PubMed Health⌕ Search

Biomedical subjects

Bert A 't Hart

Publications and source records attributed to Bert A 't Hart.

At least 19 recordsLinked to original sources
PubMed2007

Quantitative MRI-pathology correlations of brain white matter lesions developing in a non-human primate model of multiple sclerosis.

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.

Animals↗
PubMed2006

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.

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.

Animals↗
PubMed2006

No synergy between ATG induction and costimulation blockade induced kidney allograft survival in rhesus monkeys.

BACKGROUND: Costimulation blockade with antibodies directed against human CD40 and CD86 leads to prolonged kidney allograft survival in rhesus monkeys, but fails to induce permanent graft acceptance. We have tested whether costimulation blockade is more effective after peripheral T-cell ablation with antithymocyte globulin (ATG), with the aim to remove already primed autoreactive cells present in the normal repertoire. METHODS: Rhesus monkeys were transplanted with a mismatched kidney allograft. ATG was given around the time of transplantation (day -1 and 0). Costimulation blockade with anti-CD40+anti-CD86 was given at tapering dosages from day -1 to 56. Cyclosporin A (CsA) was given from day 42 onwards and first rejections occurring after day 42 were treated with prednisone. RESULTS: We observed accelerated rejection in ATG-treated monkeys, compared to animals receiving only costimulation blockade. The accelerated rejection of the kidney allograft occurred despite the application of rejection therapy with steroids and CsA. Three of the five ATG-treated animals were found seropositive for donor-specific alloantibodies. Early biopsies (day 21) from animals treated with ATG and anti-CD40+anti-CD86 show substantially reduced expression of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and forkhead box P3 (FOXP3) in focal infiltrates as compared to animals treated with only costimulation blockade. Furthermore, we observed the rapid reappearance of CD8 T-cells with a memory phenotype (disappearance of naive CD95/CD11a T-cells) in peripheral blood. CONCLUSION: We conclude that (subtotal) T-cell depletion using ATG does not add to costimulation blockade induced kidney allograft survival.

Animals↗
PubMed2006

Reactivation by exon shuffling of a conserved HLA-DR3-like pseudogene segment in a New World primate species.

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 one DRB region configuration harboring three loci. Two of these loci display moderate levels of allelic polymorphism, whereas the -DRB*W12 gene appears to be monomorphic. This study shows that only the Caja-DRB*W16 and -DRB*W12 loci produce functional transcripts. The Caja-DRB1*03 locus 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 the Caja-DRB1*03 gene. 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.

Amino Acid Sequence↗
PubMed2006

MRI-guided immunotherapy development for multiple sclerosis in a primate.

Multiple sclerosis is a serious neurological disease that affects 1 in 1000 young adults in Europe and the USA. The development of an effective therapy for this enigmatic disease is plagued by the failure of many treatments to reproduce in patients the promising effects observed in animal models. This review describes a new preclinical model in a non-human primate that might help to bridge the gap between currently used animal models and the patients.

Animals↗
PubMed2006

Phagocytes containing a disease-promoting Toll-like receptor/Nod ligand are present in the brain during demyelinating disease in primates.

Recent studies claim a central role for Toll-like receptor (TLR) ligands in stimulating autoimmune disease by activation of antigen-presenting cells in the target organ, but it is unclear if and how TLR ligands reach target organs. Most evidence comes from rodent models, and it is uncertain whether this principle holds in primates. Here we identify which cells contain peptidoglycan (PGN) in multiple sclerosis brain and in two nonhuman primate experimental autoimmune encephalomyelitis (EAE) models with different disease courses: acute (rhesus monkey) versus chronic disease (marmoset). Because persistence of TLR ligands in the central nervous system might be consequential for disease progression, we also determined the expression of two major PGN-degrading enzymes, ie, lysozyme and N-acetylmuramyl-l-alanine amidase. Distinct phagocyte subsets, including granulocytes, macrophages, and dendritic cells, contained PGN in the brain and coexpressed the inflammatory cytokine interleukin-12. The number of phagocytes carrying PGN increased in acute and chronic EAE compared with control animals, with the highest number of PGN-containing cells in acute EAE brain. Lytic enzymes were scarcely expressed in monkey and multiple sclerosis brain, favoring PGN persistence. PGN stimulated interleukin-12p70 release by leukocytes from all three primate species. The presence of PGN in the inflamed brain may have major implications because TLR2/Nod ligation potentially promotes inflammation and disease progression.

Adult↗
PubMed2005

Suppression of ongoing disease in a nonhuman primate model of multiple sclerosis by a human-anti-human IL-12p40 antibody.

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 IgG1kappa 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.

Animals↗
PubMed2005

Non-human primate models of experimental autoimmune encephalomyelitis: Variations on a theme.

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.

Animals↗
PubMed2005

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.

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.

Animals↗
PubMed2005

Decay-accelerating factor (CD55) is expressed by neurons in response to chronic but not acute autoimmune central nervous system inflammation associated with complement activation.

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.

Acute Disease↗
PubMed2005

Severe T-cell depletion from the PALS leads to altered spleen composition in common marmosets with experimental autoimmune encephalomyelitis (EAE).

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.

Acid Phosphatase↗
PubMed2004

Evaluating the validity of animal models for research into therapies for immune-based disorders.

The last few decades of the 20th century have shown an intensified search for safer and more effective medications against chronic diseases that burden ageing societies of the western world. The impressive development of biotechnological production techniques has greatly facilitated the pharmaceutical development of relatively non-toxic biological molecules. However, despite the huge investments, only a few effective therapies for immune-based diseases have reached the clinic. In this article we use examples from monoclonal antibody trials to discuss the validity and predictive strength of the animal models currently used for the development of effective therapies.

Adjuvants, Immunologic↗
PubMed2004

Non-invasive measurement of brain damage in a primate model of multiple sclerosis.

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.

Animals↗
PubMed2004

Modelling of multiple sclerosis: lessons learned in a non-human primate.

The many, highly specific, biological therapies for immune-based diseases create a need for valid preclinical animal models. The wide immunological gap between human beings and laboratory mouse or rat models makes many disease models in these species invalid. In this review, we report a non-human-primate model of chronic multiple sclerosis (MS)-experimental autoimmune encephalitis (EAE) in the common marmoset (Callithrix jacchus)-that can help bridge this wide gap. The genetic and immunological similarity of marmosets and human beings and the clinical and neuropathological similarity of the EAE model to MS provide a unique experimental platform for research into basic immunopathogenetic mechanisms and for the development of more effective treatments for MS.

Animals↗
PubMed2004

Self- and nonself-recognition by C-type lectins on dendritic cells.

Dendritic cells (DCs) are highly efficient antigen-presenting cells (APCs) that collect antigen in body tissues and transport them to draining lymph nodes. Antigenic peptides are loaded onto major histocompatibility complex (MHC) molecules for presentation to naive T cells, resulting in the induction of cellular and humoral immune responses. DCs take up antigen through phagocytosis, pinocytosis, and endocytosis via different groups of receptor families, such as Fc receptors for antigen-antibody complexes, C-type lectin receptors (CLRs) for glycoproteins, and pattern recognition receptors, such as Toll-like receptors (TLRs), for microbial antigens. Uptake of antigen by CLRs leads to presentation of antigens on MHC class I and II molecules. DCs are well equipped to distinguish between self- and nonself-antigens by the variable expression of cell-surface receptors such as CLRs and TLRs. In the steady state, DCs are not immunologically quiescent but use their antigen-handling capacities to maintain peripheral tolerance. DCs are continuously sampling and presenting self- and harmless environmental proteins to silence immune activation. Uptake of self-components in the intestine and airways are good examples of sites where continuous presentation of self- and foreign antigens occurs without immune activation. In contrast, efficient antigen-specific immune activation occurs upon encounter of DCs with nonself-pathogens. Recognition of pathogens by DCs triggers specific receptors such as TLRs that result in DC maturation and subsequently immune activation. Here we discuss the concept that cross talk between TLRs and CLRs, differentially expressed by subsets of DCs, accounts for the different pathways to peripheral tolerance, such as deletion and suppression, and immune activation.

Animals↗
PubMed2003

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.

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.

Animals↗