Endothelial Activation and Blood–Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells

Cancer Discovery, Journal Year: 2017, Volume and Issue: 7(12), P. 1404 - 1419

Published: Oct. 13, 2017

Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells can be complicated neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19+ bone marrow, cell dose, cytokine release syndrome, and preexisting comorbidities were associated increased risk AEs. Patients severe neurotoxicity demonstrated evidence endothelial activation, including disseminated intravascular coagulation, capillary leak, blood-brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from concentrations systemic cytokines, IFNγ, which induced brain vascular pericyte stress their secretion endothelium-activating cytokines. Endothelial activation multifocal disruption a patient fatal neurotoxicity. Biomarkers higher before treatment who subsequently developed grade ≥4 neurotoxicity.Significance: We provide detailed clinical, radiologic, pathologic characterization after identify factors for show dysfunction permeability find lymphodepletion may at Cancer Discov; 7(12); 1404-19. ©2017 AACR.See related commentary Mackall Miklos, p. 1371This article is highlighted This Issue feature, 1355.

Language: Английский

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The blood–brain barrier: Structure, regulation and drug delivery

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 25, 2023

Abstract Blood–brain barrier (BBB) is a natural protective membrane that prevents central nervous system (CNS) from toxins and pathogens in blood. However, the presence of BBB complicates pharmacotherapy for CNS disorders as most chemical drugs biopharmaceuticals have been impeded to enter brain. Insufficient drug delivery into brain leads low therapeutic efficacy well aggravated side effects due accumulation other organs tissues. Recent breakthrough materials science nanotechnology provides library advanced with customized structure property serving powerful toolkit targeted delivery. In-depth research field anatomical pathological study on further facilitates development brain-targeted strategies enhanced crossing. In this review, physiological different cells contributing are summarized. Various emerging permeability regulation crossing including passive transcytosis, intranasal administration, ligands conjugation, coating, stimuli-triggered disruption, overcome obstacle highlighted. Versatile systems ranging organic, inorganic, biologics-derived their synthesis procedures unique physio-chemical properties summarized analyzed. This review aims provide an up-to-date comprehensive guideline researchers diverse fields, offering perspectives system.

Language: Английский

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Role of neuroinflammation in neurodegeneration development

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: July 12, 2023

Abstract Studies in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and Amyotrophic lateral sclerosis, Huntington’s so on, have suggested that inflammation is not only a result of neurodegeneration but also crucial player this process. Protein aggregates which are very common pathological phenomenon can induce neuroinflammation further aggravates protein aggregation neurodegeneration. Actually, even happens earlier than aggregation. Neuroinflammation induced by genetic variations CNS cells or peripheral immune may deposition some susceptible population. Numerous signaling pathways range been to be involved the pathogenesis neurodegeneration, although they still far from being completely understood. Due limited success traditional treatment methods, blocking enhancing inflammatory considered promising strategies for therapy many them got exciting results animal models clinical trials. Some them, few, approved FDA usage. Here we comprehensively review factors affecting major pathogenicity sclerosis. We summarize current strategies, both clinic, diseases.

Language: Английский

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Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health

Gut Microbes, Journal Year: 2019, Volume and Issue: 11(2), P. 135 - 157

Published: Aug. 1, 2019

The human gastrointestinal (gut) microbiota comprises diverse and dynamic populations of bacteria, archaea, viruses, fungi, protozoa, coexisting in a mutualistic relationship with the host. When intestinal homeostasis is perturbed, function tract other organ systems, including brain, can be compromised. gut proposed to contribute blood-brain barrier disruption pathogenesis neurodegenerative diseases. While progress being made, better understanding interactions between microbes host cells, impact these have on signaling from brain now required. In this review, we summarise current evidence their metabolites integrity function, communication networks which they may modulate. We also discuss potential modulation strategies as therapeutic tools for promoting restoring health.

Language: Английский

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Pericytes and Neurovascular Function in the Healthy and Diseased Brain

Frontiers in Cellular Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: June 28, 2019

Pericytes are multi-functional cells embedded within the walls of capillaries throughout body, including brain. were first identified in 1870s, but little attention was paid to them during following century. More recently, numerous vascular functions pericytes have been regulation cerebral blood flow, maintenance blood-brain barrier, and control development angiogenesis. can also facilitate neuroinflammatory processes possess stem cell-like properties. form part neurovascular unit, a collection that interactions between neurons vasculature meet energy demands Pericyte structure, expression profile, function brain differ depending on their location along bed. Until it has difficult accurately define sub-types pericytes, or specifically target with pharmaceutical agents, emerging techniques both vitro vivo will improve investigation allow for identification possible roles diseases. dysfunction is increasingly recognized as contributor progression diseases such stroke neurodegenerative Alzheimer's disease. The therapeutic potential repair vessels promote angiogenesis due ability behave like recently brought light. Here, we review history pericyte research, present used study brain, current research advancements characterize therapeutically future.

Language: Английский

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Overcoming blood–brain barrier transport: Advances in nanoparticle-based drug delivery strategies

Materials Today, Journal Year: 2020, Volume and Issue: 37, P. 112 - 125

Published: March 4, 2020

Language: Английский

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Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration

Frontiers in Cellular Neuroscience, Journal Year: 2017, Volume and Issue: 11

Published: July 23, 2017

Neuroinflammatory response is primarily a protective mechanism in the brain. However, excessive and chronic inflammatory responses can lead to deleterious effects involving immune cells, brain cells signaling molecules. Neuroinflammation induces accelerates pathogenesis of Parkinson's disease (PD), Alzheimer's (AD) Multiple Sclerosis. pathways are indicated as novel therapeutic targets for these diseases. Mast hematopoietic origin that regulate inflammation upon activation release many proinflammatory mediators systemic central nervous system conditions. In addition, released from activated glial induce neurodegeneration Systemic inflammation-derived cytokines/chemokines other factors cause breach blood brain-barrier (BBB) thereby allowing entry immune/inflammatory including mast cell progenitors, cytokines chemokines into These peripheral-derived intrinsically generated cytokines/chemokines, α-synuclein, corticotropin-releasing hormone, substance P, beta amyloid 1-42 (Aβ1-42) peptide precursor proteins activate T-cells additional neurotoxic molecules contributing neuroinflammation neuronal death. The glia maturation factor, protein discovered our laboratory glia, activates chemokines. Chronic increase Aβ plaque formation AD brains PD brains. Glial reactivate each neuroinflammatory conditions augment neuroinflammation. Further, also enter peripheral through defective BBB, recruit brain, exacerbate We suggest cell-associated could This review addresses role some atypical associated with their neurodegeneration.

Language: Английский

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Regulation of blood–brain barrier integrity by microglia in health and disease: A therapeutic opportunity

Journal of Cerebral Blood Flow & Metabolism, Journal Year: 2020, Volume and Issue: 40(1_suppl), P. S6 - S24

Published: Sept. 14, 2020

The blood–brain barrier (BBB) is a critical regulator of CNS homeostasis. It possesses physical and biochemical characteristics (i.e. tight junction protein complexes, transporters) that are necessary for the BBB to perform this physiological role. Microvascular endothelial cells require support from astrocytes, pericytes, microglia, neurons, constituents extracellular matrix. This intricate relationship implies existence neurovascular unit (NVU). NVU cellular components can be activated in disease contribute dynamic remodeling BBB. especially true resident immune brain, which polarize into distinct proinflammatory (M1) or anti-inflammatory (M2) phenotypes. Current data indicate M1 pro-inflammatory microglia dysfunction vascular “leak”, while M2 play protective role at Understanding biological mechanisms involved activation provides unique opportunity develop novel treatment approaches neurological diseases. In review, we highlight describe how these phenotypes modulate physiology. Additionally, outline other cell types regulating microglial targeted with focus on ischemic stroke Alzheimer’s disease.

Language: Английский

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Meningeal Immunity and Its Function in Maintenance of the Central Nervous System in Health and Disease

Annual Review of Immunology, Journal Year: 2020, Volume and Issue: 38(1), P. 597 - 620

Published: April 26, 2020

Neuroimmunology, albeit a relatively established discipline, has recently sparked numerous exciting findings on microglia, the resident macrophages of central nervous system (CNS). This review addresses meningeal immunity, less-studied aspect neuroimmune interactions. The meninges, triple layer membranes—the pia mater, arachnoid and dura mater—surround CNS, encompassing cerebrospinal fluid produced by choroid plexus epithelium. Unlike adjacent brain parenchyma, meninges contain wide repertoire immune cells. These constitute which is primarily concerned with surveillance and—according to recent evidence—also participates in postinjury CNS recovery, chronic neurodegenerative conditions, even higher function. Meningeal immunity come under spotlight owing characterization lymphatic vessels draining CNS. Here, we current state our understanding its effects healthy diseased brains.

Language: Английский

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Cognitive impact of COVID-19: looking beyond the short term

Alzheimer s Research & Therapy, Journal Year: 2020, Volume and Issue: 12(1)

Published: Dec. 1, 2020

COVID-19 is primarily a respiratory disease but up to two thirds of hospitalised patients show evidence central nervous system (CNS) damage, predominantly ischaemic, in some cases haemorrhagic and occasionally encephalitic. It unclear how much the ischaemic damage mediated by direct or inflammatory effects virus on CNS vasculature secondary extracranial cardiorespiratory disease. Limited data suggest that causative SARS-CoV-2 may enter via nasal mucosa olfactory fibres, haematogenous spread, capable infecting endothelial cells, pericytes probably neurons. Extracranially, targets cells pericytes, causing cell dysfunction, vascular leakage immune activation, sometimes leading disseminated intravascular coagulation. remains be confirmed whether cerebral are similarly targeted. Several aspects likely impact cognition. Cerebral white matter particularly vulnerable also critically important for cognitive function. There accumulating hypoperfusion accelerates amyloid-β (Aβ) accumulation linked tau TDP-43 pathology, inducing phosphorylation α-synuclein at serine-129, ischaemia increase risk development Lewy body Current therapies understandably focused supporting function, preventing thrombosis reducing activation. Since angiotensin-converting enzyme (ACE)-2 receptor SARS-CoV-2, ACE inhibitors angiotensin blockers predicted ACE-2 expression, it was initially feared their use might exacerbate COVID-19. Recent meta-analyses have instead suggested these medications protective. This perhaps because entry deplete ACE-2, tipping balance towards II-ACE-1-mediated classical RAS activation: exacerbating promoting inflammation. relevant APOE ε4 individuals, who seem increased COVID-19, lowest activity. leave an unexpected legacy long-term neurological complications significant number survivors. Cognitive follow-up will important, especially develop cerebrovascular during acute illness.

Language: Английский

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