Synergistic Targeting of Innate Receptors TLR7 and NOD2 for Therapeutic Intervention in Multiple Sclerosis
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PROVIDER: S-EPMC11242768 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
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Project description:Modification of the innate immune cell environment has recently been recognized as a viable treatment strategy for reducing autoimmune disease pathology. MIS416 is a microparticulate immune response modifier that targets myeloid cells, activating cytosolic receptors NOD2 and TLR9, and has completed a phase 1b/2a trial for the treatment of secondary progressive multiple sclerosis. Using a mouse model of multiple sclerosis, we are investigating the pathways by which activation of TLR9 and NOD2 may modify the innate immune environment and the subsequent T cell-mediated autoimmune responses. We have found that MIS416 has profound effects on the Th subset balance by depressing antigen-specific Th1, Th17, and Th2 development. These effects coincided with an expansion of specific myeloid subpopulations and increased levels of MIS416-stimulated IFN-γ by splenocytes. Additionally, systemic IFN-γ serum levels were enhanced and correlated strongly with disease reduction, and the protective effect of MIS416 was abrogated in IFN-γ-deficient animals. Finally, treatment of secondary progressive MS patients with MIS416 similarly elevated the levels of IFN-γ and IFN-γ-associated proteins in the serum. Together, these studies demonstrate that administration of MIS416, which targets innate cells, reshapes autoimmune T cell responses and leads to a significant reduction in CNS inflammation and disease.
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Project description:The innate immune system is the first line of host's defense against invading pathogens. Multiple cellular sensors that detect viral components can induce innate antiviral immune responses. As a result, interferons and pro-inflammatory cytokines are produced which help in the elimination of invading viruses. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to Coronaviridae family, and has a single-stranded, positive-sense RNA genome. It can infect multiple hosts; in humans, it is responsible for the novel coronavirus disease 2019 (COVID-19). Successful, timely, and appropriate detection of SARS-CoV-2 can be very important for the early generation of the immune response. Several drugs that target the innate immune receptors as well as other signaling molecules generated during the innate immune response are currently being investigated in clinical trials. In this review, we summarized the current knowledge of the mechanisms underlying host sensing and innate immune responses against SARS-CoV-2 infection, as well as the role of innate immune receptors in terms of their therapeutic potential against SARS-CoV-2. Moreover, we discussed the drugs undergoing clinical trials and the FDA approved drugs against SARS-CoV-2. This review will help in understanding the interactions between SARS-CoV-2 and innate immune receptors and thus will point towards new dimensions for the development of new therapeutics, which can be beneficial in the current pandemic.
| S-EPMC9280161 | biostudies-literature
Project description:G protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants. They are considered as the most successful therapeutic targets for a broad spectrum of diseases. Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system (CNS). It is the leading cause of non-traumatic disability in young adults. Great progress has been made over the past few decades in understanding the pathogenesis of MS. Numerous data from animal and clinical studies indicate that many GPCRs are critically involved in various aspects of MS pathogenesis, including antigen presentation, cytokine production, T-cell differentiation, T-cell proliferation, T-cell invasion, etc. In this review, we summarize the recent findings regarding the expression or functional changes of GPCRs in MS patients or animal models, and the influences of GPCRs on disease severity upon genetic or pharmacological manipulations. Hopefully some of these findings will lead to the development of novel therapies for MS in the near future.
| S-EPMC3750109 | biostudies-other
Project description:Abstract Multiple sclerosis (MS) is an immune-mediated and neurodegenerative disorder that results in inflammation and demyelination of the central nervous system (CNS). MS symptoms include walking difficulties, visual weakening, as well as learning and memory impairment, thus affecting the quality of the patient’s life. Chemokines and chemokine receptors are expressed on the immune cells as well as the CNS resident cells. Several sets of chemokine receptors and their ligands tend to be pathogenic players in MS, including CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL17, CCL19, CCL21, CCL22, CXCL1, CXCL8, CXCL9, CXCL10, CXCL11, and CXCL16. Furthermore, current modulatory drugs that are used in the treatment of MS and its animal model, the experimental autoimmune encephalomyelitis (EAE), affect the expression of several chemokine and chemokine receptors. In this review, we highlight the pathogenic roles of chemokines and their receptors as well as utilizing them as potential therapeutic targets through selective agents, such as specific antibodies and receptor blockers, or indirectly through MS or EAE immunomodulatory drugs.
| S-EPMC7532903 | biostudies-literature
Project description:Background: Educational interventions are needed to overcome knowledge-to-action gaps in clinical care. We previously tested the feasibility and potential efficacy of an educational intervention that facilitates treatment decisions in multiple sclerosis care. A demonstration of the usability of such an intervention is crucial prior to demonstration of efficacy in a large trial. Objectives: To evaluate the usability of a novel, pilot-tested intervention aimed at neurologists to improve therapeutic decisions in multiple sclerosis (MS) care. Methods: We surveyed 50 neurologists from Chile, Argentina, and Canada randomized to an educational intervention arm of a pilot feasibility study using the System Usability Score (SUS) to assess the usability of a traffic light system (TLS)-based educational intervention. The TLS facilitates therapeutic decisions, allowing participants to easily recognize high-risk scenarios requiring treatment escalation. The SUS is a validated 10-item questionnaire with five response options. The primary outcome was the average and 95% confidence interval (CI) of the SUS score. Values above 68 are considered highly usable. Results: Of 50 neurologists invited to be part of the study, all completed the SUS scale and the study. For the primary outcome, the average usability score was 74.7 (95%CI 70.1-79.2). There was one outlier with a score of 35. The usability score excluding the outlier was 76.8 (95%CI 72.7-80.8). Multivariate analysis revealed no association between participants' characteristics and the SUS score. Conclusions: Our educational intervention has shown high usability among neurologists. The next step is to evaluate the effectiveness of this educational intervention in facilitating treatment decisions for the management of multiple sclerosis in a large trial.
| S-EPMC6048250 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) is a heterogeneous, recurring cancer associated with a high rate of metastasis, poor prognosis, and lack of therapeutic targets. Although target-based therapeutic options are approved for other cancers, only limited therapeutic options are available for TNBC. Cell signaling and receptor-specific targets are reportedly effective in patients with TNBC under specific clinical conditions. However, most of these cancers are unresponsive, and there is a requirement for more effective treatment modalities. Further, there is a lack of effective biomarkers that can distinguish TNBC from other BC subtypes. ER, PR, and HER2 help identify TNBC and are widely used to identify patients who are most likely to respond to diverse therapeutic strategies. In this review, we discuss the possible treatment options for TNBC based on its inherent subtype receptors and pathways, such as p53 signaling, AKT signaling, cell cycle regulation, DNA damage, and programmed cell death, which play essential roles at multiple stages of TNBC development. We focus on poly-ADP ribose polymerase 1, androgen receptor, vascular endothelial growth factor receptor, and epidermal growth factor receptor as well as the application of nanomedicine and immunotherapy in TNBC and discuss their potential applications in drug development for TNBC.
| S-EPMC8389539 | biostudies-literature
Project description:Background: Therapeutic inertia (TI) is a common phenomenon among physicians who care for patients with chronic conditions. We evaluated the efficacy of the traffic light system (TLS) educational intervention to reduce TI among neurologists with MS expertise. Methods: In this randomised, controlled trial, 90 neurologists who provide care to MS patients were randomly assigned to the TLS intervention (n = 45) or to the control group (n = 45). The educational intervention employed the TLS, a behavioral strategy that facilitates therapeutic choices by facilitating reflective decisions. The TLS consisted in a short, structured, single session intervention of 5-7 min duration. Participants made therapeutic choices of 10 simulated case-scenarios. The primary outcome was a reduction in TI based on a published TI score (case-scenarios in which a participant showed TI divided by the total number of scenarios where TI was possible ranging from 0 to 8). Results: All participants completed the study and were included in the primary analysis. TI was lower in the TLS group (1.47, 95% CI 1.32-1.61) compared to controls (1.93; 95% CI 1.79-2.08). The TLS group had a lower prevalence of TI compared to controls (0.67, 95% CI 0.62-0.71 vs. 0.82, 95% CI 0.78-0.86; p = 0.001). The multivariate analysis, adjusted for age, specialty, years of practice, and risk preference showed a 70% reduction in TI for the TLS intervention compared to controls (OR 0.30; 95% CI 0.10-0.89). Conclusions: In this randomized trial, the TLS strategy decreases the incidence of TI in MS care irrespective of age, expertise, years for training, and risk preference of participants, which would lead to better patient outcomes.
| S-EPMC6589979 | biostudies-literature
Project description:Rapid advances are occurring in multiple sclerosis disease modifying therapies. Recent therapeutic advances include modifications to improve tolerability of existing products (e.g. interferon beta and glatiramer acetate), development of novel anti-neuroinflammatory medications (e.g. fingolimod, teriflunomide and dimethyl fumarate, daclizumab, alemtuzumab, ocrelizumab) and investigation of treatments in progressive MS (e.g. natalizumab, mastinib, natalizumab, siponimod). The impact of vitamin D supplementation on the disease course in relapsing MS patients is also being studied in several clinical trials. This article reviews the current state of the field with a forward look to the next phase of MS research that could focus on strategies to promote remyelination and provide neuronal protection.
| S-EPMC3975801 | biostudies-literature
Project description:Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system that causes significant disability and healthcare burden. The treatment of MS has evolved over the past three decades with development of new, high efficacy disease modifying therapies targeting various mechanisms including immune modulation, immune cell suppression or depletion and enhanced immune cell sequestration. Emerging therapies include CNS-penetrant Bruton's tyrosine kinase inhibitors and autologous hematopoietic stem cell transplantation as well as therapies aimed at remyelination or neuroprotection. Therapy development for progressive MS has been more challenging with limited efficacy of current approved agents for inactive disease and older patients with MS. The aim of this review is to provide a broad overview of the current therapeutic landscape for MS.
| S-EPMC9205455 | biostudies-literature
Project description:Multiple sclerosis (MS) is a debilitating affliction of the central nervous system (CNS) that involves demyelination of neuronal axons and neurodegeneration resulting in disability that becomes more pronounced in progressive forms of the disease. The involvement of neurodegeneration in MS underscores the need for effective neuroprotective approaches necessitating identification of new therapeutic targets. Herein, we applied an integrated elemental analysis workflow to human MS-affected spinal cord tissue utilising multiple inductively coupled plasma-mass spectrometry methodologies. These analyses revealed shifts in atomic copper as a notable aspect of disease. Complementary gene expression and biochemical analyses demonstrated that changes in copper levels coincided with altered expression of copper handling genes and downstream functionality of cuproenzymes. Copper-related problems observed in the human MS spinal cord were largely reproduced in the experimental autoimmune encephalomyelitis (EAE) mouse model during the acute phase of disease characterised by axonal demyelination, lesion formation, and motor neuron loss. Treatment of EAE mice with the CNS-permeant copper modulating compound CuII(atsm) resulted in recovery of cuproenzyme function, improved myelination and lesion volume, and neuroprotection. These findings support targeting copper perturbations as a therapeutic strategy for MS with CuII(atsm) showing initial promise.
| S-EPMC11579877 | biostudies-literature