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: Gaining a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.
Abstract: Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. The immune system participates in the brain damage produced by ischemia, and the damaged brain, in turn, exerts an immunosuppressive effect that promotes fatal infections that threaten the survival of people after stroke. Inflammatory signaling is involved in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke engages both innate and adaptive immunity. But adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. As immunomodulation is not devoid of deleterious side effects, a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.
1,949 citations
Cites background from "Long term immunologic consequences ..."
...Worsening in the chronic phase has also been reported in tolerization applied to models of cerebral ischemi...
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TL;DR: The multifaceted role of the immune system in the pathophysiology of acute stroke is discussed, with increased incidence of infections observed after acute stroke, and might result from activation of long-distance feedback loops between the CNS and peripheral immune organs.
Abstract: Recent clinical and experimental studies have highlighted a complex role for the immune system in the pathophysiological changes that occur after acute stroke. Sensors of the innate immune system such as Toll-like receptors, or effectors such as the lectin pathway of complement activation and innate immune cells, are activated by brain ischaemia and tissue damage, leading to amplification of the inflammatory cascade. Activation of the adaptive arm of the immune system, mediated by lymphocyte populations including T and B cells, regulatory T cells, and γδT cells, in response to stroke can lead to deleterious antigen-specific autoreactive responses but can also have cytoprotective effects. Increased incidence of infections is observed after acute stroke, and might result from activation of long-distance feedback loops between the CNS and peripheral immune organs, which are thought to play a part in stroke-induced immunodepression. Ongoing clinical trials are investigating whether the preventive use of antibiotics improves functional outcome after stroke. This Review discusses the multifaceted role of the immune system in the pathophysiology of acute stroke.
511 citations
TL;DR: The selective responses of microglia and macrophages to hypoxia after stroke are discussed and relevant markers are reviewed with the aim of defining the different subpopulations of myeloid cells that are recruited to the injured site.
Abstract: Cells of myeloid origin, such as microglia and macrophages, act at the crossroads of several inflammatory mechanisms during pathophysiology. Besides pro-inflammatory activity (M1 polarization), myeloid cells acquire protective functions (M2) and participate in the neuroprotective innate mechanisms after brain injury. Experimental research is making considerable efforts to understand the rules that regulate the balance between toxic and protective brain innate immunity. Environmental changes affect microglia/macrophage functions. Hypoxia can affect myeloid cell distribution, activity, and phenotype. With their intrinsic differences, microglia and macrophages respond differently to hypoxia, the former depending on ATP to activate and the latter switching to anaerobic metabolism and adapting to hypoxia. Myeloid cell functions include homeostasis control, damage-sensing activity, chemotaxis, and phagocytosis, all distinctive features of these cells. Specific markers and morphologies enable to recognize each functional state. To ensure homeostasis and activate when needed, microglia/macrophage physiology is finely tuned. Microglia are controlled by several neuron-derived components, including contact-dependent inhibitory signals and soluble molecules. Changes in this control can cause chronic activation or priming with specific functional consequences. Strategies, such as stem cell treatment, may enhance microglia protective polarization. This review presents data from the literature that has greatly advanced our understanding of myeloid cell action in brain injury. We discuss the selective responses of microglia and macrophages to hypoxia after stroke and review relevant markers with the aim of defining the different subpopulations of myeloid cells that are recruited to the injured site. We also cover the functional consequences of chronically active microglia and review pivotal works on microglia regulation that offer new therapeutic possibilities for acute brain injury.
210 citations
Cites background from "Long term immunologic consequences ..."
...Quite possibly T-cell activation needs to be finely tuned to yield a tolerization state, associated with protective action (103, 104), rather than an aggressive (auto)-immune response....
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TL;DR: The sustained presence of Tregs in the brain after MCAO indicates a long-lasting immunological alteration and involvement of brain cells in immunoregulatory mechanisms.
Abstract: Local and peripheral immune responses are activated after ischemic stroke. In our present study, we investigated the temporal distribution, location, induction, and function of regulatory T cells (Tregs) and the possible involvement of microglia, macrophages, and dendritic cells after middle cerebral artery occlusion (MCAO). C57BL/6J and Foxp3EGFP transgenic mice were subjected to 30 minutes MCAO. On days 7, 14, and 30 after MCAO, Tregs and antigen presenting cells were analyzed using fluorescence activated cell sorting multicolor staining and immunohistochemistry. A strong accumulation of Tregs was observed on days 14 and 30 in the ischemic hemisphere accompanied by the elevated presence and activation of microglia. Dendritic cells and macrophages were found on each analyzed day. About 60% of Foxp3+ Tregs in ischemic hemispheres were positive for the proliferation marker Ki-67 on days 7 and 14 after MCAO. The transfer of naive CD4+ cells depleted of Foxp3+ Tregs into RAG1−/− mice 1 day before MCAO did not lead to a de novo generation of Tregs 14 days after surgery. After depletion of CD25+ Tregs, no changes regarding neurologic outcome were detected. The sustained presence of Tregs in the brain after MCAO indicates a long-lasting immunological alteration and involvement of brain cells in immunoregulatory mechanisms.
138 citations
TL;DR: Understanding how tumors induce Treg function to escape immune surveillance in marked contrast to autoimmune diseases will provide valuable lessons regarding Treg biology and potential therapeutic targets for CNS diseases.
Abstract: Regulatory T cells (Tregs) are critical to the human immune system, providing appropriately scaled immune responses and mediating peripheral tolerance. A central role for forkhead box protein 3 (FoxP3)(+) Tregs has been shown in the pathogenesis of mechanistically diverse central nervous system (CNS) diseases from autoimmune diseases such as multiple sclerosis to glioblastomas. Understanding how tumors induce Treg function to escape immune surveillance in marked contrast to autoimmune diseases, where there is loss of Treg function, will provide valuable lessons regarding Treg biology and potential therapeutic targets for CNS diseases.
114 citations
Cites background from "Long term immunologic consequences ..."
...Induction of mucosal tolerance to brain antigens after middle cerebral artery occlusion (MCAO) was associated with improved outcome and a reduction in infarct volume in the hours to days after stroke onset (92–95), but this was only beneficial up to a month (96)....
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TL;DR: It is demonstrated that antigen-specific modulation of the immune response decreases infarct size after focal cerebral ischemia and that sensitization to the same antigen may actually worsen outcome.
Abstract: Immune mechanisms contribute to cerebral ischemic injury. Therapeutic immunosuppressive options are limited due to systemic side effects. We attempted to achieve immunosuppression in the brain through oral tolerance to myelin basic protein (MBP). Lewis rats were fed low-dose bovine MBP or ovalbumin (1 mg, five times) before 3 h of middle cerebral artery occlusion (MCAO). A third group of animals was sensitized to MBP but did not survive the post-stroke period. Infarct size at 24 and 96 h after ischemia was significantly less in tolerized animals. Tolerance to MBP was confirmed in vivo by a decrease in delayed-type hypersensitivity to MBP. Systemic immune responses, characterized in vitro by spleen cell proliferation to Con A, lipopolysaccharide, and MBP, again confirmed antigen-specific immunologic tolerance. Immunohistochemistry revealed transforming growth factor β1 production by T cells in the brains of tolerized but not control animals. Systemic transforming growth factor β1 levels were equivalent in both groups. Corticosterone levels 24 h after surgery were elevated in all sham-operated animals and ischemic control animals but not in ischemic tolerized animals. These results demonstrate that antigen-specific modulation of the immune response decreases infarct size after focal cerebral ischemia and that sensitization to the same antigen may actually worsen outcome.
157 citations
Additional excerpts
...Discussion Previous studies demonstrated that mucosal administration of CNS or vascular antigens in experimental stroke was associated with decreased infarct volume and improved outcome in the hours to days after stroke onset [14,16-19]....
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...spective of how the TREG cells are identified, animals that evidence a TREG response to MBP appear to have a better outcome from MCAO [6,14,16-19]....
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TL;DR: It is demonstrated that IL-10-secreting CD4+ T cells induced by nasal MOG reduce injury following stroke and may contribute to secondary infarct expansion by enhancing NO synthesis that may be reduced by elevated IL- 10 levels.
Abstract: 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 MOG35–55 peptide decreased ischemic infarct size at 24 and 72 h after MCAO surgery. Nasal MOG35–55 peptide was most efficacious and reduced infarct size by 70% at 24 h and by 50% at 72 h (p ≤ 0.0001 vs control) and also improved behavior score. Immunohistochemistry demonstrated increased IL-10 and reduced IFN-γ 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.
149 citations
Additional excerpts
...Discussion Previous studies demonstrated that mucosal administration of CNS or vascular antigens in experimental stroke was associated with decreased infarct volume and improved outcome in the hours to days after stroke onset [14,16-19]....
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...spective of how the TREG cells are identified, animals that evidence a TREG response to MBP appear to have a better outcome from MCAO [6,14,16-19]....
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TL;DR: Modulation of cerebral inflammation by mucosal tolerance to myelin antigens may have applicability both as prophylactic therapy and treatment following ischemia attacks.
133 citations
Additional excerpts
...Discussion Previous studies demonstrated that mucosal administration of CNS or vascular antigens in experimental stroke was associated with decreased infarct volume and improved outcome in the hours to days after stroke onset [14,16-19]....
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...spective of how the TREG cells are identified, animals that evidence a TREG response to MBP appear to have a better outcome from MCAO [6,14,16-19]....
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TL;DR: Animals subjected to a systemic inflammatory insult at the time of stroke are predisposed to develop an autoimmune response to brain, and this response is associated with worse outcome, which may partially explain why patients who become infected after stroke experience increased morbidity.
Abstract: After stroke, the blood–brain barrier is transiently disrupted, allowing leukocytes to enter the brain and brain antigens to enter the peripheral circulation. This encounter of normally sequestered...
111 citations
"Long term immunologic consequences ..." refers methods in this paper
...Animals for ELISPOT were sacrificed 3 months after MCAO/sham surgery and mononuclear cells (MNCs) isolated from the brain and spleen using previously described methods [5,14]....
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...By inducing systemic inflammation in the peri-infarct period, however, there appears to be a fundamental change in how the immune system responds to the CNS antigens exposed in injured brain; a detrimental autoimmune response emerges, and this autoimmune response is associated with worse functional outcome 1 month after middle cerebral artery occlusion (MCAO) [5,6]....
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...In fact, we previously showed that if an immune response to CNS antigens occurs following experimental stroke, it is usually that of a regulatory response (TREG) [5]....
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TL;DR: An overview on some recent developments in mucosal tolerance induction is given where, however, much more studies are needed to define an ultimate and safe procedure.
96 citations
Additional excerpts
...Using the paradigm of mucosal tolerance, however, we demonstrated that induction of a TREG response to the brain antigen myelin basic protein (MBP) prior to cerebral ischemia could prevent development of the deleterious autoimmune response to this antigen and improve outcome (as assessed 1 month after MCAO)[6] There are, however, documented concerns about the long term consequences of mucosal tolerance/immune deviation therapy [7-9]....
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...For instance, mucosal administration of antigen during experimental autoimmune encephalomyelitis (EAE) may exacerbate inflammation and oral administration of high dose insulin may induce autoimmune diabetes [7,8]....
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