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Immune interventions in stroke.

ABSTRACT: Approaches for the effective management of acute stroke are sparse, and many measures for brain protection fail. However, our ability to modulate the immune system and modify the progression of multiple sclerosis is increasing. As a result, immune interventions are currently being explored as therapeutic interventions in acute stroke. In this Review, we compare the immunological features of acute stroke with those of multiple sclerosis, identify unique immunological features of stroke, and consider the evidence for immune interventions. In patients with acute stroke, microglial activation and cell death products trigger an inflammatory cascade that damages vessels and the parenchyma within minutes to hours of the ischaemia or haemorrhage. Immune interventions that restrict brain inflammation, vascular permeability and tissue oedema must be administered rapidly to reduce acute immune-mediated destruction and to avoid subsequent immunosuppression. Preliminary results suggest that the use of drugs that modify disease in multiple sclerosis might accomplish these goals in ischaemic and haemorrhagic stroke. Further elucidation of the immune mechanisms involved in stroke is likely to lead to successful immune interventions.

SUBMITTER: Fu Y

PROVIDER: S-EPMC4851339 | biostudies-other | 2015 Sep

REPOSITORIES: biostudies-other

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Immune interventions in stroke.

Fu Ying Y Liu Qiang Q Anrather Josef J Shi Fu-Dong FD

Nature reviews. Neurology 20150825 9

Approaches for the effective management of acute stroke are sparse, and many measures for brain protection fail. However, our ability to modulate the immune system and modify the progression of multiple sclerosis is increasing. As a result, immune interventions are currently being explored as therapeutic interventions in acute stroke. In this Review, we compare the immunological features of acute stroke with those of multiple sclerosis, identify unique immunological features of stroke, and consi ...[more]

PMID: 26303850

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Project description:BackgroundPerception is the ability to understand information from our senses. It allows us to experience and meaningfully interact with our environment. A stroke may impair perception in up to 70% of stroke survivors, leading to distress, increased dependence on others, and poorer quality of life. Interventions to address perceptual disorders may include assessment and screening, rehabilitation, non-invasive brain stimulation, pharmacological and surgical approaches.ObjectivesTo assess the effectiveness of interventions aimed at perceptual disorders after stroke compared to no intervention or control (placebo, standard care, attention control), on measures of performance in activities of daily living. SEARCH METHODS: We searched the trials registers of the Cochrane Stroke Group, CENTRAL, MEDLINE, Embase, and three other databases to August 2021. We also searched trials and research registers, reference lists of studies, handsearched journals, and contacted authors.Selection criteriaWe included randomised controlled trials (RCTs) of adult stroke survivors with perceptual disorders. We defined perception as the specific mental functions of recognising and interpreting sensory stimuli and included hearing, taste, touch, smell, somatosensation, and vision. Our definition of perception excluded visual field deficits, neglect/inattention, and pain.Data collection and analysisOne review author assessed titles, with two review authors independently screening abstracts and full-text articles for eligibility. One review author extracted, appraised, and entered data, which were checked by a second author. We assessed risk of bias (ROB) using the ROB-1 tool, and quality of evidence using GRADE. A stakeholder group, comprising stroke survivors, carers, and healthcare professionals, was involved in this review update.Main resultsWe identified 18 eligible RCTs involving 541 participants. The trials addressed touch (three trials, 70 participants), somatosensory (seven trials, 196 participants) and visual perception disorders (seven trials, 225 participants), with one (50 participants) exploring mixed touch-somatosensory disorders. None addressed stroke-related hearing, taste, or smell perception disorders. All but one examined the effectiveness of rehabilitation interventions; the exception evaluated non-invasive brain stimulation. For our main comparison of active intervention versus no treatment or control, one trial reported our primary outcome of performance in activities of daily living (ADL): Somatosensory disorders: one trial (24 participants) compared an intervention with a control intervention and reported an ADL measure. Touch perception disorder: no trials measuring ADL compared an intervention with no treatment or with a control intervention. Visual perception disorders: no trials measuring ADL compared an intervention with no treatment or control. In addition, six trials reported ADL outcomes in a comparison of active intervention versus active intervention, relating to somatosensation (three trials), touch (one trial) and vision (two trials). AUTHORS' CONCLUSIONS: Following a detailed, systematic search, we identified limited RCT evidence of the effectiveness of interventions for perceptual disorders following stroke. There is insufficient evidence to support or refute the suggestion that perceptual interventions are effective. More high-quality trials of interventions for perceptual disorders in stroke are needed. They should recruit sufficient participant numbers, include a 'usual care' comparison, and measure longer-term functional outcomes, at time points beyond the initial intervention period. People with impaired perception following a stroke should continue to receive neurorehabilitation according to clinical guidelines.

Project description:BackgroundStroke survivors are often physically inactive as well as sedentary,and may sit for long periods of time each day. This increases cardiometabolic risk and has impacts on physical and other functions. Interventions to reduce or interrupt periods of sedentary time, as well as to increase physical activity after stroke, could reduce the risk of secondary cardiovascular events and mortality during life after stroke.ObjectivesTo determine whether interventions designed to reduce sedentary behaviour after stroke, or interventions with the potential to do so, can reduce the risk of death or secondary vascular events, modify cardiovascular risk, and reduce sedentary behaviour.Search methodsIn December 2019, we searched the Cochrane Stroke Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, Conference Proceedings Citation Index, and PEDro. We also searched registers of ongoing trials, screened reference lists, and contacted experts in the field.Selection criteriaRandomised trials comparing interventions to reduce sedentary time with usual care, no intervention, or waiting-list control, attention control, sham intervention or adjunct intervention. We also included interventions intended to fragment or interrupt periods of sedentary behaviour.Data collection and analysisTwo review authors independently selected studies and performed 'Risk of bias' assessments. We analyzed data using random-effects meta-analyses and assessed the certainty of the evidence with the GRADE approach.Main resultsWe included 10 studies with 753 people with stroke. Five studies used physical activity interventions, four studies used a multicomponent lifestyle intervention, and one study used an intervention to reduce and interrupt sedentary behaviour. In all studies, the risk of bias was high or unclear in two or more domains. Nine studies had high risk of bias in at least one domain. The interventions did not increase or reduce deaths (risk difference (RD) 0.00, 95% confidence interval (CI) -0.02 to 0.03; 10 studies, 753 participants; low-certainty evidence), the incidence of recurrent cardiovascular or cerebrovascular events (RD -0.01, 95% CI -0.04 to 0.01; 10 studies, 753 participants; low-certainty evidence), the incidence of falls (and injuries) (RD 0.00, 95% CI -0.02 to 0.02; 10 studies, 753 participants; low-certainty evidence), or incidence of other adverse events (moderate-certainty evidence). Interventions did not increase or reduce the amount of sedentary behaviour time (mean difference (MD) +0.13 hours/day, 95% CI -0.42 to 0.68; 7 studies, 300 participants; very low-certainty evidence). There were too few data to examine effects on patterns of sedentary behaviour. The effect of interventions on cardiometabolic risk factors allowed very limited meta-analysis.Authors' conclusionsSedentary behaviour research in stroke seems important, yet the evidence is currently incomplete, and we found no evidence for beneficial effects. Current World Health Organization (WHO) guidelines recommend reducing the amount of sedentary time in people with disabilities, in general. The evidence is currently not strong enough to guide practice on how best to reduce sedentariness specifically in people with stroke. More high-quality randomised trials are needed, particularly involving participants with mobility limitations. Trials should include longer-term interventions specifically targeted at reducing time spent sedentary, risk factor outcomes, objective measures of sedentary behaviour (and physical activity), and long-term follow-up.

Project description:Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a wide range of tumor-induced alterations, which affect both the innate and adaptive arms of the immune response, and accumulate during disease progression. In recent years, the development of targeted therapies, such as the B-cell receptor signaling inhibitors and the Bcl-2 protein inhibitor venetoclax, has dramatically changed the treatment landscape of CLL. Despite their remarkable anti-tumor activity, targeted agents have some limitations, which include the development of drug resistance mechanisms and the inferior efficacy observed in high-risk patients. Therefore, additional treatments are necessary to obtain deeper responses and overcome drug resistance. Allogeneic hematopoietic stem cell transplantation (HSCT), which exploits immune-mediated graft-versus-leukemia effect to eradicate tumor cells, currently represents the only potentially curative therapeutic option for CLL patients. However, due to its potential toxicities, HSCT can be offered only to a restricted number of younger and fit patients. The growing understanding of the complex interplay between tumor cells and the immune system, which is responsible for immune escape mechanisms and tumor progression, has paved the way for the development of novel immune-based strategies. Despite promising preclinical observations, results from pilot clinical studies exploring the safety and efficacy of novel immune-based therapies have been sometimes suboptimal in terms of long-term tumor control. Therefore, further advances to improve their efficacy are needed. In this context, possible approaches include an earlier timing of immunotherapy within the treatment sequencing, as well as the possibility to improve the efficacy of immunotherapeutic agents by administering them in combination with other anti-tumor drugs. In this review, we will provide a comprehensive overview of main immune defects affecting patients with CLL, also describing the complex networks leading to immune evasion and tumor progression. From the therapeutic standpoint, we will go through the evolution of immune-based therapeutic approaches over time, including i) agents with broad immunomodulatory effects, such as immunomodulatory drugs, ii) currently approved and next-generation monoclonal antibodies, and iii) immunotherapeutic strategies aiming at activating or administering immune effector cells specifically targeting leukemic cells (e.g. bi-or tri-specific antibodies, tumor vaccines, chimeric antigen receptor T cells, and checkpoint inhibitors).

Project description:Background and Purpose: Stroke induces immediate profound alterations of the peripheral immune system rendering patients more susceptible to post-stroke infections. The precise mechanisms maintaining stroke-induced immune alterations (SIIA) remain unknown. High-Mobility-Group-Protein B1 (HMGB-1) is elevated for at least 7 days post-stroke and has been suggested to mediate SIIA. Patients with rapid clinical recovery of neurological deficits rarely develop severe infections. We therefore investigated whether rapid neurological recovery (either spontaneous or secondary to neurovascular recanalization therapy) alters the course of SIIA. National Institutes of Health Stroke Scale (NIHSS) served as surrogate marker for neurological improvement. Methods: Fluorescence-activated cell sorting was used to define leukocyte subpopulations. C-reactive protein (CRP), procalcitonin (PCT), HMGB-1, GM-CSF; IFN-?, IFN-?, IL-1?, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, IL-17F, IL-18, TNF-?, MIF, IL-8, MCP-1, MCP-4, MIP-3?, MIP-3?, Eotaxin, soluble IL-6 receptor, E-selectin, and P-selectin were analyzed by ELISA or Multiplex Assays. Serum miRNA expression changes were analyzed by qPCR. Results: Cellular parameters were similar in the improved and non-improved cohort on admission. In patients with rapid clinical recovery absolute and relative leukocyte, neutrophil, and lymphocyte numbers normalized promptly overnight. In contrast, HMGB-1 serum levels did not differ between the two groups. Nine miRNA were found to be differentially expressed between improved and non-improved patients. Conclusions: SIIA are detectable on admission of acute stroke patients. While it was assumed that post-stroke immunosuppression is rapidly reversed with improvement this is the first data set that shows that improvement actually is associated with a rapid reversal of SIIA demonstrating that SIIA require a constant signal to persist. The observation that HMGB-1 serum concentrations were similar in improved and non-improved cohorts argues against a role for this pro-inflammatory mediator in the maintenance of SIIA. Serum miRNA observed to be regulated in stroke in other publications was counter regulated with improvement in our cohort.

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Immune interventions in stroke.

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Immune interventions in stroke.

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