http://repub.eur.nl/res/aut/34812/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/27549/ 2010-04-01T00:00:00Z 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 (MOG34-56) 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 MOG34-56 peptide alone or in combination with the nonencephalitogenic peptide MOG74-96 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 CD3CD4/8CD56 T cells against MOG34-56. Upon ex vivo stimulation, these T cells produced more interleukin 17A compared with TH1 cytokines (e.g. interferon-γ) 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. http://repub.eur.nl/res/pub/25393/ 2009-12-01T00:00:00Z 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. http://repub.eur.nl/res/pub/37107/ 2007-09-01T00:00:00Z 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. http://repub.eur.nl/res/pub/36485/ 2007-04-01T00:00:00Z Experimental autoimmune encephalomyelitis (EAE) induced with recombinant human myelin/oligoden-drocyte 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; T1, relaxation time ± Gd-DTPA; T2relaxation time; magnetization transfer ratio, MTR, imaging) and correlated end stage MRI presentation with quantitative ex vivo MRI (formaldehyde fixed brains; T1, and T2relaxation 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 T1, relaxation times, leakage of Gd-DTPA and decrease in MTR values. The progressive enlargement of lesions was associated with stabilized T1, values, while T2initially 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. Copyright http://repub.eur.nl/res/pub/35869/ 2007-01-01T00:00:00Z Rhesus monkeys immunized with MOG34-56, 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 MOG34-56T-cells. We show that MOG34-56-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 MOG34-56. Monkeys sensitized against the viral peptide and subsequently challenged with MOG34-56display histological signs of encephalitis, but do not show overt neurological signs. http://repub.eur.nl/res/pub/31954/ 2002-06-28T00:00:00Z Multiple sclerosis (MS) is a major cause of disability in young adults affecting approximately 15,000 people in The Netberlands. Critical aspects of the disease have been modeled by experimental autoimmune encephalomyelitis (EAE) in animals. The vast majority of investigators use rats and mice for the unraveling of tbe MS immunopathogenesis and for tbe development of new tberapies. However, despite decades of intensive research, the primary cause of MS is still unknown and no curative treatment exists. With the development of EAE in the common marmoset, a new nonhuman primate model for MS has become available tbat seemed superior to tbe existing rodent and nonhuman primate models in many aspects (Massacesi. 1995). The first experiments performed at the BPRC confirmed this view ('r Hart. 1998). The etbical constraints for using nonhuman primates demand that such a model is used only for purposes that can not be investigated otherwise. The prime rationale for nonhuman primate models of human disease is tbe possibility to evaluate potentially effective therapies tbat do not sufficiently work in rodents. At the time tbat our studies were started, only the EAE model in rhesus monkeys could be regarded as being of sufficient scientific maturity. However, both clinically and neuropathologically this model did not sufficiently resemble chronic MS. It was therefore decided to further develop the marmoset EAE model and to scientifically explore whether tbis model can substantially contribute to our knowledge on the ethiopathogenesis ofMS and to the development of new therapeutics for this disease. The aims of the studies described in this thesis were: I. To investigate the immunopatbogenic mechanisms leading to the specific inflammatory demyelination of the central nervous system (CNS). 2. To investigate the genetic basis of the I 00% disease incidence observed in our outbred colony. 3. To validate the model for therapeutic purposes using antibody-mediated intervention in patbogenic pathways. http://repub.eur.nl/res/pub/10011/ 2002-01-01T00:00:00Z 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.