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Biomedical subjects

Tomas Olsson

Publications and source records attributed to Tomas Olsson.

At least 55 records · Page 3Linked to original sources
PubMed2003

Brain damage in a mouse model of global cerebral ischemia. Effect of NMDA receptor blockade.

The importance of particular genes in neuronal death following global cerebral ischemia can readily be studied in genetically modified mice provided a reliable model of ischemia is available. For that purpose, we developed a mouse model of global cerebral ischemia that induces consistent damage to different regions of the brain and with a low mortality rate. Twelve minutes of ischemia was induced in C57BL/6 mice by bilateral common carotid artery occlusion under halothane anesthesia and artificial ventilation. Body and brain temperature were monitored and cortical cerebral blood flow in each hemisphere was measured by laser Doppler flowmeter before, during, and for 5 min after ischemia. Extensive damage was found in the striatum and marked cell damage was observed in the CA1 and CA2 regions of hippocampus and in thalamus. Mild damage was seen in the CA3 region, dentate gyrus and cortex. Hippocampal damage in the CA1 region is delayed and developed over 48 h. Intraischemic hypothermia of 33 degrees C provided a robust neuroprotection. The non-competitive N-methyl-D-aspartate receptor blocker, MK-801, did not provide protection in the hippocampus, cortex, striatum or thalamus when administered 30 min prior to ischemia or 2 h after the end of ischemia, but selectively mitigated damage in the hippocampus, when administered immediately following ischemia. This model of global cerebral ischemia may be useful in pharmacological and genomic studies of ischemic brain damage.

Animals↗
PubMed2003

Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis.

The diversity of autoimmune responses poses a formidable challenge to the development of antigen-specific tolerizing therapy. We developed 'myelin proteome' microarrays to profile the evolution of autoantibody responses in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). Increased diversity of autoantibody responses in acute EAE predicted a more severe clinical course. Chronic EAE was associated with previously undescribed extensive intra- and intermolecular epitope spreading of autoreactive B-cell responses. Array analysis of autoantigens targeted in acute EAE was used to guide the choice of autoantigen cDNAs to be incorporated into expression plasmids so as to generate tolerizing vaccines. Tolerizing DNA vaccines encoding a greater number of array-determined myelin targets proved superior in treating established EAE and reduced epitope spreading of autoreactive B-cell responses. Proteomic monitoring of autoantibody responses provides a useful approach to monitor autoimmune disease and to develop and tailor disease- and patient-specific tolerizing DNA vaccines.

Animals↗
PubMed2003

Suppressive DNA vaccination in myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis involves a T1-biased immune response.

Vaccination with DNA encoding a myelin basic protein peptide suppresses Lewis rat experimental autoimmune encephalomyelitis (EAE) induced with the same peptide. Additional myelin proteins, such as myelin oligodendrocyte glycoprotein (MOG), may be important in multiple sclerosis. Here we demonstrate that DNA vaccination also suppresses MOG peptide-induced EAE. MOG(91-108) is encephalitogenic in DA rats and MHC-congenic LEW.1AV1 (RT1(av1)) and LEW.1N (RT1(n)) rats. We examined the effects of DNA vaccines encoding MOG(91-108) in tandem, with or without targeting of the hybrid gene product to IgG. In all investigated rat strains DNA vaccination suppressed clinical signs of EAE. There was no requirement for targeting the gene product to IgG, but T1-promoting CpG DNA motifs in the plasmid backbone of the construct were necessary for efficient DNA vaccination, similar to the case in DNA vaccination in myelin basic protein-induced EAE. We failed to detect any effects on ex vivo MOG-peptide-induced IFN-gamma, TNF-alpha, IL-6, IL-4, IL-10, and brain-derived neurotropic factor expression in splenocytes or CNS-derived lymphocytes. In CNS-derived lymphocytes, Fas ligand expression was down-regulated in DNA-vaccinated rats compared with controls. However, MOG-specific IgG2b responses were enhanced after DNA vaccination. The enhanced IgG2b responses together with the requirement for CpG DNA motifs in the vaccine suggest a protective mechanism involving induction of a T1-biased immune response.

Amino Acid Sequence↗
PubMed2003

Expression of the long form of human FLIP by retroviral gene transfer of hemopoietic stem cells exacerbates experimental autoimmune encephalomyelitis.

Subsidence of inflammation and clinical recovery in experimental autoimmune encephalomyelitis (EAE) is postulated to involve apoptosis of inflammatory cells. To test this concept, we examined the effects of overexpressing the long form of human FLICE-inhibitory protein, a potent inhibitor of death receptor-mediated apoptosis, in myelin oligodendrocyte glycoprotein-induced EAE in DBA/1 mice. We found that overexpression of the long form of human FLICE-inhibitory protein by retroviral gene transfer of hemopoietic stem cells led to a clinically more severe EAE in these mice compared with control mice receiving the retroviral vector alone. The exacerbated disease was evident by an enhanced and prolonged inflammatory reaction in the CNS of these animals compared with control mice. The acute phase of EAE was characterized by a massive infiltration of macrophages and granulocytes and a simultaneous increase in TNF-alpha production in the CNS. In the chronic phase of the disease, there was a prolonged inflammatory response in the form of persistent CD4(+) T and B cells in the CNS and a peripheral Th1 cytokine bias caused by elevated levels of IFN-gamma and reduced levels of IL-4 in the spleen. Our findings demonstrate that death receptor-mediated apoptosis can be important in the pathogenesis of EAE and further emphasize the need for effective apoptotic elimination of inflammatory cells to achieve disease remission.

Acute Disease↗
PubMed2003

New loci regulating rat myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis.

Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease in rats that closely mimics many clinical and histopathological aspects of multiple sclerosis. Non-MHC quantitative trait loci regulating myelin oligodendrocyte glycoprotein-induced EAE have previously been identified in the EAE-permissive strain, DA, on rat chromosomes 4, 10, 15, and 18. To find any additional gene loci in another well-known EAE-permissive strain and thereby to assess any genetic heterogeneity in the regulation of the disease, we have performed a genome-wide linkage analysis in a reciprocal (LEW.1AV1 x PVG.1AV1) male/female F(2) population (n = 185). We examined reciprocal crosses, but no parent-of-origin effect was detected. The parental rat strains share the RT1(av1) MHC haplotype; thus, non-MHC genes control differences in EAE susceptibility. We identified Eae16 on chromosome 8 and Eae17 on chromosome 13, significantly linked to EAE phenotypes. Two loci, on chromosomes 1 and 17, respectively showed suggestive linkage to clinical and histopathological EAE phenotypes. Eae16 and Eae17 differ from those found in previously studied strain combinations, thus demonstrating genetic heterogeneity of EAE. Furthermore, we detected a locus-specific parent-of-origin effect with suggestive linkage in Eae17. Further genetic and functional dissection of these loci may disclose critical disease-regulating molecular mechanisms.

Animals↗
PubMed2003

Paradoxical effects of arthritis-regulating chromosome 4 regions on myelin oligodendrocyte glycoprotein-induced encephalomyelitis in congenic rats.

Immunoregulatory gene loci in different organ-specific inflammatory diseases often co-localize. We here studied myelin oligodendrocyte glycoprotein (MOG)-induced EAE in rat strains congenic for arthritis-regulating genome regions on chromosome 4. We used congenic rats with a 70-centimorgan (cM) fragment from the EAE- and arthritis-resistant PVG.1AV1 rat strain on the arthritis- and EAE-permissive Dark Agouti (DA) rat background. In addition, we evaluated three recombinant strains, C4R1-C4R3, which overlap with arthritis-linked loci. PVG.1AV1 alleles in the C4R1 recombinant did not affect arthritis, but conferred protection against MOG-EAE. PVG.1AV1 alleles in the C4R2 recombinant down-regulated arthritis but had no effect in MOG-EAE. Paradoxically, PVG.1AV1 alleles in the C4R3 recombinant down-regulated arthritis, but the same fragment increased serum levels of anti-MOG Ab and aggravated clinical MOG-EAE. Thus, we provide original evidence that the same genome regions can have opposite effects in different organ-specific inflammatory diseases. Interestingly, no apparent difference in the MOG-EAE phenotype was observed in full-length congenic rats and parental DA rats, suggesting that the disease amelioration in C4R1 and aggravation in C4R3 functionally counteract each other. The data set the stage for definition of the mechanisms and positioning of the genes regulating two organ-specific inflammatory diseases differently.

Animals↗
PubMed2003

In-situ detection of both inflammatory and anti-inflammatory cytokines in resting peripheral blood mononuclear cells during pregnancy.

INTRODUCTION: Local and possibly systemic curtailment of the maternal immune response is important for a successful pregnancy. Although the local milieu at the utero-placental interface is likely to harbor the most prominent alterations, it is suggested, at least in mice, that systemic immunity is also tolerized during pregnancy. In the present study, we investigated mRNA expression of the key immunomodulatory cytokines; interleukin (IL)-4, IL-10, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma during normal pregnancy. MATERIAL AND METHODS: In-situ hybridization (ISH) of cytokine mRNA in resting peripheral blood mononuclear cells (PBMCs) was used to detect the number of cells spontaneously expressing cytokines. Eleven women with normal gestations were followed during pregnancy as well as 8 weeks postpartum, and compared with 10 non-pregnant healthy controls. RESULTS: The numbers of IFN-gamma and IL-4 mRNA expressing cells were found to be significantly increased during pregnancy and postpartum compared with non-pregnant controls. Pregnant women and non-pregnant controls did not differ in their expression of TNF-alpha and IL-10. CONCLUSION: Our studies demonstrated increased numbers of both IFN-gamma and IL-4 mRNA expressing cells in blood suggesting that systemic immunomodulation, albeit partial, takes place during normal pregnancy. It is proposed that enhanced IL-4 expression, possibly in concert with other elevated anti-inflammatory immunomodulatory cytokines, curtail the potentially hazardous effects of IFN-gamma on systemic immunity during pregnancy.

Adult↗
PubMed2003

Upregulation of the apoptosis regulators cFLIP, CD95 and CD95 ligand in peripheral blood mononuclear cells in relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is a chronic disease involving an inflammatory reaction within the white matter of the CNS, mediated by T cells, B cells and macrophages. The pathogenesis of MS may involve impaired activation-induced cell death of activated myelin-specific mature T cells. We investigated the mRNA expression of the apoptosis mediators cellular FLICE-inhibitory protein (cFLIP), caspase-8, CD95 and CD95L in peripheral blood mononuclear cells (PB MNCs) from MS patients using real-time PCR. The overall increased expression of the four key players in the CD95 pathway in relapsing-remitting MS suggests their involvement in the inflammatory process in this disease.

Adult↗
PubMed2003

Nitric oxide metabolite determinations reveal continuous inflammation in multiple sclerosis.

Nitric oxide (NO) is formed as a consequence of induction of the iNOS enzyme during inflammatory disorders. To investigate NO production in multiple sclerosis (MS), we determined the concentrations of its oxidation products (NOx) in the cerebrospinal fluid (CSF) and plasma of 61 MS patients. The patients were divided into three groups on the basis of their clinical disease activity. The total levels of NOx in CSF were significantly increased in all MS groups as compared to healthy controls and tension headache patients. CSF nitrite correlated with clinical disease activity. At exacerbation, the CSF nitrite levels exceed the plasma level. This suggests that clinical disease activity is due to a CNS inflammatory response, which is more intense and qualitatively different from that during clinical stable phases. This study supports NO involvement in the pathogenesis of MS and determination of nitrite levels may be useful a surrogate marker for disease activity.

Adult↗
PubMed2003

Genetic variation in myelin oligodendrocyte glycoprotein expression and susceptibility to experimental autoimmune encephalomyelitis.

Myelin oligodendrocyte glycoprotein (MOG) is encoded within the RT1.M region of the rat MHC a susceptibility locus for MOG-induced experimental autoimmune encephalomyelitis (EAE). We report that the enhanced susceptibility of Brown Norway (BN) rats to MOG-EAE is associated with higher expression of MOG mRNA and protein in the nervous system than in the less susceptible Lewis (LEW) strain. MOG mRNA was also detected in the immune system, but there was no correlation with disease susceptibility. These results suggest that differences in the expression of MOG in the target organ, rather than in the immune system may influence susceptibility to MOG-EAE.

Animals↗
PubMed2003

Comparing the pathogenesis of experimental autoimmune encephalomyelitis in CD4-/- and CD8-/- DBA/1 mice defines qualitative roles of different T cell subsets.

Experimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein (MOG(1-125)) in CD4(-/-) and CD8(-/-) DBA/1 mice. Both gene-deleted mice developed clinical signs of EAE, albeit milder than in wild-type mice, suggesting that both CD4(+) and CD8(+) cells participate in disease development. Demyelination and inflammation in the central nervous system was reduced in the absence of CD8(+) T cells. Antibody depletion of CD4(+) cells completely protected CD8(-/-) mice from MOG-induced EAE while depletion of CD8(+) cells in CD4(-/-) mice resulted in fewer EAE incidence compared to that in control antibody-treated mice. Antibody depletion of CD4(+) cells in wild-type mice protected from EAE, but not depletion of CD8(+) cells, although demyelination was reduced on removal of CD8(+) T cells. Immunization with immunodominant MOG(79-96) peptide led to EAE only in the presence of pertussis toxin (PT) in the inoculum. PT also triggered an earlier onset and more severe EAE in CD8(-/-) mice. We interpret our findings such that in an ontogenic lack of CD4(+) T cells, EAE is mediated by CD8(+) and elevated levels of alphabetaCD4(-)CD8(-) cells, and that CNS damage is partly enacted by the activity of CD8(+) T cells.

Animals↗
PubMed2003

Effector stage CC chemokine receptor-1 selective antagonism reduces multiple sclerosis-like rat disease.

We have studied the role of the chemokine receptor CCR1 during the effector stage of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in DA rats. In situ hybridization histochemistry revealed local production of the CCR1 ligands CCL3 (MIP-1 alpha) and CCL5 (RANTES), as well as large numbers of CCR1 and CCR5 expressing cells within inflammatory brain lesions. A low-molecular weight CCR1 selective antagonist potently abrogated both clinical and histopathological disease signs during a 5-day treatment period, without signs of peripheral immune compromise. Thus, we demonstrate therapeutic targeting of CCR1-dependent leukocyte recruitment to the central nervous system in a multiple sclerosis (MS)-like rat model.

Animals↗
PubMed2003

Neural stem cells: a potential source for remyelination in neuroinflammatory disease.

In multiple sclerosis, the central nervous system is lesioned through invasion of plaque-forming inflammatory cells, primarily contributing to immune attack of myelin and oligodendrocytes. In this report we address the possible activation and differentiation of central nervous system stem cells following such immunological insults in a well-characterized rat model of multiple sclerosis characterised by spinal cord pathology. Dye-labeled central nervous system stem cells, residing within the ependymal layer of the central canal responded to the multiple sclerosis-like conditions by proliferation, while some of the migrating stem cell-derived cells expressed markers typical for oligodendrocytes (04) and astrocytes (glial fibrillary acidic protein, GFAP) in the demyelinated area. Our results indicate that regenerative stem cell activation following immunoactivity is different from that after trauma, exemplified by the slower time course of stem cell proliferation and migration of progeny, in addition to the ability of the stem cell-derived cells to express oligodendrocyte markers. Finally, deleterious effects of macrophages on the stem cell population were evident and may contribute to the depletion of the stem cell population in neuroinflammatory disorders.

Animals↗
PubMed2003

Differential expression of the chemokine receptors CX3CR1 and CCR1 by microglia and macrophages in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis.

Chemokines are important for the recruitment of immune cells into sites of inflammation. To better understand their functional roles during inflammation we have here studied the in vivo expression of receptors for the chemokines CCL3/CCL5/CCL7 (MIP-1alpha/RANTES/MCP-3) and CX3CL1 (fractalkine), CCR1 and CX3CR1, respectively, in rat myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. Combined in situ hybridization and immunohistochemistry demonstrated intensely upregulated CCR1 mRNA expression in early, actively demyelinating plaques, whereas CX3CR1 displayed a more generalized expression pattern. CX3CR1 mRNA expressing cells were identified as microglia on the basis of their cellular morphology and positive GSA/B4 lectin staining. In contrast, CCR1 mRNA was preferentially expressed by ED1+ GSA/B4+ macrophages. The notion of differential chemokine receptor expression in microglia and monocyte-derived macrophages was corroborated at the protein level by extraction and flow cytometric sorting of cells infiltrating the spinal cord using gating for the surface markers CD45, ED-2 and CD11b. These observations suggest a differential receptor expression between microglia and monocyte-derived macrophages and that mainly the latter cell type is responsible for active demyelination. This has great relevance for the possibility of therapeutic intervention in demyelinating diseases such as multiple sclerosis, for example by targeting signaling events leading to monocyte recruitment.

Animals↗
PubMed2002

Prior poliomyelitis-evidence of cytokine production in the central nervous system.

In order to study the role of a possible inflammatory reaction in the post-polio syndrome (PPS) four key cytokines were determined by means of mRNA expression in mononuclear cells from cerebrospinal fluid (CSF) and peripheral blood of 13 patients. Data were compared with those of samples from eight non-inflammatory control persons. The PPS-patients displayed increased numbers of CSF cells expressing mRNA for TNF-alpha (p<0.02), IFN-gamma (p<0.02), IL-4 (p<0.001) and IL-10 (p<0.05), in comparison to the non-inflammatory controls. As positive controls, samples from patients with Multiple Sclerosis (MS) were examined. We conclude that there is a chronic intra CNS expression of inflammatory cytokines in PPS, in the range of that in MS, a well known neuroinflammatory disease. However, the pathogenic significance of this is unclear.

Aged↗
PubMed2002

Facial nerve lesion response; strain differences but no involvement of IFN-gamma, STAT4 or STAT6.

Facial nerve lesions lead to a retrograde response characterized by activation of glia surrounding axotomized motoneurons and up-regulation of immunological cell surface molecules such as major histocompatibility complex (MHC) antigens. Cytokines, in particular interferon-gamma, are potent inducers of MHC expression and glial activation. We have here tested whether axotomy-induced activation is changed in transgenic mouse strains lacking components of the IFN-gamma signaling pathway, STAT4 or STAT6. No differences regarding astrocyte activation, ss2-microglobulin or MHC class I expression were discernible as compared to wild type controls. In contrast, there were conspicuous differences in the reaction between the examined wild type strains (C57BL/6J, BALB/c and 129/SvJ), suggesting considerable polymorphisms in the genetic regulation of these events, however, not involving IFN-gamma, STAT4 or STAT6.

Animals↗