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      Stroke-induced immunosuppression and poststroke infection

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          Abstract

          Infections occur commonly after stroke and are strongly associated with an unfavourable functional outcome of these patients. Approaches for effective management of poststroke infection remain scarce, presenting an urgent need for preventive anti-infection strategies for patients who have suffered a stroke. Emerging evidence indicates that stroke impairs systemic immune responses and increases the susceptibility to infections, suggesting that the modification of impaired immune defence could be beneficial. In this review, we summarised previous attempts to prevent poststroke infections using prophylactic antibiotics and the current understanding of stroke-induced immunosuppression. Further elucidation of the immune mechanisms of stroke will pave the way to tailored design of new treatment to combat poststroke infection via modifying the immune system.

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          Most cited references44

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          Central nervous system injury-induced immune deficiency syndrome.

          Infections are a leading cause of morbidity and mortality in patients with acute CNS injury. It has recently become clear that CNS injury significantly increases susceptibility to infection by brain-specific mechanisms: CNS injury induces a disturbance of the normally well balanced interplay between the immune system and the CNS. As a result, CNS injury leads to secondary immunodeficiency - CNS injury-induced immunodepression (CIDS) - and infection. CIDS might serve as a model for the study of the mechanisms and mediators of brain control over immunity. More importantly, understanding CIDS will allow us to work on developing effective therapeutic strategies, with which the outcome after CNS damage by a host of diseases could be improved by eliminating a major determinant of poor recovery.
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            In Vitro Generation of Interleukin 10–producing Regulatory CD4+ T Cells Is Induced by Immunosuppressive Drugs and Inhibited by T Helper Type 1 (Th1)– and Th2-inducing Cytokines

            We show that a combination of the immunosuppressive drugs, vitamin D3 and Dexamethasone, induced human and mouse naive CD4+ T cells to differentiate in vitro into regulatory T cells. In contrast to the previously described in vitro derived CD4+ T cells, these cells produced only interleukin (IL)-10, but no IL-5 and interferon (IFN)-γ, and furthermore retained strong proliferative capacity. The development of these IL-10–producing cells was enhanced by neutralization of the T helper type 1 (Th1)- and Th2–inducing cytokines IL-4, IL-12, and IFN-γ. These immunosuppressive drugs also induced the development of IL-10–producing T cells in the absence of antigen-presenting cells, with IL-10 acting as a positive autocrine factor for these T cells. Furthermore, nuclear factor (NF)-κB and activator protein (AP)-1 activities were inhibited in the IL-10–producing cells described here as well as key transcription factors involved in Th1 and Th2 subset differentiation. The regulatory function of these in vitro generated IL-10–producing T cells was demonstrated by their ability to prevent central nervous system inflammation, when targeted to the site of inflammation, and this function was shown to be IL-10 dependent. Generating homogeneous populations of IL-10–producing T cells in vitro will thus facilitate the use of regulatory T cells in immunotherapy.
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              Functional innervation of hepatic iNKT cells is immunosuppressive following stroke.

              Systemic immunosuppression has been associated with stroke for many years, but the underlying mechanisms are poorly understood. In this study, we demonstrated that stroke induced profound behavioral changes in hepatic invariant NKT (iNKT) cells in mice. Unexpectedly, these effects were mediated by a noradrenergic neurotransmitter rather than a CD1d ligand or other well-characterized danger signals. Blockade of this innervation was protective in wild-type mice after stroke but had no effect in mice deficient in iNKT cells. Selective immunomodulation of iNKT cells with a specific activator (α-galactosylceramide) promoted proinflammatory cytokine production and prevented infections after stroke. Our results therefore identify a molecular mechanism that leads to immunosuppression after stroke and suggest an attractive potential therapeutic alternative to antibiotics, namely, immunomodulation of iNKT cells to prevent stroke-associated infections.
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                Author and article information

                Journal
                Stroke Vasc Neurol
                Stroke Vasc Neurol
                svnbmj
                svn
                Stroke and Vascular Neurology
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2059-8696
                March 2018
                12 January 2018
                : 3
                : 1
                : 34-41
                Affiliations
                [1 ] departmentDepartments of Neurology , Tianjin Neurological Institute, Tianjin Medical University General Hospital , Tianjin, China
                [2 ] departmentDepartments of Neurology , Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center , Phoenix, Arizona, USA
                [3 ] departmentDepartments of Neurology and Radiology, Neuroprotection Research Laboratory , Massachusetts General Hospital, Neuroscience Program, Harvard Medical School , Boston, Massachusetts, USA
                Author notes
                [Correspondence to ] Dr Qiang Liu, Departments of Neurology Tianjin Neurological Institute, Tianjin Medical University General Hospital Tianjin China; qliu.asu@ 123456gmail.com
                Article
                svn-2017-000123
                10.1136/svn-2017-000123
                5870641
                29600006
                21261d2c-21c3-4da6-abfe-31f34842fecf
                © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 04 November 2017
                : 03 December 2017
                : 11 December 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000968, American Heart Association;
                Funded by: National Basic Research Program of China Grant;
                Funded by: National Institutes of Health;
                Categories
                Review
                1506
                Custom metadata
                unlocked

                stroke,infection,post-stroke immunosuppression
                stroke, infection, post-stroke immunosuppression

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