Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vaccinations against various antigens of the central nervous system (CNS) are gaining increasing interest as a therapeutic approach in a variety of neurological diseases such as spinal cord injury, ischemic stroke, Alzheimer disease, or spongiform encephalopathy. In the present work, the time window after spinal cord injury allowing potentially therapeutic antibody to penetrate the damaged blood-brain barrier (BBB) was measured by intravenous injection of a monoclonal anti-Nogo-A antibody. Although an influx of Nogo antibodies at the lesion site was detectable up to 2 wk after injury, a significant decrease in BBB permeability was noticed within the first week. Clearly, therefore, a vaccination protocol with a rapid antibody response is required for acute therapeutic interventions after CNS trauma. We designed a conjugate vaccine paradigm with particular focus on the safety and the kinetics of the antibody response. As antigen targets, we used Nogo-A and the strongly encephalitogenic myelin-oligodendrocyte glycoprotein (MOG). Intrasplenic autoimmunization of rats with a Nogo-A-specific region fused to the Tetanus toxin C-fragment (TTC) resulted in a fast IgM response against Nogo-A. A specific switch to IgG was observed as soon as 4-7 days after intrasplenic immunization in TTC-primed animals. In spite of the induction of a specific IgG response after intrasplenic immunization, no signs of experimental autoimmune disease (EAE) or inflammatory infiltrates on histological examinations were observable. In contrast to subcutaneous immunization with MOG, in vitro cytokine secretion assays (IL-2, IL-10, and IFN-gamma) did not reveal activation of MOG-specific T cells after intrasplenic immunization. Our findings have critical implications for future strategies in the development of safe and efficient therapeutic vaccines for neurological diseases.
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PMID:Rapid induction of autoantibodies against Nogo-A and MOG in the absence of an encephalitogenic T cell response: implication for immunotherapeutic approaches in neurological diseases. 1456 89

We have demonstrated that induction of mucosal tolerance to E-selectin, a cytokine-inducible adhesion molecule restricted to activating blood vessels, prevents ischemic and hemorrhagic stroke in spontaneously hypertensive, genetically stroke-prone (SHR-SP) rats. We now examine whether mucosal tolerance to E-selectin has protective effects in ischemic brain damage after permanent middle cerebral artery occlusion (MCAO) in SHR-SP rats and whether these effects are related to generation of regulatory T cells. Rats were exposed to intranasal administration of E-selectin every other day for 10 days (single tolerization group) or on two tolerization schedules separated by 11 days (booster tolerization group). Control groups received PBS on corresponding schedules. MCAO was performed 48 h after the last dose of E-selectin or PBS. There were 45.8% and 37.9% (P < 0.05) decreases of infarction volume in the E-selectin booster group compared with the PBS group at 6 and 48 h, respectively. Single tolerization with E-selectin had only a slight trend toward a decrease in infarction volume (6.3%). CD8-positive cells were decreased in brains of E-selectin booster animals (46.6%, P < 0.01) compared with controls; splenocyte-culture supernatant levels of IL-10 were increased (59.3%, P < 0.05) in E-selectin booster animals. A decrease of infarction volume (34%, P < 0.05) was also observed in SHR-SP rats subjected to MCAO after adoptive transfer of splenocytes from E-selectin-tolerized compared with PBS-tolerized donors. The results indicate that, in addition to preventing stroke, mucosal tolerance to E-selectin is cytoprotective. Thus, immunomodulation targeted to activated blood vessel segments can both reduce stroke occurrence and attenuate brain damage if a stroke supervenes.
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PMID:Mucosal tolerance to E-selectin provides cell-mediated protection against ischemic brain injury. 1464 8

Inflammation plays an important role in ischemic stroke and in humans IL-10 may have a beneficial effect in stroke. We mucosally administered myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide to C57BL/6 mice before middle cerebral artery occlusion (MCAO) to induce an anti-inflammatory T cell response directed at CNS myelin. Nasal and oral administration of MOG(35-55) peptide decreased ischemic infarct size at 24 and 72 h after MCAO surgery. Nasal MOG(35-55) peptide was most efficacious and reduced infarct size by 70% at 24 h and by 50% at 72 h (p <or= 0.0001 vs control) and also improved behavior score. Immunohistochemistry demonstrated increased IL-10 and reduced IFN-gamma in the area surrounding the ischemic infarct following nasal treatment. Nasal MOG did not reduce infarct size in IL-10-deficient mice. Adoptive transfer of CD4(+) T cells to untreated mice from nasally tolerized mice before MCAO surgery decreased stroke size (p < 0.001 vs control), whereas, CD4(+) T cells from nasally tolerized IL-10-deficient mice had no effect. Our results demonstrate that IL-10-secreting CD4(+) T cells induced by nasal MOG reduce injury following stroke. In addition, we observed a dramatic reduction of CD11b(+) cells in nasal MOG-treated animals. CD11b(+) cells may contribute to secondary infarct expansion by enhancing NO synthesis that may be reduced by elevated IL-10 levels. Modulation of cerebral inflammation by nasal vaccination with myelin Ags that increase IL-10 in the brain may improve outcome after stroke and enhance mechanisms of recovery.
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PMID:Nasal vaccination with myelin oligodendrocyte glycoprotein reduces stroke size by inducing IL-10-producing CD4+ T cells. 1466 56

Thrombolytic therapy not always improves clinical outcome in ischemic stroke patients. This could cause lymphomonocyte accumulation in the infarcted brain area. These produce an excessive amount of proinflammatory cytokines, such as IL-1 beta, IL-6 and TNF-alfa. The aim of our study was to determine ILs levels in fibrinolytic therapy treated patients, compared with healthy controls and to evaluate if the varying levels can predictors of neurological outcome. Eighteen patients underwent thrombolytic treatment with t-PA within 3 h. Plasma levels of IL-1 beta, IL-6, TNF-alfa and IL-10 were determined by ELISA method before and within 24 h after t-PA infusion and compared with controls. Significantly higher levels of IL-1 beta and Il-6 emerged in stroke patients before treatment compared with the control group (P < 0.05 and 0.04, respectively). Slightly higher plasma levels of TNF-alfa and lower plasma levels of IL-10 were also found at base line in stroke patients. After thrombolytic treatment no significant variations were observed in the levels of TNF-alfa and IL-6, whereas a trend toward lower values for IL-1 beta and higher levels for IL-10 was observed. Positive correlations among the values of IL-6, TNF-alfa and National Institute of Health Stroke Scale (NIHSS) at discharges were observed. A similar correlation with modified Rankin scale score at 3 month was found. Pre-treatment cytokine status seems to influence pre-and long-term clinical outcome. Therefore an investigation into the possible predictor of cytokines seem worthy.
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PMID:Different cytokine levels in thrombolysis patients as predictors for clinical outcome. 1517 33

Unfractionated heparin (UH) decreases the extent of infarction after transient focal brain ischemia in the rat and abridges neuroinflammatory damage in patients with acute stroke. This study was aimed at assessing whether controlled and steady heparinemia in plasma can reduce infarct volume and exert neuroprotective effects after ischemia. Infarct volume was measured at 24 and 7 days following a 1-hr intraluminal middle cerebral artery (MCA) occlusion in rats treated with UH or with vehicle. After testing several UH administration protocols, we choose to give a bolus of 200 U/kg, which was started 3 hr after the occlusion, followed by a 24-hr intraperitoneal perfusion of 70 U/kg/hr, which maintained a 24-hr steady plasma heparinemia (0.3-0.6 U/ml) and caused no CNS or systemic bleeding. In addition, plasma IL-10 concentration was measured by ELISA, endothelial VCAM-1 expression was evaluated by i.v. injection of a (125)I-labeled monoclonal antibody against VCAM-1, and brain hemeoxygenase-1 (HO-1) expression was determined by Western blot. UH-treated rats showed smaller infarctions than rats treated with vehicle, as well as higher IL-10 plasma levels and HO-1 brain expression and lower endothelial VCAM-1 induction. The study shows that a stable plasma concentration of UH given at nonhemorrhagic doses reduces infarct volume after ischemia-reperfusion in the rat. It also shows that UH prevented the induction of cell adhesion molecules in the cerebral vasculature and increased the expression of molecules with antiinflammatory and prosurvival properties. These findings support further testing of the clinical value of parenteral, adjusted, high-dose UH in patients with acute stroke.
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PMID:Steady plasma concentration of unfractionated heparin reduces infarct volume and prevents inflammatory damage after transient focal cerebral ischemia in the rat. 1526 26

The risk of cardiovascular disease (CVD) in SLE patients is very high. It is therefore surprising that IL-10 has been discussed both as pathogenic in SLE and as an atheroprotective cytokine. In contrast, TNF is believed to be atherogenic and we recently reported that raised activity in the TNF-system is implicated in SLE-related CVD. Twenty-six (aged 52 +/- 8 years) female patients with SLE and a history of CVD (myocardial infarction, angina, stroke or claudication) were compared with 26 age-matched SLE patients without CVD (SLE controls) or 26 age-matched population controls. The -1087IL-10 gene polymorphism was determined by PCR with restriction endonuclease mapping. Serum IL-10 and TNF-levels were determined by ELISA. The A allele frequency of -1087IL-10 gene in SLE/CVD was higher than in SLE controls (0.62 versus 0.42, p < 0.05). Ten (38%) of 26 SLE/CVD exhibited IL-10 AA genotype compared with five (19%) of 26 SLE controls. Serum IL-10 and TNF-levels were raised in SLE/CVD compared with SLE controls or population controls (p < 0.001). Furthermore, in SLE/CVD, a significantly reduced IL-10:TNF ratio was observed in patients with IL-10 AA genotype compared with AG or GG genotype (0.56 versus 0.77 versus 1.24, p < 0.05). In SLE controls and population controls, individuals with IL-10 GG genotype tended to have higher IL-10:TNF ratio. In conclusion, the A-1087IL-10 allele which has been reported to cause a lower capacity for IL-10 production could contribute to CVD in SLE. Furthermore, the IL-10 AA genotype is associated with reduced ratio of atheroprotective to atherogenic cytokines in SLE patients with CVD.
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PMID:The A-1087IL-10 allele is associated with cardiovascular disease in SLE. 1553 Sep 17

Mucosal tolerance has been used successfully to treat animal models of autoimmune diseases and is being tested in human diseases. In this work we demonstrate the reduction of infarct size following mucosal tolerance by myelin oligodendrocyte glycoprotein (MOG) (35-55) peptide in mouse stroke model. Nasal MOG was most efficacious and reduced ischemic infarct size by 70% at 24 h as well as improving behavior score. Using immunohistological methods and IL-10 -/- mice, we demonstrate the importance of IL-10-producing CD4+ T cells in the reduction of the ischemic infarct volume following middle cerebral artery occlusion (MCAO). Furthermore, adoptive transfer of CD4+ T cells from nasally tolerized mice to untreated mice prior to MCAO surgery significantly decreased stroke size (p<0.001 vs. control), whereas CD4+ T cells from nasally tolerized IL-10-deficient mice had no significant effect. Based on these results, modulation of cerebral inflammation by mucosal tolerance to myelin antigens may have applicability both as prophylactic therapy and treatment following ischemia attacks.
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PMID:Neuroprotection by IL-10-producing MOG CD4+ T cells following ischemic stroke. 1589 35

Multiple mechanisms of tolerance are induced by oral antigen. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral antigen induces T-helper 2 [interleukin (IL)-4/IL-10] and Th3 [transforming growth factor (TGF)-beta] T cells plus CD4+CD25+ regulatory cells and latency-associated peptide+ T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit, Flt-3 ligand, and anti-CD40 ligand. Oral (and nasal) antigen administration suppresses animal models of autoimmune diseases including experimental autoimmune encephalitis, uveitis, thyroiditis, myasthenia, arthritis, and diabetes in the non-obese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, graft rejection, allergy, colitis, stroke, and models of Alzheimer's disease. Oral tolerance has been tested in human autoimmune diseases including multiple sclerosis (MS), arthritis, uveitis, and diabetes and in allergy, contact sensitivity to dinitrochlorobenzene (DNCB), and nickel allergy. Although positive results have been observed in phase II trials, no effect was observed in phase III trials of CII in rheumatoid arthritis or oral myelin and glatiramer acetate (GA) in MS. Large placebo effects were observed, and new trials of oral GA are underway. Oral insulin has recently been shown to delay onset of diabetes in at-risk populations, and confirmatory trials of oral insulin are being planned. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time, and antigen-specific mechanisms of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy, and early therapy.
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PMID:Oral tolerance. 1604 53

The microvasculature of the brain region affected by a stroke assumes an inflammatory phenotype that is characterized by endothelial cell activation and barrier dysfunction and the recruitment of adherent leukocytes. Although most attention has been devoted to the possible role of neutrophils in the tissue responses to ischemic stroke there is evidence that T-lymphocytes also accumulate in the postischemic brain. Although comparable detailed analyses of lymphocyte involvement in ischemic brain injury have not been performed, emerging findings suggest a role for T-cells in the pathogenesis of ischemic stroke. The recruitment of T-cells to the site of brain injury is critically dependent on the coordinated expression of adhesion molecules on the activated capillary endothelium. Whether the recruited lymphocytes are acting directly on brain tissue or indirectly through activation of other circulating blood cells and/or extravascular cells remain unclear. Cytotoxic CD8+ T-cells may induce brain injury through molecules released from their cytotoxic granules. CD4+ T-helper 1 (TH1) cells, which secrete proinflammatory cytokines, including interleukin-2 (IL-2), IL-12, interferon-gamma, and tumor necrosis factor-alpha, may play a key role in the pathogenesis of stroke, whereas CD4+TH2 cells may play a protective role through anti-inflammatory cytokines such as IL-4, IL-5, IL-10, and IL-13. T-cells should be considered as therapeutic targets for ischemic stroke. However, because infection is a leading cause of mortality in the postacute phase of ischemic stroke, and considering anti-inflammatory role of CD4+TH2, treatment targeting T-cells should be carefully designed to reduce deleterious and enhance protective actions of T-cells.
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PMID:Stroke and T-cells. 1624 83

Strokes due to transmural vasculitis associated with coccidioidal meningitis result in significant morbidity and mortality. The immunological and inflammatory processes responsible are poorly understood. To determine the inflammatory mediators, i.e. cytokines, chemokines, iNOS, matrix metalloproteinase-9 (MMP-9), that possibly contribute to vasculitis, temporal mRNA expression in brain basilar artery samples and MMP-9 protein in the CSF of male NZW rabbits infected intracisternally with 6.5 x 10(4) arthroconidia of Coccidioides immitis were assessed. Five infected and 3 sham-injected rabbits at each time point were euthanized 4, 9, 14 and 20 days post infection. All infected rabbits had neurological abnormalities and severe vasculitis in the basilar arteries on days 9-20. In basilar arteries of infected animals versus controls, mRNAs encoding for IL-6, iNOS, IFN-gamma, IL-2, MCP-1, IL-1beta, IL-10, TNF-alpha, CCR-1, MMP-9, TGF-beta, as well as MMP-9 protein in CSF, were found to be significantly up-regulated. Thus, this study identified inflammatory mediators associated with CNS vasculitis and meningitis due to C. immitis infection. Assessment of the individual contribution of each mediator to vasculitis may offer novel approaches to the treatment of coccidioidal CNS infection. This study also provides unique methodology for immunology studies in a rabbit model.
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PMID:Temporal expression of inflammatory mediators in brain basilar artery vasculitis and cerebrospinal fluid of rabbits with coccidioidal meningitis. 1648 45


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