Long term immunologic consequences of experimental stroke and mucosal tolerance
TL;DR: Induction of immunological tolerance to MBP is associated with improved outcome after stroke, however, this study raises concern about the potential for inadvertent induction of detrimental autoimmunity through mucosal administration of antigen.
Abstract: An inflammatory insult following middle cerebral artery occlusion (MCAO) is associated with a predisposition to develop a deleterious autoimmune response to the brain antigen myelin basic protein (MBP). Induction of immunologic tolerance to brain antigens prior to MCAO prevents this deleterious autoimmune response and is associated with better functional outcome early after stroke. In this study, we sought to determine the long term immunologic consequences of experimental stroke and induction of mucosal tolerance. Male Lewis rats were tolerized to MBP or ovalbumin (OVA) by intranasal administration prior to MCAO and administration of lipopolysaccharide (LPS). Neurological outcome was assessed at set points after MCAO and animals sacrificed at 3 months; the immune response to MBP in brain and spleen was determined using ELISPOT assay and degree of cellular inflammatory brain infiltrate assessed by immunocytochemistry. Animals that developed a pro-inflammatory (TH 1) response to MBP experienced worse outcome, while those that developed a regulatory response (TREG) experienced better outcome. A TREG response in spleen was also associated with decreased inflammation and an increase in the number of FoxP3 positive cells in brain. In this study, tolerization to MBP prior to MCAO was associated with a tendency to develop a TH 1 response to MBP by 3 months after MCAO. These data show that induction of immunological tolerance to MBP is associated with improved outcome after stroke. This study, however, raises concern about the potential for inadvertent induction of detrimental autoimmunity through mucosal administration of antigen.
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TL;DR: This review summarizes the latest findings on vascular and immune system action in the brain, with particular focus on the dynamic responses after ischemic brain injury.
18 citations
TL;DR: Current knowledge on the immunological alterations after brain ischemia is reviewed, particularly effects of infection for stimulation of autoimmune response against brain antigens against infection.
Abstract: Acute onset of cerebrovascular diseases seems to be related to a number of immunological alternations. After the initial pro-inflammatory response to brain ischemia accompanied by systemic inflammatory response syndrome, stroke interferes with function of the innate and the adaptive immune cells, resulting in systemic immunosuppression. Although post-stroke immunodeficiency could predispose patients to life-threatening infections, it could potentially protect brain via reducing autoimmune reaction to the brain antigens. In this paper, we review current knowledge on the immunological alterations after brain ischemia, particularly effects of infection for stimulation of autoimmune response against brain antigens.
17 citations
Cites background from "Long term immunologic consequences ..."
...is higher at 3 months than at 1 month [109]....
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...In addition, the results of clinical studies have been disappointing [111], although there are many potential reasons for the failure of mucosal tolerance induction in clinical trials, an important difference between most experimental studies and clinical trials is the period of follow-up [109]....
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TL;DR: These findings suggest that stroke-induced immunodepression might function as an adaptive mechanism in order to inhibit harmful and long-lasting CNS antigen-specific immune responses.
16 citations
TL;DR: In this paper, a review of immunology of stroke, current therapeutic scenario and future potential targets as immunotherapeutic agents in stroke therapeutics is presented, where a variety of post stroke treatments available which claim their usefulness in reducing or inhibiting post stroke and recurrent stroke damage followed by heavy inflammatory actions.
Abstract: Ischemia or brain injuries are mostly associated with emergency admissions and huge mortality rates. Stroke is a fatal cerebrovascular malady and second top root of disability and death in both developing and developed countries with a projected rise of 24.9% (from 2010) by 2030. It's the most frequent cause of morbidities and systemic permanent morbidities due to its multi-organ systemic pathology. Brain edema or active immune response cause disturbed or abnormal systemic affects causing inflammatory damage leading to secondary infection and secondary immune response which leads to activation like pneumonia or urine tract infections. There are a variety of post stroke treatments available which claims their usefulness in reducing or inhibiting post stroke and recurrent stroke damage followed by heavy inflammatory actions. Stroke does change the quality of life and also ensures daily chronic rapid neurodegeneration and cognitive decline. The only approved therapies for stroke are alteplase and thrombectomy which is associated with adverse outcomes and are not a total cure for ischemic stroke. Stroke and immune response are reciprocal to the pathology and time of event and it progresses till untreated. The immune reaction during ischemia opens new doors for advanced targeted therapeutics. Nowadays stem cell therapy has shown better results in stroke-prone individuals. Few monoclonal antibodies like natalizumab have shown great impact on pre-clinical and clinical stroke trial studies. In this current review, we have explored an immunology of stroke, current therapeutic scenario and future potential targets as immunotherapeutic agents in stroke therapeutics.
11 citations
TL;DR: The aim of the journal is to gather and disseminate knowledge in the field of experimental stroke in order to facilitate future translation and development of new clinical stroke treatments.
Abstract: published by BioMed Central. As its title suggests, thejournal is intended principally to gather and disseminatenew knowledge in the field of experimental stroke inorder to facilitate future translation and development ofnew clinical stroke treatments. There are many examplesin modern medicine of translational research openingnew perspectives for the improved diagnosis or treatmentof human diseases and enabling findings from basicbench top discoveries to be transferred into clinical appli-cations. A good example for this approach in the field ofcerebrovascular disease is diffusion weighted magneticresonance imaging. Introduced in the last decade of the20
10 citations
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...asp BioMedcentral mental autoimmunity in the long run [4]....
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TL;DR: Seven of eight rats that underwent permanent occlusion of the MCA had resolving moderately severe neurologic deficits and unilateral infarcts averaging 37.6 +/- 5.5% of the coronal sectional area at 72 hours after the onset of Occlusion.
Abstract: To develop a simple, relatively noninvasive small-animal model of reversible regional cerebral ischemia, we tested various methods of inducing infarction in the territory of the right middle cerebral artery (MCA) by extracranial vascular occlusion in rats. In preliminary studies, 60 rats were anesthetized with ketamine and different combinations of vessels were occluded; blood pressure and arterial blood gases were monitored. Neurologic deficit, mortality rate, gross pathology, and in some instances, electroencephalogram and histochemical staining results were evaluated in all surviving rats. The principal procedure consisted of introducing a 4-0 nylon intraluminal suture into the cervical internal carotid artery (ICA) and advancing it intracranially to block blood flow into the MCA; collateral blood flow was reduced by interrupting all branches of the external carotid artery (ECA) and all extracranial branches of the ICA. In some groups of rats, bilateral vertebral or contralateral carotid artery occlusion was also performed. India ink perfusion studies in 20 rats documented blockage of MCA blood flow in 14 rats subjected to permanent occlusion and the restoration of blood flow to the MCA territory in six rats after withdrawal of the suture from the ICA. The best method of MCA occlusion was then selected for further confirmatory studies, including histologic examination, in five additional groups of rats anesthetized with halothane. Seven of eight rats that underwent permanent occlusion of the MCA had resolving moderately severe neurologic deficits (Grade 2 of 4) and unilateral infarcts averaging 37.6 +/- 5.5% of the coronal sectional area at 72 hours after the onset of occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)
6,428 citations
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...0) was inserted into the common carotid artery and advanced into the internal carotid artery [11]; 20 OVA tolerized and 25 MBP tolerized animals were subjected to MCAO....
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TL;DR: In this article, the authors examined the incidence and size of infarction after occlusion of different portions of the rat middle cerebral artery (MCA) in order to define the reliability and predictability of this model of brain ischemia.
Abstract: We have examined the incidence and size of infarction after occlusion of different portions of the rat middle cerebral artery (MCA) in order to define the reliability and predictability of this model of brain ischemia. We developed a neurologic examination and have correlated changes in neurologic status with the size and location of areas of infarction. The MCA was surgically occluded at different sites in six groups of normal rats. After 24 hr, rats were evaluated for the extent of neurologic deficits and graded as having severe, moderate, or no deficit using a new examination developed for this model. After rats were sacrificed the incidence of infarction was determined at histologic examination. In a subset of rats, the size of the area of infarction was measured as a percent of the area of a standard coronal section. Focal (1-2 mm) occlusion of the MCA at its origin, at the olfactory tract, or lateral to the inferior cerebral vein produced infarction in 13%, 67%, and 0% of rats, respectively (N = 38) and produced variable neurologic deficits. However, more extensive (3 or 6 mm) occlusion of the MCA beginning proximal to the olfactory tract--thus isolating lenticulostriate end-arteries from the proximal and distal supply--produced infarctions of uniform size, location, and with severe neurologic deficit (Grade 2) in 100% of rats (N = 17). Neurologic deficit correlated significantly with the size of the infarcted area (Grade 2, N = 17, 28 +/- 5% infarction; Grade 1, N = 5, 19 +/- 5%; Grade 0, N = 3, 10 +/- 2%; p less than 0.05). We have characterized precise anatomical sites of the MCA that when surgically occluded reliably produce uniform cerebral infarction in rats, and have developed a neurologic grading system that can be used to evaluate the effects of cerebral ischemia rapidly and accurately. The model will be useful for experimental assessment of new therapies for irreversible cerebral ischemia.
2,490 citations
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...Neurological status was assessed at set time points after MCAO; tests included a modification of the Bederson scale and an adaptation of the 'sticky tape test' [12,13]....
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TL;DR: It is suggested that a catecholamine-mediated defect in early lymphocyte activation is the key factor in the impaired antibacterial immune response after stroke.
Abstract: Infections are a leading cause of death in stroke patients. In a mouse model of focal cerebral ischemia, we tested the hypothesis that a stroke-induced immunodeficiency increases the susceptibility to bacterial infections. 3 d after ischemia, all animals developed spontaneous septicemia and pneumonia. Stroke induced an extensive apoptotic loss of lymphocytes and a shift from T helper cell (Th)1 to Th2 cytokine production. Adoptive transfer of T and natural killer cells from wild-type mice, but not from interferon (IFN)-γ–deficient mice, or administration of IFN-γ at day 1 after stroke greatly decreased the bacterial burden. Importantly, the defective IFN-γ response and the occurrence of bacterial infections were prevented by blocking the sympathetic nervous system but not the hypothalamo-pituitary-adrenal axis. Furthermore, administration of the β-adrenoreceptor blocker propranolol drastically reduced mortality after stroke. These data suggest that a catecholamine-mediated defect in early lymphocyte activation is the key factor in the impaired antibacterial immune response after stroke.
797 citations
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...Despite the initial inflammatory response in the brain and periphery after stroke, the immune system later becomes incapable of adequately responding to pathogens, predisposing animals to infection [3]....
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TL;DR: It is demonstrated that T cells that are specific for different myelin epitopes generate populations characterized by different T helper type 17 (TH17) to T helpertype 1 (TH1) ratios depending on the functional avidity of interactions between TCR and peptide-MHC complexes.
Abstract: Multiple sclerosis is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by a wide range of clinical signs1 The location of lesions in the CNS is variable and is a crucial determinant of clinical outcome Multiple sclerosis is believed to be mediated by myelin-specific T cells, but the mechanisms that determine where T cells initiate inflammation are unknown Differences in lesion distribution have been linked to the HLA complex, suggesting that T cell specificity influences sites of inflammation2 We demonstrate that T cells that are specific for different myelin epitopes generate populations characterized by different T helper type 17 (TH17) to T helper type 1 (TH1) ratios depending on the functional avidity of interactions between TCR and peptide-MHC complexes Notably, the TH17:TH1 ratio of infiltrating T cells determines where inflammation occurs in the CNS Myelin-specific T cells infiltrate the meninges throughout the CNS, regardless of the TH17:TH1 ratio However, T cell infiltration and inflammation in the brain parenchyma occurs only when TH17 cells outnumber TH1 cells and trigger a disproportionate increase in interleukin-17 expression in the brain In contrast, T cells showing a wide range of TH17:TH1 ratios induce spinal cord parenchymal inflammation These findings reveal critical differences in the regulation of inflammation in the brain and spinal cord
585 citations
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...Further, the ratio of antigen specific TH17 to TH1 cells can determine the nature of the autoimmune disease [25]....
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TL;DR: Data show for the first time that focal cerebral ischemia results in dynamic and widespread activation of inflammatory cytokines, chemokines, and CCR in the peripheral immune system.
Abstract: Clinical experimental stroke induces injurious local brain inflammation. However, effects on the peripheral immune system have not been well characterized. We quantified mRNA and protein levels for cytokines, chemokines, and chemokine receptors (CCR) in brain, spinal cord, peripheral lymphoid organs (spleen, lymph node, blood, and cultured mononuclear cells from these sources), and blood plasma after reversible middle cerebral artery occlusion (MCAO) or sham treatment in male C57BL/6 mice. Middle cerebral artery occlusion induced a complex, but organ specific, pattern of inflammatory factors in the periphery. At both 6 and 22 h after MCAO, activated spleen cells from stroke-injured mice secreted significantly enhanced levels of TNF-alpha, IFN-gamma, IL-6, MCP-1, and IL-2. Unstimulated splenocytes expressed increased chemokines and CCR, including MIP-2 and CCR2, CCR7 and CCR8 at 6 h; and MIP-2, IP-10, and CCR1 and CCR2 at 22 h. Also at 22 h, T cells from blood and lymph nodes secreted increased levels of inflammatory cytokines after activation. As expected, there were striking proinflammatory changes in postischemic brain. In contrast, spinal cord displayed suppression of all mediators, suggesting a compensatory response to intracranial events. These data show for the first time that focal cerebral ischemia results in dynamic and widespread activation of inflammatory cytokines, chemokines, and CCR in the peripheral immune system.
494 citations
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...Immediately after experimental stroke, peripheral blood lymphocytes and splenocytes become activated and are capable of secreting massive amounts of proinflammatory cytokines [1]....
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