in common marmosets using an anti-IL-12p40 monoclonal antibody
- Author
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Allen Schantz, George Treacy, Erwin L. A. Blezer, Herbert P.M. Brok, David Peritt, Marjan van Meurs, Jan Bauer, Jon D. Laman, and Bert A. 't Hart
- Subjects
Pathology ,medicine.medical_specialty ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,T-Lymphocytes ,Immunology ,Central nervous system ,Cross Reactions ,Myelin oligodendrocyte glycoprotein ,Proinflammatory cytokine ,In vivo ,biology.animal ,medicine ,Immunology and Allergy ,Animals ,Humans ,B-Lymphocytes ,biology ,Interleukin-12 Subunit p40 ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Marmoset ,Antibodies, Monoclonal ,Brain ,Callithrix ,medicine.disease ,Spinal cord ,Interleukin-12 ,Antibodies, Anti-Idiotypic ,Protein Subunits ,medicine.anatomical_structure ,Spinal Cord ,biology.protein ,Cytokines ,Myelin Proteins - Abstract
The experimental autoimmune encephalomyelitis (EAE) model in the common marmoset approximates recognized features of the human disease multiple sclerosis (MS) with regard to its clinical presentation as well as neuropathological and radiological aspects of the lesions in brain and spinal cord. IL-12 is a proinflammatory cytokine that is produced by APC and promotes differentiation of Th1 effector cells. IL-12 is produced in the developing lesions of patients with MS as well as in EAE-affected animals. Previously it was shown that interference in IL-12 pathways effectively prevents EAE in rodents. In this study we report that in vivo neutralization of IL-12p40 using a novel Ab has beneficial effects in the myelin-induced EAE model in common marmosets. The Ab was injected i.v. at 7-day intervals starting well after immunization (day 14) and was continued until the end of the study (day 86). Stable levels of the Ab were measured 3 days after each injection throughout the study period. During this period anti-Ab responses could not be detected. We demonstrate that anti-IL-12p40 treatment has a protective effect on the neurological dysfunction as well as on neuropathological changes normally observed in the brain and spinal cord of EAE-affected individuals.
- Published
- 2002
24. Protection of marmoset monkeys against EAE by treatment with a murine antibody blocking CD40 (mu5D12)
- Author
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Jan Bauer, Bert A. 't Hart, M.M. Schellekens, Louis Boon, Mark de Boer, Ahmad Kasran, Herbert P.M. Brok, Marjan van Meurs, Jon D. Laman, Jan Ceuppens, and Immunology
- Subjects
Male ,Encephalomyelitis, Autoimmune, Experimental ,medicine.medical_treatment ,T cell ,Immunology ,Priming (immunology) ,Cross Reactions ,Mice ,biology.animal ,medicine ,Animals ,Immunology and Allergy ,CD40 Antigens ,CD40 ,biology ,Experimental autoimmune encephalomyelitis ,Antibodies, Monoclonal ,Marmoset ,Callithrix ,Immunotherapy ,Dendritic cell ,medicine.disease ,medicine.anatomical_structure ,biology.protein ,Female ,Antibody - Abstract
CD40-CD40 ligand interactions are crucial to cognate interactions between T cells, B cells and antigen-presenting cells (APC), and contribute to non-antigen-specific effector functions of APC in inflammatory disorders. Here we demonstrate that functional blockade of CD40 with an antagonist mouse anti-human CD40 monoclonal antibody (mAb mu5D12) effectively prevents clinical expression of chronic demyelinating experimental autoimmune encephalomyelitis (EAE) in outbred marmoset monkeys, a preclinical model of multiple sclerosis. Anti-CD40 mAb interfered with development of clinical symptoms of marmoset EAE during the treatment period, even when treatment was started several weeks after T cell priming. Magnetic resonance imaging demonstrated inflammatory activity in the brain at initiation of antibody treatment, confirming that treatment interfered with the disease process. Access of therapeutic anti-CD40 to potential sites of action, the secondary lymphoid organs and the brain white matter lesions, was visualized in situ. The present data are the first to demonstrate the clinical potential of blocking APC and effector cell functions using murine antagonist anti-CD40 mAb in the treatment of chronic inflammatory diseases.
- Published
- 2002
25. Prevention of experimental autoimmune encephalomyelitis in the common marmoset (Callithrix jacchus) using a chimeric antagonist monoclonal antibody against human CD40 is associated with altered B cell responses
- Author
-
Jan Ceuppens, M. van Meurs, Erwin L. A. Blezer, Jan Bauer, Bert A. 't Hart, Herbert P.M. Brok, Louis Boon, Antonio Ortiz-Buijsse, Jon D. Laman, Seema Ramdien-Murli, M.M. Schellekens, M de Boer, and Immunology
- Subjects
Encephalomyelitis, Autoimmune, Experimental ,Time Factors ,medicine.drug_class ,Recombinant Fusion Proteins ,Encephalomyelitis ,CD40 Ligand ,Immunology ,Lymphocyte Activation ,Monoclonal antibody ,Myelin oligodendrocyte glycoprotein ,biology.animal ,medicine ,Animals ,Humans ,Immunology and Allergy ,CD40 Antigens ,B-Lymphocytes ,biology ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Antibodies, Monoclonal ,Marmoset ,Callithrix ,medicine.disease ,biology.organism_classification ,Myelin-Associated Glycoprotein ,biology.protein ,Immunization ,Myelin-Oligodendrocyte Glycoprotein ,Antibody ,Myelin Proteins - Abstract
Inhibition of CD40-CD40 ligand interaction is a potentially effective approach for treatment of autoimmune diseases, such as multiple sclerosis. We have investigated this concept with a chimeric antagonist anti-human CD40 mAb (ch5D12) in the marmoset monkey experimental autoimmune encephalomyelitis (EAE) model. Marmosets were immunized with recombinant human myelin oligodendrocyte glycoprotein (rMOG) and treated from the day before immunization (day −1) until day 50 with either ch5D12 (5 mg/kg every 2–4 days) or placebo. On day 41 after the induction of EAE, four of four placebo-treated monkeys had developed severe clinical EAE, whereas all animals from the ch5D12-treated group were completely free of disease symptoms. High serum levels of ch5D12 associated with complete coating of CD40 on circulating B cells were found. At necropsy placebo- and ch5D12-treated animals showed similar MOG-specific lymphoproliferative responses in vitro, but ch5D12 treatment resulted in strongly reduced anti-MOG IgM Ab responses and delayed anti-MOG IgG responses. Most importantly, treatment with ch5D12 prevented intramolecular spreading of epitope recognition. Postmortem magnetic resonance imaging and immunohistologic analysis of the CNS showed a markedly reduced lesion load after ch5D12 treatment. In conclusion, the strong reduction of clinical, pathological, and radiological aspects of EAE by ch5D12 treatment in this preclinical model points to a therapeutic potential of this engineered antagonist anti-CD40 mAb for multiple sclerosis.
- Published
- 2001
26. Delivery to the central nervous system of a nonreplicative herpes simplex type 1 vector engineered with the interleukin 4 gene protects rhesus monkeys from hyperacute autoimmune encephalomyelitis
- Author
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Luciano Adorini, Antonio Uccelli, Roberto Furlan, Giancarlo Comi, Gaetano Desina, Giuseppe Penna, Francesca Ruffini, Peggy Marconi, Alessandra Bergami, Bert A. 't Hart, Gianvito Martino, Pietro Luigi Poliani, Herbert P.M. Brok, Joseph C. Glorioso, Marco Rovaris, Poliani, Pl, Brok, H, Furlan, R, Ruffini, F, Bergami, A, Desina, G, Marconi, Pc, Rovaris, M, Uccelli, A, Glorioso, Jc, Penna, G, Adorini, L, Martino, Gianvito, Comi, G, and Hart, B
- Subjects
Central Nervous System ,Male ,Time Factors ,T-Lymphocytes ,Genetic enhancement ,Encephalomyelitis ,biosynthesis/genetics ,Herpesvirus 1, Human ,medicine.disease_cause ,immunology ,Myelin ,Transforming Growth Factor beta ,Chemokine CCL2 ,Reverse Transcriptase Polymerase Chain Reaction ,Experimental autoimmune encephalomyelitis ,Brain ,Gene Therapy ,Magnetic Resonance Imaging ,Up-Regulation ,medicine.anatomical_structure ,Spinal Cord ,Blood-Brain Barrier ,Systemic administration ,Cytokines ,Molecular Medicine ,Cell Division ,Human ,Genetic Vectors ,Central nervous system ,Down-Regulation ,Enzyme-Linked Immunosorbent Assay ,Blood–brain barrier ,methods ,Autoimmune Diseases ,genetics/prevention /&/ control ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Herpesvirus 1 ,Tumor Necrosis Factor-alpha ,business.industry ,Genetic Therapy ,medicine.disease ,Macaca mulatta ,Herpes simplex virus ,Animals, Autoimmune Diseases ,genetics/prevention /&/ control, Blood-Brain Barrier, Brain ,pathology, Cell Division, Central Nervous System ,metabolism, Chemokine CCL2 ,biosynthesis, Cytokines ,biosynthesis, Down-Regulation, Encephalomyelitis ,genetics/prevention /&/ control, Enzyme-Linked Immunosorbent Assay, Gene Therapy ,methods, Genetic Vectors, Herpesvirus 1 ,genetics, Humans, Interleukin-4 ,biosynthesis/genetics, Macaca mulatta, Magnetic Resonance Imaging, Male, Reverse Transcriptase Polymerase Chain Reaction, Spinal Cord ,immunology, T-Lymphocytes ,cytology, Time Factors, Transforming Growth Factor beta ,biosynthesis, Tumor Necrosis Factor-alpha ,biosynthesis, Up-Regulation ,Immunology ,cytology ,pathology ,Interleukin-4 ,biosynthesis ,business ,metabolism - Abstract
Systemic administration of antiinflammatory molecules to patients affected by immune-mediated inflammatory demyelinating diseases of the central nervous system (CNS) has limited therapeutic efficacy due to the presence of the blood-brain barrier (BBB). We found that three of five rhesus monkeys injected intrathecally with a replication-defective herpes simplex virus (HSV) type 1-derived vector engineered with the human interleukin 4 (IL-4) gene were protected from an hyperacute and lethal form of experimental autoimmune encephalomyelitis induced by whole myelin. The intrathecally injected vector consistently diffused within the CNS via the cerebrospinal fluid and infected ependymal cells, which in turn sustained in situ production of IL-4 without overt immunological or toxic side effects. In EAE-protected monkeys, IL-4-gene therapy significantly decreased the number of brain as well as spinal cord inflammatory perivenular infiltrates and the extent of demyelination, necrosis, and axonal loss. The protective effect was associated with in situ downregulation of inflammatory mediators such as tumor necrosis factor alpha (TNF-alpha) and monocyte chemoattractant protein 1 (MCP-1), upregulation of transforming growth factor beta (TGF-beta), and preservation of BBB integrity. Our results indicate that intrathecal delivery of HSV-1-derived vectors containing antiinflammatory cytokine genes may play a major role in the future therapeutic armamentarium of inflammatory CNS-confined demyelinating diseases and, in particular, in the most fulminant forms where conventional therapeutic approaches have, so far, failed to achieve a satisfactory control of the disease evolution.
- Published
- 2001
27. Demyelination and axonal damage in a non-human primate model of multiple sclerosis
- Author
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Herbert P.M. Brok, Antonio Uccelli, B. A. ‘t Hart, Gianluigi Mancardi, Luca Massacesi, Debora Giunti, Luca Roccatagliata, Elisabetta Capello, and Ronald E. Bontrop
- Subjects
metabolism/pathology ,Pathology ,medicine.medical_specialty ,Encephalomyelitis, Autoimmune, Experimental ,Neurofilament ,Multiple Sclerosis ,Axonal loss ,Electron ,Lesion ,White matter ,Amyloid beta-Protein Precursor ,Experimental ,mental disorders ,medicine ,Amyloid precursor protein ,Animals ,Axon ,Encephalomyelitis ,Microscopy ,biology ,metabolism, Animals, Axons ,metabolism/pathology, Brain ,pathology, Callithrix, Demyelinating Diseases ,metabolism/pathology, Encephalomyelitis ,Autoimmune ,metabolism/pathology, Immunohistochemistry, Microscopy ,Electron, Multiple Sclerosis ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Brain ,Callithrix ,medicine.disease ,Immunohistochemistry ,Axons ,Microscopy, Electron ,medicine.anatomical_structure ,nervous system ,Neurology ,biology.protein ,pathology ,Neurology (clinical) ,medicine.symptom ,Neuroscience ,metabolism ,Demyelinating Diseases - Abstract
The demyelinating plaque is the paradigmatic lesion of multiple sclerosis (MS), but only recently attention has been given to axonal damage and to its role in the pathophysiology of disease. Albeit the possible relevance of axonal loss in MS and its experimental models, the amount and timing of axonal sufferance has been addressed only in experimental autoimmune encephalomyelitis (EAE) of rodents. In this report we observed that, in the marmoset model of EAE, axonal damage occurs early during the demyelinating process as assessed by immunoreactivity for amyloid precursor protein (APP) and non-phosphorylated neurofilaments (SMI-32 positive) detected mostly in early active lesions compared to late active and normal appearing white matter. The rare occurrence of morphological features of axonal transection, such as APP or SMI-32 positive spheroids and swellings, as well as an increase of neurofilament density in the demyelinated axons without accumulation of electron dense organelles or osmiophilic bodies, at electron microscopy, suggests that early axonal damage may be, at least in part, a reversible process. These findings are of relevance for the development of therapies, which can protect axons and enhance their function and survival.
- Published
- 2001
28. Rhesus monkeys are highly susceptible to experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein: characterisation of immunodominant T- and B-cell epitopes
- Author
-
Joel Kaye, Herbert P.M. Brok, Avraham Ben-Nun, Nicole Kerlero de Rosbo, Jan Bauer, and Bert A. 't Hart
- Subjects
Central Nervous System ,Male ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,Immunology ,Epitopes, T-Lymphocyte ,Biology ,medicine.disease_cause ,Major histocompatibility complex ,Epitope ,Autoimmunity ,Myelin oligodendrocyte glycoprotein ,immune system diseases ,medicine ,Immunology and Allergy ,Animals ,Cell Lineage ,B cell ,Autoantibodies ,chemistry.chemical_classification ,Immunodominant Epitopes ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,medicine.disease ,Virology ,Macaca mulatta ,nervous system diseases ,Amino acid ,Disease Models, Animal ,Myelin-Associated Glycoprotein ,medicine.anatomical_structure ,nervous system ,Neurology ,chemistry ,biology.protein ,Epitopes, B-Lymphocyte ,Female ,Immunization ,Myelin-Oligodendrocyte Glycoprotein ,Neurology (clinical) ,Myelin Proteins - Abstract
Eight rhesus monkeys with different MHC backgrounds were immunized with myelin oligodendrocyte glycoprotein (MOG). All developed severe experimental autoimmune encephalomyelitis associated with large inflammatory foci and extensive demyelination. T-cell autoreactivity to MOG was directed against three main epitopes encompassed within amino acids 4–20, 35–50 and 94–116, of which two are also immunodominant epitopes for the autoimmune T cell response to MOG in patients with MS. A strong B cell response to MOG was observed in all monkeys and major epitopes recognized were located within amino acids 4–26, 24–46 and 44–66/54–76.
- Published
- 2000
29. A new primate model for multiple sclerosis in the common marmoset
- Author
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Ronald E. Bontrop, Herbert P.M. Brok, Marjan van Meurs, Louis Boon, Luca Massacesi, Jan Bauer, Jon D. Laman, Bert A. 't Hart, and Immunology
- Subjects
Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,animal diseases ,Encephalomyelitis ,medicine.medical_treatment ,Immunology ,Genes, MHC Class II ,Receptors, Antigen, T-Cell ,Twins ,Rodentia ,Major histocompatibility complex ,Autoimmune Diseases ,Species Specificity ,biology.animal ,Histocompatibility Antigens ,medicine ,Animals ,Primate ,CD40 Antigens ,biology ,Chimera ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Marmoset ,Antibodies, Monoclonal ,Callithrix ,Cercopithecidae ,Immunotherapy ,Interferon-beta ,medicine.disease ,biology.organism_classification ,Rats ,Disease Models, Animal ,Desensitization, Immunologic ,Rats, Inbred Lew ,Cebidae ,Acute Disease ,biology.protein ,Disease Susceptibility ,Rolipram ,Immunosuppressive Agents ,Demyelinating Diseases - Abstract
Experimental autoimmune encephalomyelitis (EAE) in outbred marmoset monkeys (Callithrix jacchus) is a recently developed nonhuman primate model of multiple sclerosis. Here, Bert 't Hart and colleagues compare this model to EAE in rhesus monkeys, highlighting autoimmune mechanisms in CNS inflammation and demyelination, including the role of major histocompatibility complex restriction and preclinical evaluation of innovative immunotherapies.
- Published
- 2000
30. Restricted immune responses lead to CNS demyelination and axonal damage
- Author
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Monica Colombo, Antonio Uccelli, Herbert P.M. Brok, Nicole Kerlero de Rosbo, Gianluigi Mancardi, Luca Roccatagliata, Debora Giunti, Avraham Ben-Nun, Paola Gazzola, Bert A. 't Hart, Elisabetta Capello, and Mariella Dono
- Subjects
Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,CNS demyelination ,Immunology ,Biology ,Epitope ,Myelin oligodendrocyte glycoprotein ,Myelin ,Experimental ,medicine ,Immunology and Allergy ,Animals ,Humans ,Encephalomyelitis ,Animals, Axons ,immunology/pathology, Encephalomyelitis ,Autoimmune ,immunology/pathology, Humans, Multiple Sclerosis ,immunology/pathology ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Autoantibody ,medicine.disease ,Axons ,Myelin basic protein ,medicine.anatomical_structure ,Neurology ,biology.protein ,Neurology (clinical) - Abstract
Although autoreactive T-cells have a pivotal role in initiating the inflammatory process in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS), recent evidence suggests a relevant role for autoantibodies specific for myelin proteins as well. To examine the role of B-cells in the cerebrospinal fluid of patients with MS, we analyzed the V H gene usage in ten MS patients by PCR technologies. Analysis of HCDR3 length revealed an oligoclonal accumulation of B-cells. Sequence analysis of the V H 3 and V H 4 γ transcripts of two MS individuals demonstrated that this accumulation was related to the expansion and somatic diversification of a limited groups of B-cell clones. These findings are indicative of a chronic and intense antigenic stimulation occurring in the CNS. Animal models, such as EAE, are of particular importance in order to elucidate the pathogenetic effector mechanisms in autoimmune demyelination. In a non-human primate model of EAE, we describe that the immunodominant T-cell epitope is presented exclusively by a monomorphic DRB1 allele, suggesting that susceptibility to EAE may be linked to this unique restriction and, therefore, providing a possible mechanism for MHC linkage to diseases. Moreover, we report on the presence of inflammation, sharp demyelination and axonal damage in EAE induced with whole myelin as well as with recombinant myelin oligodendrocyte glycoprotein (MOG), but not with myelin basic protein alone. The presence of axonal pathology was supported by immunohistochemistry with anti-amyloid precursor protein and anti-non phosphorilated neurofilaments monoclonal antibodies within early active demyelinated plaques. These findings suggest that axonal damage may be an early event in the pathogenesis of autoimmune demyelinating diseases of the CNS and highlights the importance of animal models in which therapies targeting repair and axonal survival may be exploited.
- Published
- 2000
31. The common marmoset: a new world primate species with limited Mhc class II variability
- Author
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N. G. de Groot, G.G.M. Doxiadis, Nel Otting, A. A. L. Menezes, S.M.G. Antunes, Herbert P.M. Brok, and Ronald E. Bontrop
- Subjects
Male ,Population ,Genes, MHC Class II ,Molecular Sequence Data ,Locus (genetics) ,Polymerase Chain Reaction ,MHC Class II Gene ,biology.animal ,Sequence Homology, Nucleic Acid ,Genetic variation ,Animals ,Amino Acid Sequence ,Allele ,education ,Alleles ,Conserved Sequence ,Phylogeny ,DNA Primers ,Genetics ,education.field_of_study ,Multidisciplinary ,Polymorphism, Genetic ,biology ,Base Sequence ,Sequence Homology, Amino Acid ,Chimera ,Haplotype ,Histocompatibility Antigens Class II ,Marmoset ,Genetic Variation ,Callithrix ,DNA ,Biological Sciences ,biology.organism_classification ,Haplotypes ,Female - Abstract
The common marmoset (Callithrix jacchus) is a New World primate species that is highly susceptible to fatal infections caused by various strains of bacteria. We present here a first step in the molecular characterization of the common marmoset’sMhcclass II genes by nucleotide sequence analysis of the polymorphic exon 2 segments. For this study, genetic material was obtained from animals bred in captivity as well as in the wild. The results demonstrate that the common marmoset has, like other primates, apparently functionalMhc-DRand -DQregions, but theMhc-DPregion has been inactivated. At the -DRand -DQloci, only a limited number of lineages were detected. On the basis of the number of alleles found, the -DQAand -Bloci appear to be oligomorphic, whereas only a moderate degree of polymorphism was observed for two of threeMhc-DRBloci. The contact residues in the peptide-binding site of the Caja-DRB1*03 lineage members are highly conserved, whereas the -DRB*W16 lineage members show more divergence in that respect. The latter locus encodes five oligomorphic lineages whose members are not observed in any other primate species studied, suggesting rapid evolution, as illustrated by frequent exchange of polymorphic motifs. All common marmosets tested were found to share one monomorphic type ofCaja-DRB*W12allele probably encoded by a separate locus. Common marmosets apparently lack haplotype polymorphism because the number ofCaja-DRBloci present per haplotype appears to be constant. Despite this, however, an unexpectedly high number of allelic combinations are observed at the haplotypic level, suggesting thatCaja-DRBalleles are exchanged frequently between chromosomes by recombination, promoting an optimal distribution of limitedMhcpolymorphisms among individuals of a given population. This peculiar genetic make up, in combination with the limited variability of the major histocompatability complex class II repertoire, may contribute to the common marmoset’s susceptibility to particular bacterial infections.
- Published
- 1998
32. Histopathological characterization of magnetic resonance imaging-decectable brain white matter lesions in a primate model of multiple sclerosis
- Author
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Bert Melchers, Luca Massacesi, Klaas Nicolay, Jan Bauer, Ronald E. Bontrop, Henk-Jan Muller, Herbert P.M. Brok, Bert A. 't Hart, and Hans Lassmann
- Subjects
Pathology ,medicine.medical_specialty ,biology ,medicine.diagnostic_test ,business.industry ,Multiple sclerosis ,Encephalomyelitis ,Experimental autoimmune encephalomyelitis ,Magnetic resonance imaging ,Neuropathology ,medicine.disease ,biology.organism_classification ,Callithrix ,Pathology and Forensic Medicine ,White matter ,Lesion ,medicine.anatomical_structure ,Magnetic Resonance Imaging ,Brain White Matter Lesions ,Experimental Autoimmune Encephalomyelitis ,Immunology ,medicine ,medicine.symptom ,business - Abstract
Experimental autoimmune encephalomyelitis in the common marmoset, a nonhuman primate species (Callithrix jacchus), is a new model for multiple sclerosis. Given the close immunological relationship between marmosets and humans, it is an attractive model for investigating immunopathological pathways relevant to multiple sclerosis and to evaluate new treatments for the disease. Unlike in the originally documented model, experimental autoimmune encephalomyelitis induced without the use of Bordetella pertussis led to a chronic disease of moderate severity. The clinical course of experimental autoimmune encephalomyelitis in the present model was mainly chronic and progressive, but periods of incomplete remission did occur. At the chronic stage of the disease, actively demyelinating lesions were found together with inactive demyelinated and remyelinated (shadow) plaques. Before immunization and during clinically active experimental autoimmune encephalomyelitis, T1- and T2-weighted magnetic resonance brain images were obtained. Correlation of the data from the magnetic resonance images and the neuropathology analysis revealed that the hyperintense regions in T2-weighted images represented both active and inactive remyelinating lesions. Quantification showed that the number of lesions in T2-weighted magnetic resonance images equalled those found by pathological examination, and thus T2-weighted magnetic resonance imaging can be used to discern the total lesion load. Extravasation of gadolinium-diethylenetriamine-penta-acetic acid (triple dose) was found only in lesions, which by histopathology were shown to be engaged in the process of active demyelination.
- Published
- 1998
33. Non-human primate models of experimental autoimmune encephalomyelitis: variations on a theme
- Author
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Herbert P.M. Brok, Jan Bauer, Bert A. 't Hart, Sandra Amor, and Immunology
- Subjects
Encephalomyelitis, Autoimmune, Experimental ,Immunology ,Central nervous system ,Population ,Disease ,Biology ,medicine.disease_cause ,Autoimmunity ,medicine ,Animals ,Humans ,Immunology and Allergy ,education ,education.field_of_study ,Non human primate ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Callithrix ,medicine.disease ,biology.organism_classification ,Macaca mulatta ,Disease Models, Animal ,medicine.anatomical_structure ,Neurology ,Neurology (clinical) ,Neuroscience - Abstract
Despite years of intensive research into multiple sclerosis (MS) scientists have not yet succeeded in developing an absolute therapy for the treatment of this disabling disease of the human central nervous system. The wide immunological gap between inbred rodent strains and the heterogeneous human population is probably the single most important factor that hampers the translation of scientific principles developed in rodents into effective therapies for MS. Because of the closer immunological proximity to humans, non-human primates provide useful experimental models that may help to bridge this gap. Here we review the models of experimental autoimmune encephalomyelitis in rhesus macaques and common marmosets. We will discuss the salient points of the models and suggest how these may represent the spectrum of inflammatory demyelinating diseases of the central nervous system in humans.
- Published
- 2005
34. IgG4 immunotherapy for the protection of surface receptors against complement mediated damage in autoimmunity
- Author
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Paul W. H. I. Parren, Marc H. De Baets, Herbert P.M. Brok, B. A. ‘t Hart, Pilar Martinez-Martinez, and Mario Losen
- Subjects
medicine.medical_treatment ,Immunology ,medicine ,Complement receptor ,Immunotherapy ,Biology ,medicine.disease_cause ,Receptor ,Molecular Biology ,Autoimmunity ,Complement (complexity) - Published
- 2007
35. Analysis of EAE-blockade by targeting CD40-CD40L interactions in mice and marmoset monkeys
- Author
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M. van Meurs, M. de Boer, M.M. Schellekens, Hans Lassmann, Jon D. Laman, Bert A. 't Hart, Herbert P.M. Brok, Jan Bauer, Ghislain Opdenakker, and Johan Ceuppens
- Subjects
Neurology ,Cd40 cd40l ,biology.animal ,Immunology ,Immunology and Allergy ,Marmoset ,Neurology (clinical) ,Pharmacology ,Biology ,Blockade - Published
- 1998
36. Towards adoptive transfer of human MS into rhesus monkeys: Inhibition of the cellular immune response of rhesus monkeys to human PBMC in vitro by humanised antibodies against the IL-2 receptor α-chain
- Author
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Herbert P.M. Brok, Cees W. de Groot, and Bert A. 't Hart
- Subjects
Adoptive cell transfer ,Immune system ,biology ,Immunology ,biology.protein ,Immunology and Allergy ,IL-2 receptor ,Antibody ,Virology ,Peripheral blood mononuclear cell ,In vitro - Published
- 1997
37. Collagen-induced arthritis in rhesus monkeys: evaluation of markers for inflammation and joint degradation
- Author
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J. A. D. M. de Roos, Herbert P.M. Brok, B. A. ‘t Hart, Ruud A. Bank, J. M. Te Koppele, Margreet Jonker, J. Hakimi, H.M. Theuns, and Centraal Instituut voor Voedingsonderzoek TNO
- Subjects
Male ,Deoxypyridinoline ,Arthritis ,chemistry.chemical_compound ,Disease predisposition ,Cyclosporin a ,Synovial Fluid ,Pharmacology (medical) ,Disease activity ,Disease course ,Amino Acids ,Diagnostic value ,Priority journal ,Pyridinoline ,C reactive protein ,biology ,C-Reactive Protein ,Cross-Linking Reagents ,Rheumatoid arthritis ,Antirheumatic Agents ,Cyclosporine ,Collagen-induced arthritis ,Female ,Biological Markers ,Collagen ,Urine level ,medicine.medical_specialty ,Remission ,Weight reduction ,Excretion ,Rheumatology ,Cartilage degeneration ,Internal medicine ,Weight Loss ,medicine ,Synovial fluid ,Animals ,Animal model ,Animal experiment ,Disease severity ,Weight gain ,Nutrition ,Inflammation ,business.industry ,C-reactive protein ,medicine.disease ,Nonhuman ,Arthritis, Experimental ,Macaca mulatta ,Endocrinology ,chemistry ,Immunology ,biology.protein ,Rhesus monkey ,Blood level ,Joint degeneration ,Joints ,Disease marker ,business ,Controlled study ,Biomarkers ,Disease markers - Abstract
The objective of this study was to analyse parameters in rhesus monkey collagen-induced arthritis (CIA) with which the inflammation and destruction of the joints can be described in quantitative terms. CIA was induced in genetically susceptible and resistant monkeys, which can be distinguished on the basis of the dominant resistance marker Mamu-A26. The disease course was monitored daily using a semiquantitative scoring system. Plasma samples were collected once or twice weekly and analysed for C-reactive protein (CRP). Urines were collected overnight once a week and analysed for excretion rates of the collagen cross-links hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP). The results show that periods of active CIA are characterized by substantial weight loss and increased plasma CRP levels, followed shortly thereafter by increased excretion rates of the collagen cross-links HP and LP. Remission of the disease can be recognized by a decline in plasma CRP levels and especially an increase in body weight. The highest CRP levels were found in the most severely arthritic monkeys, indicating a possible relationship of the absolute plasma CRP levels to the severity of inflammation. During periods of active arthritis, increased excretion rates of collagen cross-links HP and LP in the urine were found. In particular, the major collagen cross-link in articular cartilage, HP, showed a strong increase (9- to 15-fold). The excretion rates of LP, which is considered as a bone-specific degradation marker, only increased 4- to 6-fold, thus indicating predominant destruction of cartilage and less of bone. In conclusion, the severity of CIA can be monitored in a quantitative manner using plasma CRP levels, urinary excretion rates of HP and LP, and body weights, superimposed on semiquantitative clinical scores. The parameters also facilitate a more objective assessment of the effect of anti-arthritic drugs in the model than with the clinical scores alone.
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