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Journal ArticleDOI

Long term immunologic consequences of experimental stroke and mucosal tolerance

21 Oct 2009-Experimental & Translational Stroke Medicine (BioMed Central)-Vol. 1, Iss: 1, pp 3-3
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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Citations
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Journal ArticleDOI
TL;DR: Data suggest DHT modulates peripheral immunosuppression after MCAO but with relatively little effect on early immune response of the recovering CNS.
Abstract: Stroke is a sexually dimorphic disease with male gender considered a disadvantage in terms of risk and disease outcome. In intact males, stroke induces peripheral immunosuppression, characterized by decreased splenocyte numbers and proliferation and altered percentages of viable T, B, and CD11b+ cells. To investigate whether the potent androgen and known immunomodulator, dihydrotestosterone (DHT), exacerbates post-stroke immunosuppression in castrated male mice after focal stroke, we evaluated the effect of middle cerebral artery occlusion (MCAO) on peripheral and central nervous system (CNS) immune responses in castrated mice with or without controlled levels of DHT. MCAO reduced spleen cell numbers in both groups, but altered T cell and B cell percentages in remaining splenocytes and concomitantly increased the percentage of CD11b+ blood cells solely in DHT-replaced animals at 24 h. Furthermore, DHT-replacement reduced splenocyte proliferation which was accompanied by an increased percentage of immunosuppressive regulatory T cells relative to castrates 96 h post-MCAO. In brain, the percentages of immune cell populations in the ischemic hemisphere relative to the non-ischemic hemisphere were similar between castrated and DHT-replaced mice after MCAO. These data suggest DHT modulates peripheral immunosuppression after MCAO but with relatively little effect on early immune response of the recovering CNS.

20 citations


Cites background from "Long term immunologic consequences ..."

  • ...the percentage of immunosuppressive Tregs relative to B lymphocytes may also be important (Gee et al., 2009; Offner et al., 2006b)....

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  • ...The composition of surviving splenocytes, e.g. the percentage of immunosuppressive Tregs relative to B lymphocytes may also be important (Gee et al., 2009; Offner et al., 2006b)....

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Journal ArticleDOI
TL;DR: Treatment with α-MSH at the time of stoke was associated with a decrease in TH1 response to myelin basic protein (MBP) in animals subjected to 2 hours MCAO, although treatment was not associated with improved outcome at this time point.
Abstract: Alpha-melanocyte-stimulating hormone (MSH) is a neuropeptide with profound immunomodulatory properties; we evaluated the effects of α-MSH on stroke outcome and its ability to modulate the postischemic immune response. In Lewis rats subjected to 3 hours of middle cerebral artery occlusion (MCAO), plasma concentrations of α-MSH rapidly decreased and returned to baseline over the course of days. Exogenous administration of α-MSH (100 or 500 μg/kg) improved 24 hour outcome in animals subjected to 2 hours MCAO; α-MSH 500 μg/kg also decreased infarct volume at this time point. Both doses of α-MSH were ineffective in improving outcome or decreasing infarct volume in animals subjected to 3 hours MCAO. The splenocyte response to phytohemagglutin in animals treated with α-MSH was attenuated at 24 hours after MCAO. At 1 month after MCAO, treatment with α-MSH 500 μg/kg at the time of stoke was associated with a decrease in TH1 response to myelin basic protein (MBP) in animals subjected to 2 hours MCAO, although treatment was not associated with improved outcome at this time point. Given the early benefits of α-MSH treatment and its effect on immunologic outcome, further studies to evaluate the utility of α-MSH for the treatment of cerebral ischemia are warranted.

20 citations


Cites background or result from "Long term immunologic consequences ..."

  • ...Similar to our findings in other studies (Gee et al, 2008, 2009; Zierath et al, 2010), the data in this study show an inverse relationship between the TH1 immune response to brain antigens in the spleen and performance on the rotarod in animals subjected to 2 hours MCAO....

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  • ...A Treg response can be induced through mucosal administration of antigen, but there are data that question the longterm safety of this strategy (Bai et al, 1998; Blanas et al, 1996; Gee et al, 2009; Genain et al, 1996; Xiao and Link, 1997)....

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Journal ArticleDOI
TL;DR: Computer automated analysis of rotational activity was more sensitive than subjective assessment for detecting behavioral changes, with SD rats showing a preference for clockwise rotations to 49 days after stroke despite normalization of the neurological score after 21 days.
Abstract: Pre-clinical models of stroke therapeutics depend upon the ability to detect differences in infarct volume as well as in the short- and long-term outcomes of treated animals. Little attention has been paid to interstrain differences in these outcomes and the importance of defining the most appropriate behavioral tests. In this study, we evaluate long-term outcome from stroke in three different rat strains. Lewis, Wistar, and Sprague Dawley (SD) rats were subjected to 2-h middle cerebral artery occlusion and survived for up to 49 days. Behavioral tests were performed weekly. There was continuous assessment of rotational/circling activity in the home cage by use of an automated software program. A separate group of animals was sacrificed at 24 h to determine infarct volume. Infarct volume was similar in all three strains. Mortality was significantly higher in SD rats (P < 0.001). Rotational/circling activity at 24 h was correlated with cortical infarct volume in Wistar and SD rats (ρ = 0.67, P = 0.04 and ρ = 0.72, P = 0.01, respectively). Wistar and SD rats displayed more rotational/circling activity following stroke than Lewis rats, but Lewis rats evidenced more impairment on complex motor tasks like the rotarod. Further, computer automated analysis of rotational activity was more sensitive than subjective assessment, with SD rats showing a preference for clockwise rotations to 49 days after stroke despite normalization of the neurological score after 21 days. There are significant interstrain differences in survival and in the patterns of neurological impairment and recovery after stroke. These differences must be taken into account in pre-clinical studies, but may also be capitalized upon to understand genetic contributions to injury. Finally, computerized assessment of behavior is more sensitive than subjective assessment for detecting behavioral changes.

20 citations

Journal ArticleDOI
TL;DR: The data demonstrate that the immunologic phenotype of antigen specific lymphocytes influences stroke outcome, and the degree of impairment correlated with the robustness of MBP specific Th1(+) and Th17(+) responses.

19 citations


Cites background from "Long term immunologic consequences ..."

  • ...We previously showed that a TH1 type immune response to MBP is associated with worse outcome in experimental models of stroke (Becker et al., 2005; Gee et al., 2008; Gee et al., 2009) and that TH1 responses to MBP are associated with worse clinical outcome in a cohort of stroke patients 3 months after stroke onset (Becker et al....

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  • ...In these experiments, a TH1(+) response to MBP was associated with worse stroke outcome (Becker et al., 2005; Gee et al., 2008, 2009)....

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Journal ArticleDOI
TL;DR: Examination of Th1 and Th17 immune responses to rat myelin basic protein in Lewis rats shows that immune responses following immunization with rat MBP are promiscuous with cross reaction to MBP from other species.

19 citations


Cites background or result from "Long term immunologic consequences ..."

  • ...And while animals with TH1(+) responses to MBP perform worse on behavioral tests after stroke, they do not manifest overt signs of experimental allergic encephalomyelitis (EAE) (Becker et al., 2005; Gee et al., 2008, 2009; Zierath et al., 2010b)....

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  • ...These proportions are similar to what we have seen previously among animals subjected to MCAO (although the likelihood of developing a TH1 response can be increased by exposing animals to an inflammatory stimulus at the time of MCAO) (Becker et al., 2005; Gee et al., 2009; Zierath et al., 2010a, 2013)....

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References
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Journal ArticleDOI
01 Jan 1989-Stroke
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


Additional excerpts

  • ...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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Journal ArticleDOI
01 May 1986-Stroke
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


Additional excerpts

  • ...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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Journal ArticleDOI
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


Additional excerpts

  • ...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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Journal ArticleDOI
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


Additional excerpts

  • ...Further, the ratio of antigen specific TH17 to TH1 cells can determine the nature of the autoimmune disease [25]....

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Journal ArticleDOI
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


Additional excerpts

  • ...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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