Figure - available from: Immunologic Research
This content is subject to copyright. Terms and conditions apply.
Cellular mechanisms of multiple sclerosis and summary of drug targets. Multiple sclerosis is a disease of autoimmune origin that is characterized by demyelination of neurons, axonal injury, and loss of oligodendrocytes. Immune cells are produced in the bone marrow and travel to the lymphatic system where they are educated, and sent out to the periphery. Normally, these cells do not cross the blood–brain barrier, but in the case of multiple sclerosis, the barrier is breached and autoreactive immune cells elicit an inflammatory response. This response involves the secretion of pro-inflammatory cytokines, stimulation of microglia and astrocytes, and recruitment of additional inflammatory cells, all leading to tissue damage. The treatment of multiple sclerosis has been centered on reducing the inflammatory response, which has been approached two main ways: decreasing circulating immune cells and preventing immune cells from crossing the blood–brain barrier. Fingolimod (1) decreases the amount of immune cells in the periphery by sequestering lymphocytes in secondary lymphoid tissue. Rituximab (2) and Obinutuzumab (3) deplete CD20+ B cells. Teriflunomide (4) slows production of T cells and B cells by inhibiting an enzyme vital to the de novo synthesis of pyrimidines. Alemtuzumab (5) binds to CD52 on B cells, T cells, and on the other mononuclear leukocytes. Glatiramer Acetate (6) inhibits T cells reactive to myelin basic protein by induction of suppressor T cells. Natalizumab (7) interacts with integrins, preventing the movement of leukocytes across the BBB into the central nervous system. Not pictured in this figure are glucocorticoids, interferon-β, mitoxantrone, and dimethyl fumarate. Glucocorticoids inhibit transcription of factors involved in inflammatory response. Interferon-β is an immunomodulatory agent that inhibits T cell proliferation, the production of pro-inflammatory cytokines, and the transit of immune cells across the BBB. Mitoxantrone intercalates DNA and interferes with topoisomerase II, giving it general immunosuppressive characteristics. Dimethyl fumarate is believed to act through modulation of expression of cytokines and the induction of antioxidant response (B B cell, T T cell, DCs dendritic cell, MØ monocyte, NK natural killer cell)
Source publication
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. It is characterized by demyelination of neurons and loss of neuronal axons and oligodendrocytes. In MS, auto-reactive T cells and B cells cross the blood-brain barrier (BBB), causing perivenous demyelinating lesions that form multiple discrete inflam...
Similar publications
Multiple sclerosis (MS) is a chronic inflammatory and autoimmune disease characterized by demyelination of the central nervous system (CNS). Neuregulin 1 (NRG1) is a signaling protein that plays an important role in a variety of biological processes, including potentiate oligodendrocyte differentiation and myelination in the CNS, immune response re...
Oligodendrocytes exert a profound influence on neural circuits by accelerating action potential conduction, altering excitability, and providing metabolic support. As oligodendrogenesis continues in the adult brain and is essential for myelin repair, uncovering the factors that control their dynamics is necessary to understand the consequences of a...
Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain ba...
NG2 cells are highly proliferative glial cells that can self-renew or differentiate into oligodendrocytes, promoting remyelination. Following demyelination, the proliferative and differentiation potentials of NG2 cells increase rapidly, enhancing their differentiation into functional myelinating cells. Levels of the transcription factors Olig1 and...
Multiple Sclerosis is an autoimmune demyelination disorder with unknown etiology. Despite the myelin damage, the roles of myelinating oligodendrocytes in driving disease progression remain unknown. We hypothesize that disrupting vesicular transport in oligodendrocytes during adolescence will disrupt myelin integrity and causes neuroinflammation. By...
Citations
... Many clinical trials using MSCs are performed for the recovery of multiple sclerosis [12]. It turned out that MSCs were utilized to prevent circulating immune cells from crossing the BBB as disease-modifying therapies [84]. However, these processes are not considered as the drug delivers into the brain across the BBB using MSCs. ...
At present, stem cell-based therapies using induced pluripotent stem cells (iPSCs) or mesenchymal stem cells (MSCs) are being used to explore the potential for regenerative medicine in the treatment of various diseases, owing to their ability for multilineage differentiation. Interestingly, MSCs are employed not only in regenerative medicine, but also as carriers for drug delivery, homing to target sites in injured or damaged tissues including the brain by crossing the blood-brain barrier (BBB). In drug research and development, membrane impermeability is a serious problem. The development of central nervous system drugs for the treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, remains difficult due to impermeability in capillary endothelial cells at the BBB, in addition to their complicated pathogenesis and pathology. Thus, intravenously or intraarterially administered MSC-mediated drug delivery in a non-invasive way is a solution to this transendothelial problem at the BBB. Substances delivered by MSCs are divided into artificially included materials in advance, such as low molecular weight compounds including doxorubicin, and expected protein expression products of genetic modification, such as interleukins. After internalizing into the brain through the fenestration between the capillary endothelial cells, MSCs release their cargos to the injured brain cells. In this review, I introduce the potential and advantages of drug delivery into the brain across the BBB using MSCs as a carrier that moves into the brain as if they acted of their own will.
... In the last two decades, the emergence of drugs active in reducing outbreaks and/or disease progression, the so-called immunomodulators and immunosuppressants, in turn, represented a significant evolution in the treatment of multiple sclerosis (BRASIL, 2021). In the course of the disease, modifying therapies promote the decrease of circulating immunogenic cells, the suppression of their adhesion to the epithelium and, consequently, the reduction of their migration to the parenchyma and the resulting inflammatory response (TABANSKY et al., 2015). Among the drugs used and approved by the National Health Surveillance Agency (ANVISA) for use in Brazil until April 2020, contained in the Clinical Protocol and Therapeutic Guidelines (PCDT) of multiple sclerosis, we find teriflunomide, dimethyl fumarate, fingolimod, natalizumab, interferon beta and glatiramer acetate (BRASIL, 2021). ...
Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system, characterized by mononuclear cell infiltration, axon demyelination and gliosis in the myelin sheath, with formation of multiple plaques. It affects individuals aged between 25 and 50 years old, female and residents of higher latitudes. The etiology of multiple sclerosis is multifactorial and not fully understood; however, the influence of genetic predisposition and environmental factors on immune dysregulation is recognized. The pathophysiology of the disease is mediated by self-reactive T lymphocytes that respond to autoantigens from the central nervous system. The emergence of multifocal regions of demyelination, axonal loss, loss of oligodendrocytes and astroglial scarring result in impaired neurological function, leading to neurodegeneration. Although there is still no cure for multiple sclerosis, scientific research has provided great advances in therapeutic strategies. Currently there are approaches to attenuate specific signs and symptoms, drugs to control disease relapses and treatments designed to modify or delay the course of multiple sclerosis. Although these drugs show promising effects, they are ineffective in curing the patient. In addition, they present a fundamental problem, which is the non-selective action on the cells of the immune system, which triggers serious side effects. Considering the limitations of studies in humans due to the difficulty of accessing the affected tissues, the use of experimental models that simulate the singularities of multiple sclerosis is a key element for the study of the pathogenesis of inflammation and therapeutic alternatives. Experimental autoimmune encephalomyelitis, an animal model that presents several similarities with pathophysiological, histological and clinical aspects of multiple sclerosis, is the most used model for these studies. Therefore, in this chapter, the aim was to review the historical context, definition, etiology, pathophysiology, clinical manifestations, diagnosis and treatment of multiple sclerosis and, at the same time, address aspects of the timeline, induction, the evolutionary course and the immunopathogenesis of the most studied model for the investigation of the nuances of multiple sclerosis, correlating the similarities and differences between both.
... Many clinical trials using MSCs are performed for the recovery of multiple sclerosis [12]. It turned out that MSCs were utilized to prevent circulating immune cells from crossing the BBB as disease-modifying therapies [84]. However, these processes are not considered as the drug delivers into the brain across the BBB using MSCs. ...
We will be serving as the Guest Editor for this very interesting Special Issue on “Non-Invasive Device-Mediated Brain Drug Delivery across the Blood-Brain Barrier” (Pharmaceutics, EISSN 1999-4923, Published by MDPI)(https://www.mdpi.com/journal/pharmaceutics/special_issues/6M57N69SSA).
It is well-known that the blood–brain barrier (BBB), substantially composed of tight junctions between the capillary endothelial cells and efflux transporters such as MDR1 at the apical membrane of the capillary endothelial cells, prevents drugs from entering the brain. Accordingly, drug delivery into the brain across the BBB is a challenging task, particularly in central nervous system diseases such as Alzheimer’s disease and Parkinson’s disease as well as brain cancers such as glioma. It is true that drugs in systemic circulation go through intentional membrane disruption or intentional tight junction disruption into the brain across the BBB, but bystander harmful compounds can enter the brain together. Moreover, although craniotomy is often conducted for surgical removal or direct drug administration, this process burdens and torments patients. Thus, non-invasive, device-mediated brain drug delivery across the BBB should be developed to improve not only patient health, but also quality of life. At present, brain drug delivery systems that utilize biological transport machineries such as carrier-mediated transport, receptor-mediated transcytosis, lipid-raft-mediated transcytosis, or macropinocytosis at the BBB have been extensively investigated. This Special Issue aims to share recent progress and trends in this field. We welcome submissions of all types of original articles concerned with noninvasive drug delivery into the brain across the BBB.
Topics include, but are not limited to, the strategies outlined below:
˗ Carrier-Mediated Transport
· drugs containing transporter recognition unit;
· substrate-drug conjugates with cleavable linkers
˗ Receptor-Mediated Transcytosis
· antibody-drug conjugates with cleavable or uncleavable linkers;
· bispecific antibodies as antibody drugs;
· ligand-drug conjugates using ligands such as cell-penetrating peptides or homing peptides
· drug-encapsulated nanoparticles covered with ligands using nanodelivery systems
˗ Other strategies
Keywords
· Drug Delivery System
· The Blood-Brain Barrier (BBB)
· Non-Invasive Brain Drug Delivery
· Nanodelivery System
· Transporter-Consciously Designed Drug
· Carrier-Mediated Transport
· Receptor-Mediated Transcytosis
· Central Nervous System Disease
· Alzheimer's disease (AD)
· Parkinson's Disease (PD)
· Brain Cancer
... MS is a heavy socio-economic burden disease, which affects not only patients and their families but also society. This immune-related disorder occurs 2-3 times higher in females than males (Tabansky et al., 2015;Nally et al., 2019). A number of neurological symptoms may occur as a result of damaged parts of the CNS, which will vary in kind and severity among patients with MS. ...
Background
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that causes chronic inflammation. Cyclotides are small plant proteins with a wide range of biological activity, making them a target for researchers to investigate. This study was conducted to investigate the possible effects of cyclotide-rich fractions from Viola odorata as an immunomodulatory agent in an experimental autoimmune encephalomyelitis (EAE) model of MS.
Methods
At room temperature, the plant materials were subjected to maceration in methanol: dichloromethane (1:1; v/v) for 3 days. The extraction was repeated 3 times, and the final concentrated extract was partitioned 3 times by 1/2 volume of double-distilled water. The aqueous phases were separated and freeze-dried. Finally, the crude extract was fractionated by C18 silicagel using vacuum liquid chromatography, with mobile phases of 30%, 50% and 80% of ethanol: water, respectively. The 50%, and 80% fractions were analyzed by HPLC and MALDI-TOF analysis and administrated intraperitoneally to forty-five female C57BL/6 EAE-induced mice, at 5, 25, and 50 mg/kg doses. After 28 days, the animals were evaluated using EAE clinical scoring which was done every 3 days, cytokine levels, and myelination level.
Results
The results confirmed the presence of cyclotides in V. odorata based on their retention time and the composition of mobile phase in HPLC and the molecular weight of the peaks in MALDI-TOF analysis. It was observed that cyclotides, especially in the 80% fraction group at the dose of 50 mg/kg significantly reduced the clinical scores, inflammation, and demyelination in EAE mice compared with the normal saline group (P<0.05), and the results of this group were comparable with fingolimod (P>0.05).
Conclusion
It could be concluded that V. odorata is a rich source of cyclotides which they could be extracted by an easily available process and also, they could be used as immunomodulatory agents in MS, with similar effects to fingolimod.
... 111 Based on the preparation process, polymeric nanoparticles (PNPs) may be considered nanoparticulate systems with an average size of 0.001−100 μm and have been widely used for various purposes. 112 Delivery of drugs and vaccines, as well as immunomodulatory methods based on nanoparticles and microparticles, can provide unique ways to manage and modify therapeutic agents. 113−115 In the design of PNPs against CNS-related diseases like neurodegenerative diseases, nanocarriers should be small enough to penetrate the CNS. ...
... In addition to the therapeutic form, these nanocarriers can be transformed into theranostic agents by combining the loading of various imaging modules with therapeutic cargos. 112 SLNs are the first generation of LNPs with major constituents of surfactants/emulsifiers as stabilizers (Poloxamer 188, polysorbate 80, and dimethyl dioctadecyl ammonium bromide) and solid lipids at body and room temperatures (fatty acids; waxes; monoglycerides, diglycerides, triglycerides, or complex glyceride mixtures; steroids; compritol 888 ATO; precirol ATO5; and stearyl alcohol). 182 The average diameter of SLNs usually ranges between 10 and 1000 nm. ...
Multiple sclerosis (MS) is a neurodegenerative condition of the central nervous system (CNS) that presents with varying levels of disability in patients, displaying the significance of timely and effective management of this complication. Though several treatments have been developed to protect nerves, comprehensive improvement of MS is still considered an essential bottleneck. Therefore, the development of innovative treatment methods for MS is one of the core research areas. In this regard, nanoscale platforms can offer practical and ideal approaches to the diagnosis and treatment of various diseases, especially immunological disorders such as MS, to improve the effectiveness of conventional therapies. It should be noted that there is significant progress in the development of neuroprotective strategies through the implementation of various nanoparticles, monoclonal antibodies, peptides, and aptamers. In this study, we summarize different particle systems as well as targeted therapies, such as antibodies, peptides, nucleic acids, and engineered cells for the treatment of MS, and discuss their potential in the treatment of MS in the preclinical and clinical stages. Future advances in targeted delivery of medical supplies may offer new strategies for complete recovery as well as practical treatment of progressive forms of MS.
... MS is caused by a combination of environmental, genetic, and epigenetic factors, which may combine with various identified modifiable risk factors [34]. MS pathological markers include demyelination across the blood-brain barrier by autoreactive T and B cells, neuronal and axonal damage and loss, and astrocyte growth [35,36]. In severe MS, axonal damage progresses slowly to axonal transection inside demyelinated plaques, eventually culminating in irreparable damage [36,37]. ...
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. This disorder may cause progressive and permanent impairment, placing significant physical and psychological strain on sufferers. Each progress in MS therapy marks a significant advancement in neurological research. Hydrogels can serve as a scaffold with high water content, high expansibility, and biocompatibility to improve MS cell proliferation in vitro and therapeutic drug delivery to cells in vivo. Hydrogels may also be utilized as biosensors to detect MS-related proteins. Recent research has employed hydrogels as an adjuvant imaging agent in immunohistochemistry assays. Following an overview of the development and use of hydrogels in MS diagnostic and therapy, this review discussed hydrogel’s advantages and future opportunities in the diagnosis and treatment of MS.
Graphical abstract
... The principles of treatment are based on the usage of disease modifying therapies or immunomodulators that target impediment of the progression of relapsing-remitting multiple sclerosis and prevent relapse by diminishing circulating immune cells (CICs) or by limiting these cells from passing the blood-brain barrier, by decreasing the inflammatory response (5,6). ...
Multiple sclerosis is defined as an immune-mediated disease that affects the central nervous system, and also is characterized by the presence of immune cells and mediators which contribute to the subsidiary neuroinflammation associated with multiple sclerosis. Throughout the evolution of multiple sclerosis, it has been observed that circulating immune complexes (CICs) have higher values in these patients, especially in the acute phase of the disease. Thus, the aim of the present study was to observe, if in acute attack, relapsing-remitting multiple sclerosis patients still present high values of CICs after treatment with glatiramer and prednisone. We divided 70 patients with multiple sclerosis with high values of CICs into two treatment groups, one treated with glatiramer (Copaxone) (immunomodulatory treatment) and the other with prednisone (corticosteroid treatment). After three months of treatment, we assessed the levels of CICs of the two multiple sclerosis groups and we observed that the patients that followed the immunomodulatory treatment had lower values of CICs than the group that followed the corticosteroid treatment. In addition, another observation established was that the glatiramer treatment group had higher levels of vitamin D in the serum than the prednisone group of multiple sclerosis patients. To conclude, better outcomes, from the point of view of the results obtained from the comparative analysis of the values of CICs and vitamin D, were demonstrated by following immunomodulatory treatment.
... The treatment, based on the use of Disease Modifying Therapies (DMTs) or immunomodulators, aims to delay the progression of RRMS and prevents relapse by decreasing circulating immune cells or by preventing these cells from crossing the blood-brain barrier, thereby reducing the inflammatory response [7,8]. Until December 2015, interferon beta (βINF) and glatiramer were the only alternatives for first-line treatment of patients who met the guideline criteria in the Brazilian public health system (SUS). ...
Background
Relapsing-remitting multiple sclerosis (RRMM) is a chronic, progressive, inflammatory and immune-mediated disease that affects the central nervous system and is characterized by episodes of neurological dysfunction followed by a period of remission. The pharmacological strategy aims to delay the progression of the disease and prevent relapse. Interferon beta and glatiramer are commonly used in the Brazilian public health system and are available to patients who meet the guideline criteria. The scenario of multiple treatments available and in development brings the need for discussion and evaluation of the technologies already available before the incorporation of new drugs. This study analyses the effectiveness of first-line treatment of RRMS measured by real-world evidence data, from the Brazilian National Health System (SUS).Methods and findingsWe conducted a non-concurrent national cohort between 2000 and 2015. The study population consisted of 22,722 patients with RRMS using one of the following first-line drugs of interest: glatiramer or one of three presentations of interferon beta. Kaplan-Meier analysis was used to estimate the time to treatment failure. A univariate and multivariate Cox proportional hazard model was used to evaluate factors associated with treatment failure. In addition, patients were propensity score-matched (1:1) in six groups of comparative first-line treatments to evaluate the effectiveness among them. The analysis indicated a higher risk of treatment failure in female patients (HR = 1.08; P = 0,01), those with comorbidities at baseline (HR = 1.20; P
... In recent decades, different strategies have been pursued for the development of carriers [175][176][177][178][179] loaded/conjugated with myelin antigens or combinations of myelin peptides and immunomodulating agents. The developed carriers have been designed to target TCR signaling pathways, as well as cytokines and co-signaling molecules, aiming to enhance TCR-mediated tolerance [30,62,177]. ...
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system and is considered to be the leading non-traumatic cause of neurological disability in young adults. Current treatments for MS comprise long-term immunosuppressant drugs and disease-modifying therapies (DMTs) designed to alter its progress with the enhanced risk of severe side effects. The Holy Grail for the treatment of MS is to specifically suppress the disease while at the same time allow the immune system to be functionally active against infectious diseases and malignancy. This could be achieved via the development of immunotherapies designed to specifically suppress immune responses to self-antigens (e.g., myelin antigens). The present study attempts to highlight the various antigen-specific immunotherapies developed so far for the treatment of multiple sclerosis (e.g., vaccination with myelin-derived peptides/proteins, plasmid DNA encoding myelin epitopes, tolerogenic dendritic cells pulsed with encephalitogenic epitopes of myelin proteins, attenuated autologous T cells specific for myelin antigens, T cell receptor peptides, carriers loaded/conjugated with myelin immunodominant peptides, etc), focusing on the outcome of their recent preclinical and clinical evaluation, and to shed light on the mechanisms involved in the immunopathogenesis and treatment of multiple sclerosis.
... More specific monoclonal antibodies, such as natalizumab, have been used to prevent mononuclear leukocyte migration across the bloodbrain barrier (BBB) into the brain parenchyma, while Rituximab has been used to deplete B-cells. However, in spite of the improved specificity of their suppression, these and similar treatments still may have incapacitating side effects, such as an increased incidence of opportunistic infections, including progressive multifunctional leukoencephalopathy [12,13]. Through efforts to avoid some of these complications and improve outcomes, delivering nanoparticles to target sites of inflammation has recently been identified as a promising alternative approach [14]. ...
Inflammation associated with autoimmune diseases and chronic injury is an initiating event that leads to tissue degeneration and dysfunction. Inflammatory monocytes and neutrophils systemically circulate and enter inflamed tissue, and pharmaceutical based targeting of these cells has not substantially improved outcomes and has had side effects. Herein, we investigated the design of drug-free biodegradable nanoparticles, notably without any active pharmaceutical ingredient or targeting ligand, that target circulating inflammatory monocytes and neutrophils in the vasculature to inhibit them from migrating into inflamed tissue. Nanoparticles were formed from 50:50 poly(DL-lactide-co-glycolide) (PLG) with two molecular weights (Low, High) and poly(DL-lactide) (PLA) (termed PLG-L, PLG-H, and PDLA, respectively) and were analyzed for their association with monocytes and neutrophils and their impact on disease course along with immune cell trafficking. For particles injected intravenously for 6 consecutive days to mice with experimental autoimmune encephalomyelitis (EAE), PLG-H particles had significantly lower EAE clinical scores than PBS control, while PLG-L and PDLA particles had modest or negligible effect on EAE onset. In vivo and in vitro data suggests that PLG-H particles had high association with immune cells, with preferential association with blood neutrophils relative to other particles. PLG-H particles restrained immune cells from the central nervous system (CNS), with increased accumulation in the spleen, which was not observed for mice receiving PDLA or control treatments. These results demonstrate that the particle composition influences the association with inflammatory monocytes and neutrophils in the vasculature, with the potential to redirect trafficking and ameliorate inflammation.
