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Scooped by
Gilbert C FAURE
December 30, 2017 1:52 PM
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GM-CSF has been portrayed as a critical cytokine in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and, ostensibly, in multiple sclerosis. C57BL/6 mice deficient in GM-CSF are resistant to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG)35–55. The mechanism of action of GM-CSF in EAE is poorly understood. In this study, we show that GM-CSF augments the accumulation of MOG35–55-specific T cells in the skin draining lymph nodes of primed mice, but it is not required for the development of encephalitogenic T cells. Abrogation of GM-CSF receptor signaling in adoptive transfer recipients of MOG35–55-specific T cells did not alter the incidence of EAE or the trajectory of its initial clinical course, but it limited the extent of chronic CNS tissue damage and neurologic disability. The attenuated clinical course was associated with a relative dearth of MOG35–55-specific T cells, myeloid dendritic cells, and neutrophils, as well as an abundance of B cells, within CNS infiltrates. Our data indicate that GM-CSF drives chronic tissue damage and disability in EAE via pleiotropic pathways, but it is dispensable during early lesion formation and the onset of neurologic deficits.
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Scooped by
Gilbert C FAURE
December 26, 2017 3:59 AM
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Journal of Immunology Research is a peer-reviewed, Open Access journal that provides a platform for scientists and clinicians working in different areas of immunology and therapy. The journal publishes research articles, review articles, as well as clinical studies related to classical immunology, molecular immunology, clinical immunology, cancer immunology, transplantation immunology, immune pathology, immunodeficiency, autoimmune diseases, immune disorders, and immunotherapy.
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Scooped by
Gilbert C FAURE
from MRC research in the news
December 19, 2017 9:27 AM
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The breakthrough, inspired by Joy Milne's sense of smell, could lead to the first diagnostic test.
Via MRC press office
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Scooped by
Gilbert C FAURE
December 8, 2017 2:28 PM
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Recent evidence indicates that hematopoietic stem and progenitor cells (HSPCs) can serve as vehicles for therapeutic molecular delivery to the brain by contributing to the turnover of resident myeloid cell populations. However, such engraftment needs to be fast and efficient to exert its therapeutic potential for diseases affecting the central nervous system. Moreover, the nature of the cells reconstituted after transplantation and whether they could comprise bona fide microglia remain to be assessed. We demonstrate that transplantation of HSPCs in the cerebral lateral ventricles provides rapid engraftment of morphologically, antigenically, and transcriptionally dependable microglia-like cells. We show that the cells comprised within the hematopoietic stem cell compartment and enriched early progenitor fractions generate this microglia-like population when injected in the brain ventricles in the absence of engraftment in the bone marrow. This delivery route has therapeutic relevance because it increases the delivery of therapeutic molecules to the brain, as shown in a humanized animal model of a prototypical lysosomal storage disease affecting the central nervous system.
Isolation of blood-brain barrier-crossing antibodies from a phage display library by competitive elution and their ability to penetrate the central nervous system. mAbs. Accepted 20 November 2017.
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
December 4, 2017 10:06 AM
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Mayo Clinic develops neuro test that distinguishes demyelinating diseases from MS
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Scooped by
Gilbert C FAURE
November 30, 2017 2:30 PM
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Anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) recently emerged as a potential biomarker in patients with inflammatory demyelinating diseases of the central nervous system. We here compa
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Scooped by
Gilbert C FAURE
November 27, 2017 1:41 PM
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The recent discovery of meningeal lymphatic vessels (LVs) has raised interest in their possible involvement in neuropathological processes, yet little is known about their development or maintenance. We show here that meningeal LVs develop postnatally, appearing first around the foramina in the basal parts of the skull and spinal canal, sprouting along the blood vessels and cranial and spinal nerves to various parts of the meninges surrounding the central nervous system (CNS). VEGF-C, expressed mainly in vascular smooth muscle cells, and VEGFR3 in lymphatic endothelial cells were essential for their development, whereas VEGF-D deletion had no effect. Surprisingly, in adult mice, the LVs showed regression after VEGF-C or VEGFR3 deletion, administration of the tyrosine kinase inhibitor sunitinib, or expression of VEGF-C/D trap, which also compromised the lymphatic drainage function. Conversely, an excess of VEGF-C induced meningeal lymphangiogenesis. The plasticity and regenerative potential of meningeal LVs should allow manipulation of cerebrospinal fluid drainage and neuropathological processes in the CNS.
Abstract
Background: B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19+ B cells.
Objectives: To assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS. Methods: This phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19+ B-cell count to ⩾80 cells/µL.
Results: Complete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively.
Conclusion: Inebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions.
Keywords B cells, intravenous administration, pharmacodynamics, pharmacokinetics, subcutaneous administration
Via Krishan Maggon
Calcitonin gene-related peptide (CGRP), a neuropeptide abundant in the trigeminal system and widely expressed in both the peripheral and central nervous systems, has recently emerged as a promising ta
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
November 13, 2017 1:38 PM
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Scooped by
Gilbert C FAURE
November 7, 2017 11:48 AM
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Editorial: Induction of Central Nervous System Disease by the Adaptive Immune Response
Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination and consequent neuron injury. Although the pathogenesis of MS is largely unknown, a breach in immune self-tolerance to myelin followed by development of autoreactive encephalitogenic T cells is suggested to play the central role. The myelin basic protein (MBP) is believed to be one of the main targets for autoreactive lymphocytes. Recently, immunodominant MBP peptides encapsulated into the mannosylated liposomes, referred as Xemys, were shown to suppress development of experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, and furthermore passed the initial stage of clinical trials. Here, we investigated the role of individual polypeptide components (MBP peptides 46–62 [GH17], 124–139 [GK16] and 147–170 [QR24]) of this liposomal peptide therapeutic in cytokine release and activation of immune cells from MS patients and healthy donors. The overall effects were assessed using peripheral blood mononuclear cells (PBMCs), whereas alterations in antigen-presenting capacities were studied utilizing plasmacytoid dendritic cells (pDCs). Among three MBP-immunodominant peptides, QR24 and GK16 activated leukocytes, while GH17 was characterized by an immunosuppressive effect. Peptides QR24 and GK16 upregulated CD4 over CD8 T cells and induced proliferation of CD25-positive cells, whereas GH17 decreased the CD4/CD8 T cell ratio and had limited effects on CD25+ T cells. Accordingly, components of liposomal peptide therapeutic differed in upregulation of cytokines upon addition to PBMCs and pDCs. Peptide QR24 was evidently more effective in upregulation of proinflammatory cytokines, whereas GH17 significantly increased production of IL-10 through treated cells. Altogether, these data suggest a complexity of action of the liposomal peptide therapeutic that does not seem to involve a simple helper T cells (Th)-shift but rather the rebalancing of the immune system.
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
December 30, 2017 12:36 PM
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Yu et al. show that the ligand-binding domain of ionotropic glutamate receptors has
structural features on its surface that guide the agonist glutamate to its binding
site. This phenomenon serves to accelerate receptor activation.
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Scooped by
Gilbert C FAURE
December 23, 2017 11:32 AM
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Review Article
Abstract Glioblastoma multiforme (GBM) is a highly malignant primary brain cancer with a dreadful overall survival and for which treatment options are limited. Recent breakthroughs in novel immune-related treatment strategies for cancer have spurred interests in usurping the power of the patient’s immune system to recognize and eliminate GBM. Here, we discuss the unique properties of GBM’s tumor microenvironment, the effects of GBM standard on care therapy on tumor-associated immune cells, and review several approaches aimed at therapeutically targeting the immune system for GBM treatment. We believe that a comprehensive understanding of the intricate micro-environmental landscape of GBM will abound into the development of novel immunotherapy strategies for GBM patients.
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
December 8, 2017 11:13 AM
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It has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. We used single-cell whole-genome sequencing to perform genome-wide somatic single-nucleotide variant (sSNV) identification on DNA from 161 single neurons from the prefrontal cortex and hippocampus of fifteen normal individuals (aged 4 months to 82 years) as well as nine individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and Xeroderma pigmentosum). sSNVs increased approximately linearly with age in both areas (with a higher rate in hippocampus) and were more abundant in neurodegenerative disease. The accumulation of somatic mutations with age—which we term genosenium—shows age-related, region-related, and disease-related molecular signatures, and may be important in other human age-associated conditions.
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Scooped by
Gilbert C FAURE
December 5, 2017 11:39 AM
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Scooped by
Gilbert C FAURE
December 3, 2017 4:15 AM
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Illustration by William Hogan Early in the 19th century, the nervous system was believed to be a continuous network— essentially one giant cell with many spidery extensions bundled to form the brain and spinal cord.
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Scooped by
Gilbert C FAURE
November 28, 2017 8:48 AM
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In this issue of JEM, Antila et al. (<https://doi.org/10.1084/jem.20170391>;) demonstrate that central nervous system lymphatics develop in the mouse meninges during early postnatal periods and display remarkable plasticity in adult periods through manipulation of VEGF-C–VEGFR3 signaling.
Abstract Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system in which inflammation, demyelination, and axonal loss occurs from early stages of the disease. It mainly affects people between 20 and 40 years old, with a female predominance. Treatment options have been increasingly growing in the past years and newer drugs, some with novel mechanisms of action, are being developed for treating patients with MS. There is an increasing interest in developing new drugs that will promote neuroprotection and/or myelin repair through different mechanisms of action that may target the most degenerative component of the disease.
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
November 13, 2017 1:38 PM
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The molecular pathways underlying tau pathology–induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer’s disease patients.
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Scooped by
Gilbert C FAURE
November 13, 2017 1:24 AM
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Microglia are tissue macrophages of the central nervous system (CNS). Their key tasks are immune surveillance as well as responding to infections or other pathological states such as neurologica
Abstract The advent of biological medicines has significantly transformed the landscapes of many disease spaces and improved the lives of millions around the world. However, the structural complexity and sensitivity of such products result in a high price tag, adding to already financially strained healthcare systems. As these and other expensive complex drugs lose market exclusivity, stakeholders eagerly await the arrival of lower cost alternatives, such as biosimilars and subsequent entry non-biological complex drugs (NBCDs). Nevertheless, stakeholders remain uncertain about key issues which have resulted in heterogeneous reimbursement policies and varying levels of biosimilar uptake and subsequent entry NBCD approval processes between different markets. With the imminent introduction of both subsequent entry NBCDs and biosimilars for multiple sclerosis (MS), it is important to get a better understanding of this new class of products and how healthcare systems have been adapting to their use. This article defines biosimilars and subsequent entry NBCDs and provides an overview of how these products have been introduced in Europe, the United States, and Canada from a regulatory, health technology, and reimbursement perspective. In addition, this article briefly explores the potential impact and outlook of biosimilar and NBCD products related to MS.
Via Krishan Maggon
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