Stroke-induced immunosuppression: implications for the prevention and prediction of post-stroke infections.
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ABSTRACT:
SUBMITTER: Faura J
PROVIDER: S-EPMC8183083 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although the initial concepts of stem cell therapy aimed at replacing lost tissue, more recent evidence has suggested that stem and progenitor cells alike promote postischemic neurological recovery by secreted factors that restore the injured brain's capacity to reshape. Specifically, extracellular vesicles (EVs) derived from stem cells such as exosomes have recently been suggested to mediate restorative stem cell effects. In order to define whether EVs indeed improve postischemic neurological impairment and brain remodeling, we systematically compared the effects of mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) with MSCs that were i.v. delivered to mice on days 1, 3, and 5 (MSC-EVs) or on day 1 (MSCs) after focal cerebral ischemia in C57BL6 mice. For as long as 28 days after stroke, motor coordination deficits, histological brain injury, immune responses in the peripheral blood and brain, and cerebral angiogenesis and neurogenesis were analyzed. Improved neurological impairment and long-term neuroprotection associated with enhanced angioneurogenesis were noticed in stroke mice receiving EVs from two different bone marrow-derived MSC lineages. MSC-EV administration closely resembled responses to MSCs and persisted throughout the observation period. Although cerebral immune cell infiltration was not affected by MSC-EVs, postischemic immunosuppression (i.e., B-cell, natural killer cell, and T-cell lymphopenia) was attenuated in the peripheral blood at 6 days after ischemia, providing an appropriate external milieu for successful brain remodeling. Because MSC-EVs have recently been shown to be apparently safe in humans, the present study provides clinically relevant evidence warranting rapid proof-of-concept studies in stroke patients.Transplantation of mesenchymal stem cells (MSCs) offers an interesting adjuvant approach next to thrombolysis for treatment of ischemic stroke. However, MSCs are not integrated into residing neural networks but act indirectly, inducing neuroprotection and promoting neuroregeneration. Although the mechanisms by which MSCs act are still elusive, recent evidence has suggested that extracellular vesicles (EVs) might be responsible for MSC-induced effects under physiological and pathological conditions. The present study has demonstrated that EVs are not inferior to MSCs in a rodent stroke model. EVs induce long-term neuroprotection, promote neuroregeneration and neurological recovery, and modulate peripheral post-stroke immune responses. Also, because EVs are well-tolerated in humans, as previously reported, the administration of EVs under clinical settings might set the path for a novel and innovative therapeutic stroke concept without the putative side effects attached to stem cell transplantation.
| S-EPMC4572905 | biostudies-other
Project description:Post-transplant diabetes mellitus (PTDM) shows a relationship with risk factors including obesity and tacrolimus-based immunosuppression, which decreases pancreatic insulin secretion. Several of the sodium-glucose-linked transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) dramatically improve outcomes of individuals with type 2 diabetes with and without chronic kidney disease, which is, as heart failure and atherosclerotic cardiovascular disease, differentially affected by both drug classes (presumably). Here, we discuss SGLT2is and GLP1-RAs in context with other PTDM management strategies, including modification of immunosuppression, active lifestyle intervention, and early postoperative insulin administration. We also review recent studies with SGLT2is in PTDM, reporting their safety and antihyperglycemic efficacy, which is moderate to low, depending on kidney function. Finally, we reference retrospective case reports with GLP1-RAs that have not brought forth major concerns, likely indicating that GLP1-RAs are ideal for PTDM patients suffering from obesity. Although our article encompasses PTDM after solid organ transplantation in general, data from kidney transplant recipients constitute the largest proportion. The PTDM research community still requires data that treating and preventing PTDM will improve clinical conditions beyond hyperglycemia. We therefore suggest that it is time to collaborate, in testing novel antidiabetics among patients of all transplant disciplines.
| S-EPMC7839745 | biostudies-literature
Project description:BackgroundCorticosteroids are routinely utilized to alleviate edema in patients with intracranial lesions and are first-line agents to combat immune-related adverse events (irAEs) that arise with immune checkpoint blockade treatment. However, it is not known if or when corticosteroids can be administered without abrogating the efforts of immunotherapy. The purpose of this study was to evaluate the impact of dexamethasone on lymphocyte activation and proliferation during checkpoint blockade to provide guidance for corticosteroid use while immunotherapy is being implemented as a cancer treatment.MethodsLymphocyte proliferation, differentiation, and cytokine production were evaluated during dexamethasone exposure. Human T cells were stimulated through CD3 ligation and co-stimulated either directly by CD28 ligation or by providing CD80, a shared ligand for CD28 and CTLA-4. CTLA-4 signaling was inhibited by antibody blockade using ipilimumab which has been approved for the treatment of several solid tumors. The in vivo effects of dexamethasone during checkpoint blockade were evaluated using the GL261 syngeneic mouse intracranial model, and immune populations were profiled by flow cytometry.ResultsDexamethasone upregulated CTLA-4 mRNA and protein in CD4 and CD8 T cells and blocked CD28-mediated cell cycle entry and differentiation. Naïve T cells were most sensitive, leading to a decrease of the development of more differentiated subsets. Resistance to dexamethasone was conferred by blocking CTLA-4 or providing strong CD28 co-stimulation prior to dexamethasone exposure. CTLA-4 blockade increased IFNγ expression, but not IL-2, in stimulated human peripheral blood T cells exposed to dexamethasone. Finally, we found that CTLA-4 blockade partially rescued T cell numbers in mice bearing intracranial gliomas. CTLA-4 blockade was associated with increased IFNγ-producing tumor-infiltrating T cells and extended survival of dexamethasone-treated mice.ConclusionsDexamethasone-mediated T cell suppression diminishes naïve T cell proliferation and differentiation by attenuating the CD28 co-stimulatory pathway. However, CTLA-4, but not PD-1 blockade can partially prevent some of the inhibitory effects of dexamethasone on the immune response.
| S-EPMC5996496 | biostudies-literature
Project description:The risk of having a stroke event doubles each decade after the age of 55. Therefore, it is of great interest to develop neurorestorative therapies of stroke which occurs mostly in elderly people. However, to date, patients at risk for these sequels of stroke are not duly diagnosed and treated due to the lack of reliable biomarkers. Extracellular vesicles (EVs) are lipid bilayer-delimited particles that are shed by the brain cells and are able to cross the blood-brain barrier and enter the blood stream; thus, they may be used to interrogate molecular and cellular events in the brain damaged area. In this review, we summarize the major molecular and cellular responses of astroglia and neurons to cerebral ischemia and assess their impact on post-stroke recovery and rehabilitation. In particular, we ask if EVs secreted by brain cells are responses to cerebral ischemia, and they may shed new light on the interplay between exosomes-mediated interactions between brain cells and the question of how to exploit it in order to predict the individual course of the disease and to introduce specific preventive or therapeutic strategies. Given these findings, we are left with two options: either to (i) transplant neuronal precursors into the damaged cortical area or (ii) to covert abundantly present proliferating astrocytes in the perilesional area into neurons by using recently developed genetic technologies. However, given the complexity of molecular and cellular responses to cerebral ischemia and our limited capabilities to restore brain structure and function, we are left with only one realistic aim: to invest more in prevention.
| S-EPMC8466486 | biostudies-literature
Project description:After major trauma, the human immune system initiates a series of inflammatory events at the injury site that is later followed by suppression of local inflammation favoring the repair and remodeling of the damaged tissues. This local immune response involves complex interactions between resident cells such as macrophages and dendritic cells, soluble mediators such as cytokines and chemokines, and recruited cells such as neutrophils, monocytes and mesenchymal stromal cells. If of sufficient magnitude, these initial immune responses nevertheless have systemic consequences resulting in a state called post-traumatic immunosuppression (PTI). However, controversy exists regarding the exact immunological changes occurring in systemic compartments triggered by these local immune responses. PTI is one of the leading causes of post-surgical mortality and makes patients vulnerable to hospital-acquired infections, multiple organ failure and many other complications. In addition, hemorrhage, blood transfusion, immunesenescence and immunosuppressant drugs aggravate PTI. PTI has been intensively studied, but published results are frequently cloudy. The purpose of this review is to focus on the contributions made by different responsive modalities to immunosuppression following sterile trauma and to try to integrate these into an overall scheme of PTI.
| S-EPMC4855263 | biostudies-literature
Project description:Sublancin is a glycosylated antimicrobial peptide produced by Bacillus subtilis 168 with combined antibacterial and immunomodulatory activities. The purpose of this study was to evaluate the protective effects of sublancin on immunosuppression in cyclophosphamide-treated mice. In normal mice, the phagocytic activity of mouse peritoneal macrophages was significantly enhanced by oral administration of sublancin (1.0?mg/kg body weight) to BALB/c mice for 7 days (P < 0.01). In addition, the mRNA expression of IL-1?, IL-6, and TNF-? in peritoneal macrophages from sublancin- (1.0?mg/kg body weight) administered mice was significantly increased (P < 0.05). In cyclophosphamide-treated mice, oral sublancin administration accelerated the recovery of peripheral white blood cells, red blood cells, hemoglobins, and platelets and enhanced the macrophage phagocytic activity. Furthermore, sublancin restored the mRNA levels of IL-2, IL-4, and IL-6 in the spleen. Finally, the intestinal absorption of sublancin was poor as detected in the Caco-2 transwell system. Taken together, these findings suggest that sublancin plays a crucial role in the protection against immunosuppression in cyclophosphamide-treated mice and could be a potential candidate for use in immune therapy regimens.
| S-EPMC5964538 | biostudies-literature
Project description:IntroductionPatients with acute stroke are at high risk for infection. These infections are associated with unfavourable outcome after stroke. A prediction rule can identify the patients at the highest risk for strategies to prevent infection. We aim to develop a prediction rule for post-stroke pneumonia and other infections in patients with acute stroke.Patients and methodsWe used data from the Preventive Antibiotics in Stroke Study, a multicentre randomised trial comparing preventive ceftriaxone vs. standard stroke care in patients with acute stroke. Possible predictors for post-stroke pneumonia or infection were selected from the literature. Backward elimination logistic regression analysis was used to construct prediction rules for pneumonia or infection. Internal validation was performed and a risk chart was constructed. We adjusted for preventive antibiotic use.ResultsPneumonia was diagnosed in 159 of the 2538 included patients, and infection in 348. Pneumonia was predicted by higher age, male sex, pre-stroke disability, medical history of chronic obstructive pulmonary disease, more severe stroke, dysphagia and intracerebral haemorrhage (rather than ischaemic stroke). Infections were predicted by higher age, male sex, history of diabetes, chronic obstructive pulmonary disease, more severe stroke, dysphagia, use of bladder catheter, preventive antibiotic use and intracerebral haemorrhage. With the prediction rule developed, risks for pneumonia ranged from 0.4% to 56.2% and from 1.8% to 88.0% for infection. Discrimination of the score was good (C-statistic, 0.84; 95% CI: 0.81-0.87 and 0.82; 95% CI: 0.79-0.84 for pneumonia and infection).ConclusionsThe Preventive Antibiotics in Stroke Study pneumonia and infection rule identify patients at the highest risk for post-stroke pneumonia or infection and may be used for future studies and novel therapies, after confirmation in an external population.
| S-EPMC5992742 | biostudies-literature
Project description:Sepsis, sepsis-induced hyperinflammation and subsequent sepsis-associated immunosuppression (SAIS) are important causes of death. Here we show in humans that the loss of the major reactive oxygen species (ROS) scavenger, glutathione (GSH), during SAIS directly correlates with an increase in the expression of activating transcription factor 3 (ATF3). In endotoxin-stimulated monocytes, ROS stress strongly superinduced NF-E2-related factor 2 (NRF2)-dependent ATF3. In vivo, this ROS-mediated superinduction of ATF3 protected against endotoxic shock by inhibiting innate cytokines, as Atf3(-/-) mice remained susceptible to endotoxic shock even under conditions of ROS stress. Although it protected against endotoxic shock, this ROS-mediated superinduction of ATF3 caused high susceptibility to bacterial and fungal infections through the suppression of interleukin 6 (IL-6). As a result, Atf3(-/-) mice were protected against bacterial and fungal infections, even under conditions of ROS stress, whereas Atf3(-/-)Il6(-/-) mice were highly susceptible to these infections. Moreover, in a model of SAIS, secondary infections caused considerably less mortality in Atf3(-/-) mice than in wild-type mice, indicating that ROS-induced ATF3 crucially determines susceptibility to secondary infections during SAIS.
| S-EPMC3555699 | biostudies-literature
Project description:Background and objectivesPost-stroke cognitive impairment (PSCI) occurs in up to 50% of patients with acute ischemic stroke (AIS). Thus, the prediction of cognitive outcomes in AIS may be useful for treatment decisions. This PSCI cohort study aimed to determine the applicability of a machine learning approach for predicting PSCI after stroke.MethodsThis retrospective study used a prospective PSCI cohort of patients with AIS. Demographic features, clinical characteristics, and brain imaging variables previously known to be associated with PSCI were included in the analysis. The primary outcome was PSCI at 3-6 months, defined as an adjusted z-score of less than - 2.0 standard deviation in at least one of the four cognitive domains (memory, executive/frontal, visuospatial, and language), using the Korean version of the Vascular Cognitive Impairment Harmonization Standards-Neuropsychological Protocol (VCIHS-NP). We developed four machine learning models (logistic regression, support vector machine, extreme gradient boost, and artificial neural network) and compared their accuracies for outcome variables.ResultsA total of 951 patients (mean age 65.7 ± 11.9; male 61.5%) with AIS were included in this study. The area under the curve for the extreme gradient boost and the artificial neural network was the highest (0.7919 and 0.7365, respectively) among the four models for predicting PSCI according to the VCIHS-NP definition. The most important features for predicting PSCI include the presence of cortical infarcts, mesial temporal lobe atrophy, initial stroke severity, stroke history, and strategic lesion infarcts.ConclusionOur findings indicate that machine-learning algorithms, particularly the extreme gradient boost and the artificial neural network models, can best predict cognitive outcomes after ischemic stroke.
| S-EPMC10468853 | biostudies-literature
Project description:Ischemic stroke (IS) greatly threatens human health resulting in high mortality and substantial loss of function. Recent studies have shown that the outcome of IS has sex specific, but its mechanism is still unclear. This study is aimed at identifying the sexually dimorphic to peripheral immune response in IS progression, predicting potential prognostic biomarkers that can lead to sex-specific outcome, and revealing potential treatment targets. Gene expression dataset GSE37587, including 68 peripheral whole blood samples which were collected within 24 hours from known onset of symptom and again at 24-48 hours after onset (20 women and 14 men), was downloaded from the Gene Expression Omnibus (GEO) datasets. First, using Bioconductor R package, two kinds of differentially expressed genes (DEGs) (nonsex-specific- and sex-specific-DEGs) were screened by follow-up (24-48 hours) vs. baseline (24 hours). 30 nonsex-specific DEGs (1 upregulated and 29 downregulated), 79 female-specific DEGs (25 upregulated and 54 downregulated), and none of male-specific DEGs were obtained finally. Second, bioinformatics analysis of female-specific DEGs was performed. Gene Ontology (GO) functional annotation analysis shows that DEGs were mainly enriched in translational initiation, cytosolic ribosome, and structural constituent of ribosome. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis shows that the top 6 enrichment pathways are ribosome, nuclear factor-kappa B (NF-kappa B) signaling pathway, apoptosis, mineral absorption, nonalcoholic fatty liver disease, and pertussis. Three functional modules were clustered in the protein–protein interaction (PPI) network of DEGs. The top 10 key genes of the PPI network constructed were selected, including RPS14, RPS15A, RPS24, FAU, RPL27, RPL31, RPL34, RPL35A, RSL24D1, and EEF1B2. Sex difference of ribosome in stroke-induced peripheral immunosuppression may be the potential mechanism of sex disparities in outcome after IS, and women are more likely to have stroke-induced immunosuppression. RPS14, RPS15A, RPS24, FAU, RPL27, RPL31, RPL34, RPL35A, RSL24D1, and EEF1B2 may be novel prognostic biomarkers and potential therapeutic targets for IS.
| S-EPMC7735851 | biostudies-literature